OPDIVO 10mg / ml perfusive solution concentrate medication leaflet

OPDIVO 10 mg/mL concentrate for solution for infusion.

Each mL of concentrate for solution for infusion contains 10 mg of nivolumab.

One vial of 4 mL contains 40 mg of nivolumab.

One vial of 10 mL contains 100 mg of nivolumab.

One vial of 12 mL contains 120 mg of nivolumab.

One vial of 24 mL contains 240 mg of nivolumab.

Nivolumab is produced in Chinese hamster ovary cells by recombinant DNA technology.

Each mL of concentrate contains 0.1 mmol (or 2.5 mg) sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to pale yellow liquid that may contain few light particles. The solutionhas a pH of approximately 6.0 and an osmolality of approximately 340 mOsm/kg.

OPDIVO as monotherapy or in combination with ipilimumab is indicated for the treatment ofadvanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older.

Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overallsurvival (OS) for the combination of nivolumab with ipilimumab is established only in patients withlow tumour PD-L1 expression (see sections 4.4 and 5.1).

OPDIVO as monotherapy is indicated for the adjuvant treatment of adults and adolescents 12 years ofage and older with Stage IIB or IIC melanoma, or melanoma with involvement of lymph nodes ormetastatic disease who have undergone complete resection (see section 5.1).

OPDIVO in combination with ipilimumab and 2 cycles of platinum-based chemotherapy is indicatedfor the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have nosensitising EGFR mutation or ALK translocation.

OPDIVO as monotherapy is indicated for the treatment of locally advanced or metastatic non-smallcell lung cancer after prior chemotherapy in adults.

Neoadjuvant treatment of NSCLC

OPDIVO in combination with platinum-based chemotherapy is indicated for the neoadjuvanttreatment of resectable non-small cell lung cancer at high risk of recurrence in adult patients whosetumours have PD-L1 expression ≥ 1% (see section 5.1 for selection criteria).

Neoadjuvant and adjuvant treatment of NSCLC

OPDIVO, in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by

OPDIVO as monotherapy as adjuvant treatment, is indicated for the treatment of resectable non-smallcell lung cancer at high risk of recurrence in adult patients whose tumours have PD-L1 expression≥ 1% (see section 5.1 for selection criteria).

Malignant pleural mesothelioma (MPM)

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients withunresectable malignant pleural mesothelioma.

OPDIVO as monotherapy is indicated for the treatment of advanced renal cell carcinoma after priortherapy in adults.

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients withintermediate/poor-risk advanced renal cell carcinoma (see section 5.1).

OPDIVO in combination with cabozantinib is indicated for the first-line treatment of adult patientswith advanced renal cell carcinoma (see section 5.1).

OPDIVO as monotherapy is indicated for the treatment of adult patients with relapsed or refractoryclassical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and treatment withbrentuximab vedotin.

Squamous cell cancer of the head and neck (SCCHN)

OPDIVO as monotherapy is indicated for the treatment of recurrent or metastatic squamous cellcancer of the head and neck in adults progressing on or after platinum-based therapy (see section 5.1).

OPDIVO in combination with cisplatin and gemcitabine is indicated for the first-line treatment ofadult patients with unresectable or metastatic urothelial carcinoma.

OPDIVO as monotherapy is indicated for the treatment of locally advanced unresectable or metastaticurothelial carcinoma in adults after failure of prior platinum-containing therapy.

Adjuvant treatment of urothelial carcinoma

OPDIVO as monotherapy is indicated for the adjuvant treatment of adults with muscle invasiveurothelial carcinoma (MIUC) with tumour cell PD-L1 expression ≥ 1%, who are at high risk ofrecurrence after undergoing radical resection of MIUC (see section 5.1).

Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC)

OPDIVO in combination with ipilimumab is indicated for the treatment of adult patients withmismatch repair deficient or microsatellite instability-high colorectal cancer in the following settings:

- first-line treatment of unresectable or metastatic colorectal cancer;

- treatment of metastatic colorectal cancer after prior fluoropyrimidine-based combinationchemotherapy (see section 5.1).

Oesophageal squamous cell carcinoma (OSCC)

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients withunresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell

PD-L1 expression ≥ 1%.

OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy isindicated for the first-line treatment of adult patients with unresectable advanced, recurrent ormetastatic oesophageal squamous cell carcinoma with tumour cell PD-L1 expression ≥ 1%.

OPDIVO as monotherapy is indicated for the treatment of adult patients with unresectable advanced,recurrent or metastatic oesophageal squamous cell carcinoma after prior fluoropyrimidine- andplatinum-based combination chemotherapy.

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer (OC or GEJC)

OPDIVO as monotherapy is indicated for the adjuvant treatment of adult patients with oesophageal orgastro-oesophageal junction cancer who have residual pathologic disease following prior neoadjuvantchemoradiotherapy (see section 5.1).

Gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma

OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy isindicated for the first-line treatment of adult patients with HER2-negative advanced or metastaticgastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1with a combined positive score (CPS) ≥ 5.

Hepatocellular carcinoma (HCC)

OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients withunresectable or advanced hepatocellular carcinoma.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.

If specified in the indication, patient selection for treatment with OPDIVO based on the tumourexpression of PD-L1 should be assessed by a CE-marked in vitro IVD medical device test. If the CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, pct. 4.4,and 5.1).

MSI/MMR testing

If specified in the indication, patient selection for treatment with OPDIVO based on MSI-H/dMMRtumour status should be assessed by a CE-marked IVD with the corresponding intended purpose. If the

CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, pct. 4.4, and5.1).

OPDIVO as monotherapy

The recommended dose of OPDIVO is either nivolumab 240 mg every 2 weeks or 480 mgevery 4 weeks depending on the indication and population (see sections 5.1 and 5.2), as presented in

Table 1.

Table 1: Recommended dose and infusion time for intravenous administration ofnivolumab monotherapy

Indication* Recommended dose and infusion time

Adults and adolescents (12 years of age and older andweighing at least 50 kg):240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 60 minutes or over 30 minutes

Melanoma (advanced or adjuvant (adjuvant melanoma, see section 5.1)t reatment)

Adolescents (12 years of age and older and weighing less than50 kg):3 mg/kg every 2 weeks over 30 minutes or6 mg/kg every 4 weeks over 60 minutes

Muscle invasive urothelial 240 mg every 2 weeks over 30 minutes orcarcinoma (MIUC) (adjuvant 480 mg every 4 weeks over 60 minutestreatment)

Oesophageal or gastro-oesophageal 240 mg every 2 weeks over 30 minutes orjunction cancer (adjuvant 480 mg every 4 weeks over 30 minutes for the first 16 weeks,treatment) followed by 480 mg every 4 weeks over 30 minutes

Squamous cell cancer of the headand neck 240 mg every 2 weeks over 30 minutes

Oesophageal squamous cellcarcinoma

*As per monotherapy indication in section 4.1.

If melanoma, RCC, OC, GEJC or MIUC (adjuvant treatment) patients need to be switched from the240 mg every 2 weeks schedule to the 480 mg every 4 weeks schedule, the first 480 mg dose shouldbe administered two weeks after the last 240 mg dose. Conversely, if patients need to be switchedfrom the 480 mg every 4 weeks schedule to the 240 mg every 2 weeks schedule, the first 240 mg doseshould be administered four weeks after the last 480 mg dose.

OPDIVO in combination with ipilimumab

In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommendeddose is 1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab administered intravenously every3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumabmonotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every4 weeks (see sections 5.1 and 5.2), as presented in Table 2. For the monotherapy phase, the first doseof nivolumab should be administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mgevery 2 weeks; or 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mgevery 4 weeks.

In adolescents 12 years of age and older and weighing less than 50 kg, the recommended dose is1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab administered intravenously every3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumabmonotherapy is administered intravenously at either 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks(see sections 5.1 and 5.2), as presented in Table 2. For the monotherapy phase, the first dose ofnivolumab should be administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kgevery 2 weeks; or 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kgevery 4 weeks.

Table 2: Recommended doses and infusion times for intravenous administration ofnivolumab in combination with ipilimumab for melanoma

Combination phase, every3 weeks for 4 dosing cycles Monotherapy phase

Adults and adolescents (12 years of age and older andweighing at least 50 kg):240 mg every 2 weeks over 30 minutes or

Adults and adolescents 480 mg every 4 weeks over 60 minutes

Nivolumab 12 years of age and older:

1 mg/kg over 30 minutes Adolescents (12 years of age and older and weighing lessthan 50 kg):3 mg/kg every 2 weeks over 30 minutes or6 mg/kg every 4 weeks over 60 minutes

Adults and adolescents

Ipilimumab 12 years of age and older: -3 mg/kg over 30 minutes

Malignant pleural mesothelioma

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes every3 weeks in combination with 1 mg/kg ipilimumab administered intravenously over 30 minutes every6 weeks. Treatment is continued for up to 24 months in patients without disease progression.

The recommended dose is 3 mg/kg nivolumab in combination with 1 mg/kg ipilimumab administeredintravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in whichnivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mgevery 4 weeks, as presented in Table 3. For the monotherapy phase, the first dose of nivolumab shouldbe administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mgevery 2 weeks; or 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mgevery 4 weeks.

Table 3: Recommended doses and infusion times for intravenous administration ofnivolumab in combination with ipilimumab for RCC

Combination phase, every3 weeks for 4 dosing cycles Monotherapy phase

Nivolumab 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 60 minutes

Ipilimumab 1 mg/kg over 30 minutes -dMMR or MSI-H colorectal cancer

The recommended dose for first-line treatment of dMMR or MSI-H CRC is 240 mg of nivolumab incombination with 1 mg/kg ipilimumab administered intravenously every 3 weeks for a maximum of4 doses, followed by nivolumab monotherapy administered intravenously at either 240 mg every2 weeks or at 480 mg every 4 weeks, as presented in Table 4. For the monotherapy phase, the firstdose of nivolumab should be administered 3 weeks after the last dose of the combination of nivolumaband ipilimumab. Treatment with nivolumab is recommended until disease progression, unacceptabletoxicity, or up to 24 months in patients without disease progression.

The recommended dose in patients who received prior fluoropyrimidine-based combinationchemotherapy for dMMR or MSI-H CRC is 3 mg/kg nivolumab in combination with 1 mg/kgipilimumab administered intravenously every 3 weeks for the first 4 doses, followed by nivolumabmonotherapy administered intravenously 240 mg every 2 weeks, as presented in Table 4. For themonotherapy phase, the first dose of nivolumab should be administered 3 weeks after the last dose ofthe combination of nivolumab and ipilimumab.

Table 4: Recommended doses and infusion times for intravenous administration ofnivolumab in combination with ipilimumab for dMMR or MSI-H CRC

Combination phase,every 3 weeks for Monotherapy phase4 dosing cycles

First-line 240 mg over 30 minutes 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 30 minutes

Nivolumab After priorfluoropyrimidine-basedcombination 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minuteschemotherapy

Ipilimumab 1 mg/kg over 30 minutes -

Oesophageal squamous cell carcinoma

The recommended dose is either 3 mg/kg nivolumab every 2 weeks or 360 mg nivolumab every3 weeks administered intravenously over 30 minutes in combination with 1 mg/kg ipilimumabadministered intravenously over 30 minutes every 6 weeks. Treatment is recommended until diseaseprogression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Hepatocellular carcinoma

The recommended dose is 1 mg/kg nivolumab in combination with 3 mg/kg ipilimumab administeredintravenously every 3 weeks for up to 4 doses. This is then followed by a second phase in whichnivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mgevery 4 weeks (see sections 5.1 and 5.2), as presented in Table 5. Treatment is recommended untildisease progression, unacceptable toxicity, or up to 24 months. For the monotherapy phase, the firstdose of nivolumab should be administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mgevery 2 weeks or 480 mg every 4 weeks.

Table 5: Recommended doses and infusion times for intravenous administration ofnivolumab in combination with ipilimumab for HCC

Combination phase, every3 weeks for 4 dosing cycles Monotherapy phase

Nivolumab 1 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 30 minutes

Ipilimumab 3 mg/kg over 30 minutes -

OPDIVO in combination with cabozantinib

The recommended dose is nivolumab administered intravenously at either 240 mg every 2 weeks or480 mg every 4 weeks in combination with 40 mg cabozantinib administered orally every day.

Table 6: Recommended doses and infusion times for intravenous administration ofnivolumab in combination with oral administration of cabozantinib for RCC

Combination phase

Nivolumab 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 60 minutes

Cabozantinib 40 mg once daily

OPDIVO in combination with ipilimumab and chemotherapy

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes every3 weeks in combination with 1 mg/kg ipilimumab administered intravenously over 30 minutes every6 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cyclesof chemotherapy, treatment is continued with 360 mg nivolumab administered intravenously every3 weeks in combination with 1 mg/kg ipilimumab every 6 weeks. Treatment is recommended untildisease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

OPDIVO in combination with chemotherapy

Neoadjuvant treatment of non-small cell lung cancer

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes incombination with platinum-based chemotherapy every 3 weeks for 3 cycles (see section 5.1).

Neoadjuvant and adjuvant treatment of non-small cell lung cancer

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes incombination with platinum-based chemotherapy every 3 weeks for 4 cycles in the neoadjuvant phase,followed by adjuvant treatment with nivolumab 480 mg as monotherapy every 4 weeks. Treatment isrecommended until disease progression or recurrence, unacceptable toxicity, or up to 13 cycles (seesection 5.1).

Oesophageal squamous cell carcinoma

The recommended dose of nivolumab is 240 mg every 2 weeks or 480 mg every 4 weeks administeredintravenously over 30 minutes in combination with fluoropyrimidine- and platinum-basedchemotherapy (see section 5.1). Treatment with nivolumab is recommended until disease progression,unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes incombination with fluoropyrimidine- and platinum-based chemotherapy administered every 3 weeks or240 mg nivolumab administered intravenously over 30 minutes in combination withfluoropyrimidine- and platinum-based chemotherapy administered every 2 weeks (see section 5.1).

Treatment with nivolumab is recommended until disease progression, unacceptable toxicity, or up to24 months in patients without disease progression.

First-line treatment of unresectable or metastatic urothelial carcinoma

The recommended dose is 360 mg nivolumab administered intravenously over 30 minutes incombination with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by nivolumabmonotherapy administered intravenously at either 240 mg every 2 weeks over 30 minutes or at480 mg every 4 weeks over 30 minutes (see section 5.1). Treatment with nivolumab is recommendeduntil disease progression, unacceptable toxicity, or up to 24 months from first dose, whichever comesfirst.

Treatment with OPDIVO, either as a monotherapy or in combination with ipilimumab or othertherapeutic agents, should be continued as long as clinical benefit is observed or until treatment is nolonger tolerated by the patient (and up to maximum duration of therapy if specified for an indication).

For adjuvant therapy, the maximum treatment duration with OPDIVO is 12 months.

For OPDIVO in combination with cabozantinib, OPDIVO should be continued until diseaseprogression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cabozantinib should be continued until disease progression or unacceptable toxicity. Refer to the

Summary of Product Characteristics (SmPC) for cabozantinib.

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the firstfew months followed by tumour shrinkage) have been observed. It is recommended to continuetreatment with nivolumab or nivolumab in combination with ipilimumab for clinically stable patientswith initial evidence of disease progression until disease progression is confirmed.

Dose escalation or reduction is not recommended for OPDIVO as monotherapy or in combination withother therapeutic agents. Dosing delay or discontinuation may be required based on individual safetyand tolerability. Guidelines for permanent discontinuation or withholding of doses are described in

Table 7. Detailed guidelines for the management of immune-related adverse reactions are described insection 4.4. When nivolumab is administered in combination with other therapeutic agents, refer to the

SmPC of these other combination therapeutic agents regarding dosing.

Table 7: Recommended treatment modifications for OPDIVO or OPDIVO in combination

Immune-related Severity Treatment modificationadverse reaction

Grade 2 pneumonitis Withhold dose(s) until symptomsresolve, radiographicabnormalities improve, and

Immune-related management with corticosteroidspneumonitis is complete

Grade 3 or 4 pneumonitis Permanently discontinuetreatment

Grade 2 diarrhoea or colitis Withhold dose(s) until symptomsresolve and management withcorticosteroids, if needed, iscomplete

Grade 3 diarrhoea or colitis

- OPDIVO monotherapy Withhold dose(s) until symptoms

Immune-related colitis resolve and management withcorticosteroids is complete

- OPDIVO+ipilimumaba Permanently discontinuetreatment

Grade 4 diarrhoea or colitis Permanently discontinuetreatment

Immune-related Grade 2 elevation in aspartate Withhold dose(s) until laboratoryhepatitis without HCC aminotransferase (AST), alanine values return to baseline andaminotransferase (ALT), or total bilirubin management with corticosteroids,

NOTE: for RCC if needed, is completepatients treatedwith OPDIVO in Grade 3 or 4 elevation in AST, ALT, or total Permanently discontinuecombination with bilirubin treatmentcabozantinib withliver enzymeelevations, see dosingguidelines followingthis table.

Immune-related Severity Treatment modificationadverse reaction

If AST/ALT is within normal limits at Withhold dose(s) until laboratorybaseline and increases to > 3 and ≤ 10 times values return to baseline and

ULN management with corticosteroids,or if needed, is complete

Baseline AST/ALT is > 1 and ≤ 3 times ULNand increases to > 5 and ≤ 10 times ULN

Immune-related orhepatitis with HCC Baseline AST/ALT is > 3 and ≤ 5 times ULNand increases to > 8 and ≤ 10 times ULN.

AST/ALT increases to > 10 times ULN Permanently discontinueor treatment

Total bilirubin increases to > 3 times ULN

Grade 2 or 3 creatinine elevation Withhold dose(s) until creatininereturns to baseline and

Immune-related management with corticosteroidsnephritis and renal is completedysfunction

Grade 4 creatinine elevation Permanently discontinuetreatment

Symptomatic Grade 2 or 3 hypothyroidism, Withhold dose(s) until symptomshyperthyroidism, hypophysitis, resolve and management with

Grade 2 adrenal insufficiency corticosteroids (if needed for

Grade 3 diabetes symptoms of acute inflammation)is complete. Treatment should becontinued in the presence of

Immune-related hormone replacement therapyb asendocrinopathies long as no symptoms are present

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis Permanently discontinue

Grade 3 or 4 adrenal insufficiency treatment

Grade 4 diabetes

Grade 3 rash Withhold dose(s) until symptomsresolve and management withcorticosteroids is complete

Immune-related skinadverse reactions Grade 4 rash Permanently discontinuetreatment

Stevens-Johnson syndrome (SJS) or toxic Permanently discontinueepidermal necrolysis (TEN) treatment (see section 4.4)

Grade 2 myocarditis Withhold dose(s) until symptomsresolve and management with

Immune-related corticosteroids is completecmyocarditis

Grade 3 or 4 myocarditis Permanently discontinuetreatment

Grade 3 (first occurrence) Withhold dose(s)

Other immune-related Grade 4 or recurrent Grade 3; persistentadverse reactions Grade 2 or 3 despite treatment modification; Permanently discontinueinability to reduce corticosteroid dose treatmentto 10 mg prednisone or equivalent per day

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events

Version 4.0 (NCI-CTCAE v4).a During administration of the second phase of treatment (nivolumab monotherapy) following combination treatment,permanently discontinue treatment if Grade 3 diarrhoea or colitis occurs.

b Recommendation for the use of hormone replacement therapy is provided in section 4.4.c The safety of re-initiating nivolumab or nivolumab in combination with ipilimumab therapy in patients previouslyexperiencing immune-related myocarditis is not known.

OPDIVO as monotherapy or in combination with other therapeutic agents should be permanentlydiscontinued for:

* Grade 4 or recurrent Grade 3 adverse reactions;

* Persistent Grade 2 or 3 adverse reactions despite management.

Patients treated with OPDIVO must be given the patient alert card and be informed about the risks of

OPDIVO (see also package leaflet).

When OPDIVO is administered in combination with ipilimumab, if either agent is withheld, the otheragent should also be withheld. If dosing is resumed after a delay, either the combination treatment or

OPDIVO monotherapy could be resumed based on the evaluation of the individual patient.

When OPDIVO is administered in combination with chemotherapy, refer to the SmPC of the othercombination therapy agents regarding dosing. If any agents are withheld, the other agents may becontinued. If dosing is resumed after a delay, either the combination treatment, OPDIVO monotherapyor chemotherapy alone could be resumed based on the evaluation of the individual patient.

OPDIVO in combination with cabozantinib in RCC

When OPDIVO is used in combination with cabozantinib, the above treatment modifications in

Table 7 also apply to the OPDIVO component. In addition, for liver enzyme elevations, in patientswith RCC being treated with OPDIVO in combination with cabozantinib:

* If ALT or AST > 3 times ULN but ≤ 10 times ULN without concurrent total bilirubin ≥ 2 times

ULN, both OPDIVO and cabozantinib should be withheld until these adverse reactions recoverto Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine orrechallenge with both medicines after recovery may be considered. If rechallenging withcabozantinib, refer to cabozantinib SmPC.

* If ALT or AST > 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times

ULN, both OPDIVO and cabozantinib should be permanently discontinued and corticosteroidtherapy may be considered.

The safety and efficacy of OPDIVO in children below 18 years of age have not been establishedexcept in adolescents 12 years of age and older with melanoma. Currently available data of OPDIVOas monotherapy or in combination with ipilimumab are described in sections 4.2, pct. 4.8, 5.1 and 5.2.

No dose adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients withmild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairmentare too limited to draw conclusions on this population.

Based on the population PK results, no dose adjustment is required in patients with mild or moderatehepatic impairment (see section 5.2). Data from patients with severe hepatic impairment are toolimited to draw conclusions on this population. OPDIVO must be administered with caution inpatients with severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.

OPDIVO is for intravenous use only. It is to be administered as an intravenous infusion over a periodof 30 or 60 minutes depending on the dose (see Tables 1, 2, 3, 4 and 5). The infusion must beadministered through a sterile, non-pyrogenic, low protein binding in-line filter with a pore sizeof 0.2-1.2 μm.

OPDIVO must not be administered as an intravenous push or bolus injection.

The total dose of OPDIVO required can be infused directly as a 10 mg/mL solution or can be dilutedwith sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution forinjection (see section 6.6).

When administered in combination with ipilimumab and/or chemotherapy, OPDIVO should be givenfirst followed by ipilimumab (if applicable) and then by chemotherapy on the same day. Use separateinfusion bags and filters for each infusion.

For instructions on the preparation and handling of the medicinal product before administration, seesection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robustmethodology is used.

Assessment of MSI/MMR status

When assessing the MSI-H and dMMR status of the tumour, it is important that a well-validated androbust methodology is used.

When nivolumab is administered in combination, refer to the SmPC of the other combination therapyagents prior to initiation of treatment. Immune-related adverse reactions have occurred at higherfrequencies when nivolumab was administered in combination with ipilimumab compared withnivolumab as monotherapy. Immune-related adverse reactions have occurred at similar frequencieswhen OPDIVO was administered in combination with cabozantinib relative to nivolumabmonotherapy. Therefore, the guidance below for immune-related adverse reactions applies to the

OPDIVO component of the combination, except where specifically noted. Most immune-relatedadverse reactions improved or resolved with appropriate management, including initiation ofcorticosteroids and treatment modifications (see section 4.2).

Immune-related adverse reactions affecting more than one body system can occur simultaneously.

Cardiac and pulmonary adverse reactions including pulmonary embolism have also been reported withcombination therapy. Patients should be monitored for cardiac and pulmonary adverse reactionscontinuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative ofelectrolyte disturbances and dehydration prior to and periodically during treatment. Nivolumab incombination with ipilimumab should be discontinued for life-threatening or recurrent severe cardiacand pulmonary adverse reactions (see section 4.2).

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adversereaction with nivolumab or nivolumab in combination with ipilimumab may occur at any time duringor after discontinuation of therapy.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirmaetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab ornivolumab in combination with ipilimumab should be withheld and corticosteroids administered. Ifimmunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 monthduration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence ofthe adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there isworsening or no improvement despite corticosteroid use.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest thatthe risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy maybe increased as compared with the risk in patients without pre-existing AID. In addition, flares of theunderlying AID were frequent, but the majority were mild and manageable.

Nivolumab or nivolumab in combination with ipilimumab should not be resumed while the patient isreceiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy.

Prophylactic antibiotics should be used to prevent opportunistic infections in patients receivingimmunosuppressive therapy.

Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinued for anysevere immune-related adverse reaction that recurs and for any life-threatening immune-relatedadverse reaction.

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed withnivolumab monotherapy or nivolumab in combination with ipilimumab (see section 4.8). Patientsshould be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g., focalground glass opacities, patchy filtrates), dyspnoea, and hypoxia. Infectious and disease-relatedaetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, nivolumab or nivolumab in combination with ipilimumab must bepermanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/daymethylprednisolone equivalents.

For Grade 2 (symptomatic) pneumonitis, nivolumab or nivolumab in combination with ipilimumabshould be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisoloneequivalents. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may beresumed after corticosteroid taper. If worsening or no improvement occurs despite initiation ofcorticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisoloneequivalents and nivolumab or nivolumab in combination with ipilimumab must be permanentlydiscontinued.

Severe diarrhoea or colitis has been observed with nivolumab monotherapy or nivolumab incombination with ipilimumab (see section 4.8). Patients should be monitored for diarrhoea andadditional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Cytomegalovirus(CMV) infection/reactivation has been reported in patients with corticosteroid-refractoryimmune-related colitis. Infectious and other aetiologies of diarrhoea should be ruled out, thereforeappropriate laboratory tests and additional examinations must be performed. If diagnosis ofcorticosteroid-refractory immune-related colitis is confirmed addition of an alternativeimmunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy,should be considered.

For Grade 4 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab must bepermanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/daymethylprednisolone equivalents.

Nivolumab monotherapy should be withheld for Grade 3 diarrhoea or colitis, and corticosteroidsinitiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement,nivolumab monotherapy may be resumed after corticosteroid taper. If worsening or no improvementoccurs despite initiation of corticosteroids, nivolumab monotherapy must be permanentlydiscontinued. Grade 3 diarrhoea or colitis observed with nivolumab in combination with ipilimumabrequires permanent discontinuation of treatment and initiation of corticosteroids at a dose of1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 diarrhoea or colitis, nivolumab or nivolumab in combination with ipilimumab should bewithheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a doseof 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, nivolumab or nivolumabin combination with ipilimumab may be resumed after corticosteroid taper, if needed. If worsening orno improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increasedto 1 to 2 mg/kg/day methylprednisolone equivalents and nivolumab or nivolumab in combination withipilimumab must be permanently discontinued.

Severe hepatitis has been observed with nivolumab monotherapy or nivolumab in combination withipilimumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such astransaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruledout.

For Grade 3 or 4 transaminase or total bilirubin elevation, nivolumab or nivolumab in combinationwith ipilimumab must be permanently discontinued, and corticosteroids should be initiated at a doseof 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 transaminase or total bilirubin elevation, nivolumab or nivolumab in combination withipilimumab should be withheld. Persistent elevations in these laboratory values should be managedwith corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Uponimprovement, nivolumab or nivolumab in combination with ipilimumab may be resumed aftercorticosteroid taper, if needed. If worsening or no improvement occurs despite initiation ofcorticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisoloneequivalents and nivolumab or nivolumab in combination with ipilimumab must be permanentlydiscontinued.

Severe nephritis and renal dysfunction have been observed with monotherapy treatment or nivolumabin combination with ipilimumab (see section 4.8). Patients should be monitored for signs andsymptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases inserum creatinine. Disease-related aetiologies should be ruled out.

For Grade 4 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumabmust be permanently discontinued, and corticosteroids should be initiated at a doseof 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, nivolumab or nivolumab in combination with ipilimumabshould be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/daymethylprednisolone equivalents. Upon improvement, nivolumab or nivolumab in combination withipilimumab may be resumed after corticosteroid taper. If worsening or no improvement occurs despiteinitiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/daymethylprednisolone equivalents, and nivolumab or nivolumab in combination with ipilimumab mustbe permanently discontinued.

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (includingsecondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus,and diabetic ketoacidosis have been observed with nivolumab monotherapy or nivolumab incombination with ipilimumab (see section 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies and forhyperglycaemia and changes in thyroid function (at the start of treatment, periodically duringtreatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache,mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecificsymptoms which may resemble other causes such as brain metastasis or underlying disease. Unless analternate aetiology has been identified, signs or symptoms of endocrinopathies should be consideredimmune-related.

For symptomatic hypothyroidism, nivolumab or nivolumab in combination with ipilimumab should bewithheld, and thyroid hormone replacement should be initiated as needed. For symptomatichyperthyroidism, nivolumab or nivolumab in combination with ipilimumab should be withheld andantithyroid medication should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/daymethylprednisolone equivalents should also be considered if acute inflammation of the thyroid issuspected. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may beresumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensureappropriate hormone replacement is utilised. Nivolumab or nivolumab in combination withipilimumab must be permanently discontinued for life-threatening hyperthyroidism or hypothyroidism.

For symptomatic Grade 2 adrenal insufficiency, nivolumab or nivolumab in combination withipilimumab should be withheld, and physiologic corticosteroid replacement should be initiated asneeded. Nivolumab or nivolumab in combination with ipilimumab must be permanently discontinuedfor severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenalfunction and hormone levels should continue to ensure appropriate corticosteroid replacement isutilised.

For symptomatic Grade 2 or 3 hypophysitis, nivolumab or nivolumab in combination with ipilimumabshould be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a doseof 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammationof the pituitary gland is suspected. Upon improvement, nivolumab or nivolumab in combination withipilimumab may be resumed after corticosteroid taper, if needed. Nivolumab or nivolumab incombination with ipilimumab must be permanently discontinued for life-threatening (Grade 4)hypophysitis. Monitoring of pituitary function and hormone levels should continue to ensureappropriate hormone replacement is utilised.

For symptomatic diabetes, nivolumab or nivolumab in combination with ipilimumab should bewithheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar shouldcontinue to ensure appropriate insulin replacement is utilised. Nivolumab or nivolumab incombination with ipilimumab must be permanently discontinued for life-threatening diabetes.

Severe rash has been observed with nivolumab in combination with ipilimumab and, less commonly,with nivolumab as monotherapy (see section 4.8). Nivolumab or nivolumab in combination withipilimumab should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash shouldbe managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisoloneequivalents.

Rare cases of SJS and TEN some of them with fatal outcome have been observed. If symptoms orsigns of SJS or TEN appear, treatment with nivolumab or nivolumab in combination with ipilimumabshould be discontinued and the patient referred to a specialised unit for assessment and treatment. Ifthe patient has developed SJS or TEN with the use of nivolumab or nivolumab in combination withipilimumab, permanent discontinuation of treatment is recommended (see section 4.2).

Caution should be used when considering the use of nivolumab in a patient who has previouslyexperienced a severe or life-threatening skin adverse reaction on prior treatment with otherimmune-stimulatory anticancer agents.

The following immune-related adverse reactions were reported in less than 1% of patients treated withnivolumab monotherapy or nivolumab in combination with ipilimumab in clinical trials across dosesand tumour types: pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial andabducens nerve paresis), Guillain-Barré syndrome, myasthenia gravis, myasthenic syndrome, asepticmeningitis, encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis, rhabdomyolysis, andmyelitis. Cases of Vogt-Koyanagi-Harada syndrome, hypoparathyroidism, and cystitis noninfectivehave been reported post-marketing (see sections 4.2 and 4.8).

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirmaetiology or exclude other causes. Based on the severity of the adverse reaction, nivolumab ornivolumab in combination with ipilimumab should be withheld and corticosteroids administered.

Upon improvement, nivolumab or nivolumab in combination with ipilimumab may be resumed aftercorticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab must be permanentlydiscontinued for any severe immune-related adverse reaction that recurs and for any life-threateningimmune-related adverse reaction.

Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, havebeen reported with nivolumab or nivolumab in combination with ipilimumab. If a patient developssigns and symptoms of myotoxicity, close monitoring should be implemented, and the patient referredto a specialist for assessment and treatment without delay. Based on the severity of myotoxicity,nivolumab or nivolumab in combination with ipilimumab should be withheld or discontinued (seesection 4.2), and appropriate treatment instituted.

The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac orcardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected,prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to currentclinical guidelines should be initiated. Once a diagnosis of myocarditis is established, nivolumab ornivolumab in combination with ipilimumab should be withheld or permanently discontinued (seesection 4.2).

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with

PD-1 inhibitors. Treatment with nivolumab may increase the risk of rejection in solid organ transplantrecipients. The benefit of treatment with nivolumab versus the risk of possible organ rejection shouldbe considered in these patients.

Haemophagocytic lymphohistiocytosis (HLH) has been observed with nivolumab as monotherapy andnivolumab in combination with ipilimumab. Caution should be taken when nivolumab is administeredas monotherapy or in combination with ipilimumab. If HLH is confirmed, administration ofnivolumab or nivolumab in combination with ipilimumab should be discontinued and treatment for

HLH initiated.

Infusion reactions

Severe infusion reactions have been reported in clinical trials of nivolumab or nivolumab incombination with ipilimumab (see section 4.8). In case of a severe or life-threatening infusionreaction, the nivolumab or nivolumab in combination with ipilimumab infusion must be discontinuedand appropriate medical therapy administered. Patients with mild or moderate infusion reaction mayreceive nivolumab or nivolumab in combination with ipilimumab with close monitoring and use ofpremedication according to local treatment guidelines for prophylaxis of infusion reactions.

Advanced melanoma

Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases,autoimmune disease, and patients who had been receiving systemic immunosuppressants prior tostudy entry were excluded from the pivotal clinical trials of nivolumab or nivolumab in combinationwith ipilimumab (see sections 4.5 and 5.1). Patients with ocular/uveal melanoma were excluded frompivotal clinical trials of melanoma. In addition, CA209037 excluded patients who have had a Grade 4adverse reaction that was related to anti-CTLA-4 therapy (see section 5.1). Patients with baselineperformance score of 2, treated leptomeningeal metastases, ocular/uveal melanoma, autoimmunedisease and patients who have had a Grade 3-4 adverse reaction that was related to prior anti-CTLA-4therapy were included in study CA209172 (see section 5.1). In the absence of data for patients whohad been receiving systemic immunosuppressants prior to study entry, and for patients with activebrain or leptomeningeal metastases, nivolumab should be used with caution in these populations aftercareful consideration of the potential benefit/risk on an individual basis.

Relative to nivolumab monotherapy, an increase in PFS for the combination of nivolumab withipilimumab is established only in patients with low tumour PD-L1 expression. The improvement in

OS was similar between nivolumab in combination with ipilimumab and nivolumab monotherapy inpatients with high tumour PD-L1 expression (PD-L1 ≥ 1%). Before initiating treatment with thecombination, physicians are advised to carefully evaluate the individual patient and tumourcharacteristics, taking into consideration the observed benefits and the toxicity of the combinationrelative to nivolumab monotherapy (see sections 4.8 and 5.1).

Use of nivolumab in melanoma patients with rapidly progressing disease

Physicians should consider the delayed onset of nivolumab effect before initiating treatment inpatients with rapidly progressing disease (see section 5.1).

There are no data on adjuvant treatment in patients with melanoma with the following risk factors (seesections 4.5 and 5.1):

* patients with prior autoimmune disease, and any condition requiring systemic treatment witheither corticosteroids (≥ 10 mg daily prednisone or equivalent) or other immunosuppressivemedications,

* patients with prior therapy for melanoma (except patients with surgery, adjuvant radiotherapyafter neurosurgical resection for lesions of the central nervous system, and prior adjuvantinterferon completed ≥ 6 months prior to randomisation),

* patients treated with prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti

CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting

T cell co-stimulation or checkpoint pathways),

* subjects under the age of 18 years.

In the absence of data, nivolumab should be used with caution in these populations after carefulconsideration of the potential benefit/risk on an individual basis.

First-line treatment of NSCLC

Patients with active autoimmune disease, symptomatic interstitial lung disease, medical conditionsrequiring systemic immunosuppression, active (untreated) brain metastasis, who received priorsystemic treatment for advanced disease, or who had sensitising EGFR mutations or ALKtranslocations were excluded from the pivotal trial in first-line treatment of NSCLC (see sections 4.5and 5.1). Limited data are available in elderly patients (≥ 75 years) (see section 5.1). In these patients,nivolumab in combination with ipilimumab and chemotherapy should be used with caution aftercareful consideration of the potential benefit/risk on an individual basis.

Treatment of NSCLC after prior chemotherapy

Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease,symptomatic interstitial lung disease, and patients who had been receiving systemicimmunosuppressants prior to study entry were excluded from the pivotal clinical trials of NSCLC (seesections 4.5 and 5.1). Patients with baseline performance score of 2 were included in study CA209171(see section 5.1). In the absence of data for patients with autoimmune disease, symptomatic interstitiallung disease, active brain metastases and patients who had been receiving systemicimmunosuppressants prior to study entry, nivolumab should be used with caution in these populationsafter careful consideration of the potential benefit/risk on an individual basis.

Physicians should consider the delayed onset of nivolumab effect before initiating treatment inpatients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a highernumber of deaths within 3 months was observed in nivolumab compared to docetaxel. Factorsassociated with early deaths were poorer prognostic factors and/or more aggressive disease combinedwith low or no tumour PD-L1 expression (see section 5.1).

Neoadjuvant treatment of NSCLC

Patients with a baseline performance score ≥ 2, active autoimmune disease, symptomatic interstitiallung disease, medical conditions requiring systemic immunosuppression, unresectable or metastaticdisease, who received prior anti-cancer treatment for resectable disease, or who had known

EGFR mutations or ALK translocations were excluded from the pivotal trial in neoadjuvant treatmentof resectable NSCLC (see section 5.1). In the absence of data, nivolumab in combination withchemotherapy should be used with caution in these populations after careful consideration of thepotential benefit/risk on an individual basis.

Neoadjuvant and adjuvant treatment of non-small cell lung cancer

Patients with a baseline performance score ≥ 2, Grade 2 or greater peripheral neuropathy, activeautoimmune disease, symptomatic interstitial lung disease, medical conditions requiring systemicimmunosuppression, unresectable or metastatic disease, who received prior anti-cancer treatment forresectable disease, who had EGFR mutations or known ALK translocations, or who had brainmetastasis, were excluded from the pivotal trial in neoadjuvant and adjuvant treatment of NSCLC (seesections 4.5 and 5.1). In the absence of data, nivolumab in combination with chemotherapy should beused with caution in these populations after careful consideration of the potential benefit/risk on anindividual basis.

Malignant pleural mesothelioma

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lungdisease, active autoimmune disease, medical conditions requiring systemic immunosuppression, andbrain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolutionwithin 3 months prior to inclusion in the study) were excluded from the pivotal trial in first-linetreatment of MPM (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination withipilimumab should be used with caution in these populations after careful consideration of thepotential benefit/risk on an individual basis.

Nivolumab or nivolumab in combination with ipilimumab

Patients with any history of concurrent brain metastases, active autoimmune disease, or medicalconditions requiring systemic immunosuppression were excluded from the clinical trials of nivolumabor nivolumab in combination with ipilimumab (see sections 4.5 and 5.1). In the absence of data,nivolumab or nivolumab in combination with ipilimumab should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.

Nivolumab in combination with cabozantinib

Patients with any active brain metastases, autoimmune disease, or medical conditions requiringsystemic immunosuppression were excluded from the clinical trials of nivolumab in combination withcabozantinib (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination withcabozantinib should be used with caution in these populations after careful consideration of thepotential benefit/risk on an individual basis.

When nivolumab is given with cabozantinib, higher frequencies of Grades 3 and 4 ALT and ASTelevations have been reported relative to nivolumab monotherapy in patients with advanced RCC (seesection 4.8). Liver enzymes should be monitored before initiation of and periodically throughouttreatment. Medical management guidelines for both medicines should be followed (see section 4.2 andrefer to the SmPC for cabozantinib).

Patients with active autoimmune disease and symptomatic interstitial lung disease were excluded fromclinical trials of cHL (see section 5.1). In the absence of data, nivolumab should be used with cautionin these populations after careful consideration of the potential benefit/risk on an individual basis.

Complications of allogeneic haematopoietic stem cell transplant (HSCT) in classical Hodgkinlymphoma

Cases of acute graft-versus-host disease (GVHD) and transplant related mortality (TRM) have beenobserved from the follow-up of patients with cHL undergoing allogeneic HSCT after previousexposure to nivolumab. Careful consideration to the potential benefits of HSCT and the possibleincreased risk of transplant related complications should be made case-by-case (see section 4.8).

In patients treated with nivolumab after allogeneic HSCT, rapid-onset and severe GVHD, some withfatal outcome, have been reported in the post-marketing setting. Treatment with nivolumab mayincrease the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainlyin those with prior history of GVHD. The benefit of treatment with nivolumab versus the possible riskshould be considered in these patients (see section 4.8).

Head and neck cancer

Patients with a baseline performance score ≥ 2, active brain or leptomeningeal metastases, activeautoimmune disease, medical conditions requiring systemic immunosuppression, or carcinoma of thenasopharynx or salivary gland as the primary tumour sites were excluded from the SCCHN clinicaltrial (see sections 4.5 and 5.1). In the absence of data, nivolumab should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.

Physicians should consider the delayed onset of nivolumab effect before initiating treatment inpatients with poorer prognostic features and/or aggressive disease. In head and neck cancer, a highernumber of deaths within 3 months was observed in nivolumab compared to docetaxel. Factorsassociated with early deaths were ECOG performance status, fast progressive disease on priorplatinum therapy and high tumour burden.

Treatment of advanced urothelial carcinoma

Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases,active autoimmune disease, or medical conditions requiring systemic immunosuppression wereexcluded from the clinical trials of urothelial carcinoma (see sections 4.5 and 5.1). In the absence ofdata, nivolumab should be used with caution in these populations after careful consideration of thepotential benefit/risk on an individual basis.

Adjuvant treatment of urothelial carcinoma

Patients with a baseline performance score of ≥ 2 (except patients with a baseline performance scoreof 2 who have not received cisplatin based neoadjuvant chemotherapy and are considered ineligiblefor cisplatin adjuvant chemotherapy), evidence of disease after surgery, active autoimmune disease, ormedical conditions requiring systemic immunosuppression were excluded from the clinical trial ofadjuvant treatment of urothelial carcinoma (see sections 4.5 and 5.1). In the absence of data,nivolumab should be used with caution in these populations after careful consideration of the potentialbenefit/risk on an individual basis.

dMMR or MSI-H colorectal cancer

Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases,active autoimmune disease, or medical conditions requiring systemic immunosuppression wereexcluded from the clinical trial in dMMR or MSI-H metastatic CRC (see sections 4.5 and 5.1). In theabsence of data, nivolumab in combination with ipilimumab should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.

Oesophageal squamous cell carcinoma

First-line treatment of OSCC

Patients with a baseline performance score ≥ 2, any history of concurrent brain metastases, activeautoimmune disease, medical conditions requiring systemic immunosuppression, or at high risk ofbleeding or fistula due to apparent invasion of tumour to organs adjacent to the oesophageal tumourwere excluded from the clinical trial in OSCC (see sections 4.5 and 5.1). In the absence of data,nivolumab in combination with ipilimumab or chemotherapy should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.

In the first-line OSCC trial, a higher number of deaths within 4 months was observed with nivolumabin combination with ipilimumab compared to chemotherapy. Physicians should consider the delayedonset of effect of nivolumab in combination with ipilimumab before initiating treatment in patientswith poorer prognostic features and/or aggressive disease (see section 5.1).

Treatment of OSCC after prior first-line chemotherapy

The majority of clinical data available in oesophageal squamous cell carcinoma are in patients of

Asian origin (see section 5.1).

Patients with a baseline performance score ≥ 2, brain metastases that were symptomatic or requiredtreatment, apparent tumour invasion in organs located adjacent to the oesophagus (e.g. the aorta orrespiratory tract), active autoimmune disease, or medical conditions requiring systemicimmunosuppression were excluded from the clinical study in OSCC (see sections 4.5 and 5.1). In theabsence of data, nivolumab should be used with caution in these populations after carefulconsideration of the potential benefit/risk on an individual basis.

Physicians should consider the delayed onset of nivolumab effect before initiating treatment inpatients with OSCC. A higher number of deaths within 2.5 months after randomisation was observedwith nivolumab compared to chemotherapy. No specific factor(s) associated with early deaths couldbe identified (see section 5.1).

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer

Patients with a baseline performance score ≥ 2, who did not receive concurrent chemoradiotherapy(CRT) prior to surgery, with stage IV resectable disease, active autoimmune disease, or medicalconditions requiring systemic immunosuppression were excluded from the clinical study inoesophageal and gastro-oesophageal junction cancer (see sections 4.5 and 5.1). In the absence of data,nivolumab should be used with caution in these populations after careful consideration of the potentialbenefit/risk on an individual basis.

Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma

Patients who had baseline ECOG performance score ≥ 2, untreated central nervous system metastases,active, known, or suspected autoimmune disease, or medical conditions requiring systemicimmunosuppression were excluded from the clinical study in gastric, GEJ or oesophagealadenocarcinoma (see sections 4.5 and 5.1). In the absence of data, nivolumab in combination withchemotherapy should be used with caution in these populations after careful consideration of thepotential benefit/risk on an individual basis.

Study CA209649 excluded patients with known HER2-positive status. Patients with undeterminedstatus were allowed in the study and represented 40.3% of patients (see section 5.1).

Hepatocellular carcinoma

Patients who had baseline ECOG performance score ≥ 2, prior liver transplant, Child-Pugh C liverdisease, a history of concurrent brain metastases, a history of hepatic encephalopathy (within12 months of randomisation), clinically significant ascites, infection with HIV, or active co-infectionwith hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV), activeautoimmune disease, or medical conditions requiring systemic immunosuppression were excludedfrom the clinical study in HCC (see sections 4.5 and 5.1). Limited data are available in HCC patientswith Child-Pugh B. In the absence of data, nivolumab in combination with ipilimumab followed bynivolumab should be used with caution in these populations after careful consideration of the potentialbenefit/risk on an individual basis.

In HCC, a higher number of deaths within 6 months was observed with nivolumab in combinationwith ipilimumab compared to lenvatinib or sorafenib. A higher risk of death may be associated withpoor prognostic features. Physicians should consider this risk before initiating treatment withnivolumab in combination with ipilimumab in patients with poor prognostic features.

Patients on controlled sodium diet

Each mL of this medicinal product contains 0.1 mmol (or 2.5 mg) sodium. This medicinal productcontains 10 mg sodium per 4 mL vial, 25 mg sodium per 10 mL vial, 30 mg sodium per 12 mL vial or60 mg sodium per 24 mL vial, which is equivalent to 0.5%, 1.25%, 1.5% or 3% respectively, of the

WHO recommended maximum daily intake of 2 g sodium for an adult. Sodium intake could vary incase sodium chloride is used for the dilution steps.

All prescribers of OPDIVO must be familiar with the physician information and managementguidelines. The prescriber must discuss the risks of OPDIVO therapy with the patient. The patient willbe provided with the patient alert card with each prescription.

Nivolumab is a human monoclonal antibody, as such pharmacokinetic interaction studies have notbeen conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymesor other drug metabolising enzymes, inhibition or induction of these enzymes by co-administeredmedicinal products is not anticipated to affect the pharmacokinetics of nivolumab.

Other forms of interaction

Systemic immunosuppression

The use of systemic corticosteroids and other immunosuppressants at baseline, before startingnivolumab, should be avoided because of their potential interference with the pharmacodynamicactivity. However, systemic corticosteroids and other immunosuppressants can be used after startingnivolumab to treat immune-related adverse reactions. The preliminary results show that systemicimmunosuppression after starting nivolumab treatment does not appear to preclude the response onnivolumab.

There are no data from the use of nivolumab in pregnant women. Studies in animals have shownembryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier andnivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from the mother to thedeveloping foetus. Nivolumab is not recommended during pregnancy and in women of childbearingpotential not using effective contraception unless the clinical benefit outweighs the potential risk.

Effective contraception should be used for at least 5 months following the last dose of nivolumab.

It is unknown whether nivolumab is secreted in human milk. Because many medicinal products,including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue fromnivolumab therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

Studies to evaluate the effect of nivolumab on fertility have not been performed. Thus, the effect ofnivolumab on male and female fertility is unknown.

Nivolumab or nivolumab in combination with ipilimumab may have a minor influence on the abilityto drive and use machines. Because of potential adverse reactions such as fatigue (see section 4.8),patients should be advised to use caution when driving or operating machinery until they are certainthat nivolumab does not adversely affect them.

Nivolumab as monotherapy (see section 4.2)

In the pooled dataset of nivolumab as monotherapy across tumour types (n = 4646) with minimumfollow-up ranging from 2.3 to 28 months, the most frequent adverse reactions (≥ 10%) were fatigue(44%), musculoskeletal pain (28%), diarrhoea (26%), rash (24%),cough (22%), nausea (22%), pruritus(19%), decreased appetite (17%), arthralgia (17%), constipation (16%), dyspnoea (16%), abdominalpain (15%), upper respiratory tract infection (15%), pyrexia (13%), headache (13%), anaemia (13%)and vomiting (12%). The majority of adverse reactions were mild to moderate (Grade 1 or 2). Theincidence of Grade 3-5 adverse reactions was 44%, with 0.3% fatal adverse reactions attributed tostudy drug. With a minimum of 63 months follow-up in NSCLC, no new safety signals wereidentified.

Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy(n = 4646) are presented in Table 8. These reactions are presented by system organ class and byfrequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known(cannot be estimated from available post-marketing data). Within each frequency grouping, adversereactions are presented in the order of decreasing seriousness.

Table 8: Adverse reactions with nivolumab monotherapy

Nivolumab monotherapy

Very common upper respiratory tract infection

Common pneumoniaa, bronchitis

Rare aseptic meningitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Rare histiocytic necrotising lymphadenitis (Kikuchi lymphadenitis)

Very common lymphopaeniab, anaemiab,i, leucopoeniab, neutropaeniaa,b, thrombocytopaeniab

Uncommon eosinophilia

Not known haemophagocytic lymphohistiocytosis

Common infusion related reaction (including cytokine release syndrome),hypersensitivity (including anaphylactic reaction)

Uncommon sarcoidosis

Not known solid organ transplant rejectionf

Nivolumab monotherapy

Common hypothyroidism, hyperthyroidism, thyroiditis

Uncommon adrenal insufficiencyj, hypopituitarism, hypophysitis, diabetes mellitus

Rare diabetic ketoacidosis, hypoparathyroidism

Very common decreased appetite, hyperglycaemiab

Common dehydration, weight decreased, hypoglycaemiab

Uncommon metabolic acidosis

Not known tumour lysis syndromeg

Very common headache

Common peripheral neuropathy, dizziness

Uncommon polyneuropathy, autoimmune neuropathy (including facial and abducens nerveparesis)

Rare Guillain-Barré syndrome, demyelination, myasthenic syndrome, encephalitisa,k,optic neuritis

Not known myelitis (including transverse myelitis)

Common blurred vision, dry eye

Uncommon uveitis

Not known Vogt-Koyanagi-Harada syndromef

Common tachycardia, atrial fibrillation

Uncommon myocarditisa, pericardial disordersh, arrhythmia (including ventricular arrhythmia)

Common hypertension

Rare vasculitis

Very common dyspnoeaa, cough

Common pneumonitisa, pleural effusion

Uncommon lung infiltration

Very common diarrhoea, vomiting, nausea, abdominal pain, constipation

Common colitisa, stomatitis, dry mouth

Uncommon pancreatitis, gastritis

Rare duodenal ulcer, pancreatic exocrine insufficiency, coeliac disease

Uncommon hepatitis, cholestasis

Very common rashc, pruritus

Common vitiligo, dry skin, erythema, alopecia

Uncommon psoriasis, rosacea, erythema multiforme, urticaria

Rare toxic epidermal necrolysisa, d, Stevens-Johnson syndromea

Not known lichen sclerosusg, other lichen disorders

Nivolumab monotherapy

Very common musculoskeletal paine, arthralgia

Common arthritis

Uncommon polymyalgia rheumatica

Rare Sjogren’s syndrome, myopathy, myositis (including polymyositis)a,,rhabdomyolysisa,d

Common renal failure (including acute kidney injury)a

Rare tubulointerstitial nephritis, cystitis noninfective

Very common fatigue, pyrexia

Common pain, chest pain, oedemal

Investigationsb

Very common increased AST, hyponatraemia, hypoalbuminaemia, increased alkalinephosphatase, increased creatinine, increased ALT, increased lipase,hyperkalaemia, increased amylase, hypocalcaemia, hypomagnesaemia,hypokalaemia, hypercalcaemia

Common increased total bilirubin, hypernatraemia, hypermagnesaemia

Adverse reaction frequencies presented in Table 8 may not be fully attributable to nivolumab alone but may containcontributions from the underlying disease.a Fatal cases have been reported in completed or ongoing clinical studies.b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline inlaboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.c Rash is a composite term which includes rash maculopapular, rash erythematous, rash pruritic, rash follicular, rashmacular, rash morbilliform, rash papular, rash pustular, rash vesicular, exfoliative rash, dermatitis, dermatitisacneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform,drug eruption and pemphigoid.

d Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain,musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.f Post-marketing event (also see section 4.4).g Reported in clinical studies and in the post-marketing setting.h Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and

Dressler’s syndrome.i Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia,haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.j Includes adrenal insufficiency, adrenocortical insufficiency acute, and secondary adrenocortical insufficiency.k Includes encephalitis and limbic encephalitis.l Oedema is a composite term which includes generalised oedema, oedema peripheral, peripheral swelling andswelling.

Nivolumab in combination with other therapeutic agents (see section 4.2)

When nivolumab is administered in combination, refer to the SmPC for the other therapeutic agentsfor additional information on the safety profile, prior to initiation of treatment.

Nivolumab in combination with ipilimumab (with or without chemotherapy)

In the pooled dataset of nivolumab administered in combination with ipilimumab (with or withoutchemotherapy) across tumour types (n = 2626) with minimum follow-up ranging from 6 to 47 months,the most frequent adverse reactions (≥ 10%) were fatigue (47%), diarrhoea (35%), rash (37%), nausea(27%), pruritus (29%), musculoskeletal pain (26%), pyrexia (23%), decreased appetite (22%), cough(21%), abdominal pain (18%), vomiting (18%), constipation (18%), arthralgia (18%), dyspnoea(17%), hypothyroidism (16%), headache (15%), upper respiratory tract infection (13%), oedema(13%), and dizziness (10%). The incidence of Grade 3-5 adverse reactions was 66% for nivolumab incombination with ipilimumab (with or without chemotherapy), with 1.0% fatal adverse reactionsattributed to study drug. Among patients treated with nivolumab 1 mg/kg in combination withipilimumab 3 mg/kg for melanoma, fatigue (62%), rash (57%), diarrhoea (52%), nausea (42%),pruritus (40%), pyrexia (36%), and headache (26%) were reported at an incidence rate ≥ 10% higherthan the rates reported in the pooled dataset of nivolumab in combination with ipilimumab (with orwithout chemotherapy) incidence rate. Among patients treated with nivolumab 360 mg in combinationwith ipilimumab 1 mg/kg and chemotherapy for NSCLC, anaemia (32%) and neutropaenia (15%)were reported at an incidence rate ≥ 10% higher than the rates reported in the pooled dataset ofnivolumab in combination with ipilimumab (with or without chemotherapy) incidence rate.

Nivolumab in combination with chemotherapy

In the pooled dataset of nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combinationwith chemotherapy across tumour types (n = 1800), with a minimum follow-up ranging from 7.4 to23.6 months, or following 3 cycles of treatment for resectable NSCLC, the most frequent adversereactions (≥ 10%) were nausea (48%), fatigue (40%), peripheral neuropathy (33%), decreased appetite(31%), constipation (31%), diarrhoea (28%), vomiting (24%), rash (19%), abdominal pain (18%),stomatitis (18%), musculoskeletal pain (18%), pyrexia (16%), cough (13%), oedema (includingperipheral oedema) (12%), and pruritus (11%). Incidences of Grade 3-5 adverse reactions were 69%for nivolumab in combination with chemotherapy, with 1.2% fatal adverse reactions attributed tonivolumab in combination with chemotherapy. Median duration of therapy was 6.14 months(95% CI: 5.78, 6.60) for nivolumab in combination with chemotherapy. For resectable NSCLC,ninety-three percent (93%) of patients received 3 cycles of nivolumab in combination withchemotherapy.

Nivolumab in combination with cabozantinib

In the dataset of nivolumab 240 mg every 2 weeks in combination with cabozantinib 40 mg once dailyin RCC (n =320), with a minimum follow -up of 16.0 months, the most frequent adversereactions (≥ 10%) were diarrhoea (64.7%), fatigue (51.3%), -palmar plantar erythrodysaesthesiasyndrome (40.0%), stomatitis (38.8%), musculoskeletal pain (37.5%), hypertension (37.2%), rash(36.3%), hypothyroidism (35.6%), decreased appetite (30.3%), nausea (28.8%), abdominal pain(25.0%), dysgeusia (23.8%), upper respiratory tract infection (20.6%), cough (20.6%), pruritus(20.6%), arthralgia (19.4%), vomiting (18.4%), dysphonia (17.8%), headache (16.3%), dyspepsia(15.9%), dizziness (14.1%), constipation (14.1%), pyrexia (14.1%), oedema (13.4%), muscle spasm(12.2%), dyspnoea (11.6%), proteinuria (10.9%) and hyperthyroidism (10.0%). The incidence of

Grade 3-5 adverse reactions was 78%, with 0.3% fatal adverse reactions attributed to study drug.

Adverse reactions reported in the pooled dataset for patients treated with nivolumab in combinationwith ipilimumab (with or without chemotherapy) (n = 2626), nivolumab in combination withchemotherapy (n = 1800), and nivolumab in combination with cabozantinib (n = 320) are presented in

Table 9. These reactions are presented by system organ class and by frequency. Frequencies aredefined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100);rare (≥ 1/10 000 to < 1/1 000), not known (cannot be estimated from available post-marketing data).

Within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness.

Table 9: Adverse reactions with nivolumab in combination with other therapeutic agents

Combination with Combination with Combination withipilimumab (with or chemotherapy cabozantinibwithout chemotherapy)

Very common upper respiratory tract upper respiratory tractinfection infection

Common pneumonia, bronchitis, upper respiratory tract pneumoniaconjunctivitis infection, pneumoniaa

Rare aseptic meningitis

Combination with Combination with Combination withipilimumab (with or chemotherapy cabozantinibwithout chemotherapy)

Very common anaemiab,j, neutropaeniab, anaemiab,j, anaemiab,thrombocytopaeniab, leucopoeniab, thrombocytopaeniab,leucopoeniab, lymphopaeniab, leucopoeniab, lymphopaeniab,lymphopaeniab, thrombocytopaeniab neutropaeniabneutropaeniab

Common eosinophilia febrile neutropaeniaa eosinophilia

Uncommon febrile neutropaenia eosinophilia

Not known haemophagocyticlymphohistiocytosis

Common infusion related reaction hypersensitivity, infusion hypersensitivity (including(including cytokine release related reaction anaphylactic reaction)syndrome), (including cytokinehypersensitivity release syndrome)

Uncommon infusion relatedhypersensitivity reaction

Rare sarcoidosis

Not known solid organ transplantrejectiong

Very common hypothyroidism hypothyroidism,hyperthyroidism

Common hyperthyroidism, hypothyroidism, adrenal insufficiencythyroiditis, adrenal hyperthyroidism,insufficiency, hypophysitis, diabetes mellitushypopituitarism, diabetesmellitus

Uncommon diabetic ketoacidosis adrenal insufficiency, hypophysitis, thyroiditisthyroiditis,hypopituitarism,hypophysitis

Rare hypoparathyroidism

Very common decreased appetite, decreased appetite, decreased appetite,hyperglycaemiab, hyperglycaemiab, hypoglycaemiab,hypoglycaemiab hypoglycaemiab hyperglycaemiab, weightdecreased

Common dehydration, hypoalbuminaemia, dehydrationhypoalbuminaemia, hypophosphataemiahypophosphataemia,weight decreased

Uncommon metabolic acidosis

Rare tumour lysis syndrome

Not known tumour lysis syndromeh

Combination with Combination with Combination withipilimumab (with or chemotherapy cabozantinibwithout chemotherapy)

Very common headache peripheral neuropathy dysgeusia, dizziness, headache

Common dizziness, peripheral paraesthesia, dizziness, peripheral neuropathyneuropathy headache

Uncommon polyneuropathy, peroneal Guillain-Barré syndrome encephalitis autoimmune,nerve palsy, autoimmune Guillain-Barré syndrome,neuropathy (including myasthenic syndromefacial and abducens nerveparesis), encephalitis,myasthenia gravis

Rare Guillain-Barré syndrome, encephalitisneuritis, myelitis (includingtransverse myelitis), opticneuritis

Not known myelitis (includingtransverse myelitis),optic neuritis

Ear and labyrinth disorders

Common tinnitus

Common blurred vision, dry eye dry eye, blurred vision dry eye, blurred vision

Uncommon uveitis, episcleritis uveitis uveitis

Rare Vogt Koyanagi Haradasyndrome

Common tachycardia, atrial tachycardia, atrial atrial fibrillation, tachycardiafibrillation fibrillation

Uncommon myocarditisa, arrhythmia myocarditis myocarditis(including ventriculararrhythmia)a, bradycardia

Not known pericardial disordersi

Very common hypertension

Common hypertension thrombosisa, k, thrombosiskhypertension, vasculitis

Very common cough, dyspnoea cough dysphonia, dyspnoea, cough

Common pneumonitisa, pulmonary pneumonitisa, dyspnoea pneumonitis, pulmonaryembolisma, pleural effusion embolism, pleural effusion,epistaxis

Combination with Combination with Combination withipilimumab (with or chemotherapy cabozantinibwithout chemotherapy)

Very common diarrhoea, vomiting, diarrhoeaa, stomatitis, diarrhoea, vomiting, nausea,nausea, abdominal pain, vomiting, nausea, constipation, stomatitis,constipation abdominal pain, abdominal pain, dyspepsiaconstipation

Common colitisa, pancreatitis, colitis, dry mouth colitis, gastritis, oral pain, drystomatitis, gastritis, dry mouth, haemorrhoidsmouth

Uncommon duodenitis pancreatitis pancreatitis, small intestineperforationa, glossodynia

Rare intestinal perforationa,pancreatic exocrineinsufficiency, coeliacdisease

Not known pancreatic exocrine pancreatic exocrineinsufficiency, coeliac insufficiency, coeliac diseasedisease

Common hepatitis hepatitis

Uncommon hepatitis

Very common rashc, pruritus rashc, pruritus palmar-plantarerythrodysaesthesia syndrome,rashc, pruritus

Common alopecia, vitiligo, urticaria, palmar-plantar alopecia, dry skin, erythema,dry skin, erythema, erythrodysaesthesia hair colour changesyndrome, skinhyperpigmentation,alopecia, dry skin,erythema

Uncommon Stevens-Johnson psoriasis, urticariasyndrome, erythemamultiforme, psoriasis, otherlichen disordersd

Rare toxic epidermalnecrolysisa,e , lichensclerosus

Not known lichen sclerosus, other lichendisorders

Very common musculoskeletal painf, musculoskeletal painf musculoskeletal painf,arthralgia arthralgia, muscle spasm

Common muscle spasms, muscular arthralgia, muscular arthritisweakness, arthritis weakness

Uncommon polymyalgia rheumatica, myopathy, osteonecrosis ofmyopathy, myositis the jaw, fistula(including polymyositis)a

Rare spondyloarthropathy,

Sjogren’s syndrome,rhabdomyolysisa

Combination with Combination with Combination withipilimumab (with or chemotherapy cabozantinibwithout chemotherapy)

Very common proteinuria

Common renal failure (including renal failurea renal failure, acute kidneyacute kidney injury)a injury

Uncommon tubulointerstitial nephritis, cystitis noninfective, nephritisnephritis nephritis

Rare cystitis noninfective cystitis noninfectiveh

Very common fatigue, pyrexia, oedema fatigue, pyrexia, oedema fatigue, pyrexia, oedema(including peripheral (including peripheraloedema) oedema)

Common chest pain, pain, chills malaise pain, chest pain

Very common increased alkaline hypocalcaemiab, increased alkalinephosphataseb, increased increased AST b, phosphataseb, increased ALTb,

ASTb, increased ALTb, increased ALT b, increased ASTb, increasedincreased total bilirubinb, hyponatraemiab, total bilirubinb, increasedincreased creatinineb, increased amylaseb, creatinineb, increasedincreased amylaseb, hypomagnesaemiab, amylaseb, increased lipaseb,increased lipaseb, increased alkaline hypokalaemiab,hyponatraemiab, phosphataseb, hypomagnesaemiab,hyperkalaemiab, hypokalaemiab,, hyponatraemiab,hypokalaemiab, increased creatinineb, hypocalcaemiab,hypercalcaemiab, increased lipaseb, hypercalcaemiab,hypocalcaemiab hyperkalaemiab, hypophosphataemiab,increased total bilirubinb hyperkalaemiab,hypermagnesaemiab,hypernatraemiab

Common hypernatraemiab, hypernatraemiab, blood cholesterol increased,hypermagnesaemiab, hypercalcaemiab, hypertriglyceridaemiaincreased thyroid hypermagnesaemiabstimulating hormone,increased gamma-glutamyltransferase

Adverse reaction frequencies presented in Table 9 may not be fully attributable to nivolumab alone or in combination withother therapeutic agents, but may contain contributions from the underlying disease or from medicinal product used incombination.a Fatal cases have been reported in completed or ongoing clinical studies.b Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline inlaboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.c Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rashmacular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised,exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitisexfoliative, dermatitis psoriasiform, drug eruption, nodular rash, and pemphigoid.

d Lichen disorders is a composite term which includes lichen keratosis and lichen planus.e Reported also in studies outside the pooled dataset. The frequency is based on the program-wide exposure.f Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain,musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.g Post-marketing event (also see section 4.4).h Reported in clinical studies and in the post-marketing setting.i Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and

Dressler’s syndrome.j Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia,haemoglobin decreased, iron deficiency anaemia and red blood cell count decreased.k Thrombosis is a composite term which includes portal vein thrombosis, pulmonary vein thrombosis, pulmonarythrombosis, aortic thrombosis, arterial thrombosis, deep vein thrombosis, pelvic vein thrombosis, vena cavathrombosis, venous thrombosis, limb venous thrombosis.

Nivolumab or nivolumab in combination with other therapeutic agents is associated withimmune-related adverse reactions. With appropriate medical therapy, immune-related adversereactions resolved in most cases. Permanent discontinuation of treatment generally was required in agreater proportion of patients receiving nivolumab in combination with other agents than in thosereceiving nivolumab monotherapy. Table 10 presents the percentage of patients with immune-relatedadverse reactions who were permanently discontinued from treatment by dosing regimen.

Additionally, for patients who experienced an event, Table 10 presents the percentage of patients whorequired high-dose corticosteroids (at least 40 mg daily prednisone equivalents) by dosing regimen.

The management guidelines for these adverse reactions are described in section 4.4.

Table 10: Immune-related adverse reactions leading to permanent discontinuation orrequiring high-dose corticosteroids by dosing regimen (nivolumab monotherapy,nivolumab in combination with ipilimumab (with or without chemotherapy),nivolumab in combination with chemotherapy, or nivolumab in combination withcabozantinib)

Nivolumab Nivolumab in Nivolumab in Nivolumab inmonotherapy combination combination combination% with ipilimumab with with(with or without chemotherapy cabozantinibchemotherapy) % %%

Immune-related adverse reaction leading to permanent discontinuation

Pneumonitis 1.4 2.1 2.0 2.5

Colitis 1.2 6 1.8 2.5

Hepatitis 1.1 5 0.7 4.1

Nephritis and renal 0.3 1.1 3.1 0.6dysfunction

Endocrinopathies 0.5 2.2 0.6 1.3

Skin 0.8 1.0 0.9 2.2

Hypersensitivity/Infusion 0.1 0.3 1.7 0reaction

Immune-related adverse reaction requiring high-dose corticosteroidsa,b

Pneumonitis 65 59 59 56

Colitis 14 32 9 8

Hepatitis 21 39 7 23

Nephritis and renal 22 27 9 9dysfunction

Endocrinopathies 5 18 4.3 4.2

Skin 3.3 8 6 8

Hypersensitivity/Infusion 18 18 22 0reactiona at least 40 mg daily prednisone equivalentsb frequency is based on the number of patients who experienced the immune-related adverse reaction

In patients treated with nivolumab monotherapy, the incidence of pneumonitis, including interstitiallung disease and lung infiltration, was 3.3% (155/4646). The majority of cases were Grade 1 or 2 inseverity reported in 0.9% (42/4646) and 1.7% (77/4646) of patients respectively. Grade 3 and 4 caseswere reported in 0.7% (33/4646) and <0.1% (1/4646) of patients respectively. Six patients (0.1%) hada fatal outcome. Median time to onset was 15.1 weeks (range: 0.7-85.1). Resolution occurred in107 patients (69.0%) with a median time to resolution of 6.7 weeks (range: 0.1+-109.1+); + denotes acensored observation.

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of pneumonitis including interstitial lung disease, was 6.0% (157/2626). Grade 2,

Grade 3, and Grade 4 cases were reported in 3.0% (78/2626), 1.0% (27/2626), and 0.3% (8/2626) ofpatients, respectively. Four patients (0.2%) had a fatal outcome. Median time to onset was 2.7 months(range: 0.1-56.8). Resolution occurred in 129 patients (82.2%) with a median time to resolution of6.1 weeks (range: 0.1+-149.3+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of pneumonitisincluding interstitial lung disease was 4.4% (80/1800). Grade 2, Grade 3, and Grade 4 cases werereported in 2.2% (40/1800), 0.9% (17/1800), and 0.2% (3/1800), of patients, respectively. Threepatients (0.2%) had a fatal outcome. Median time to onset was 24.6 weeks (range: 0.6-96.9).

Resolution occurred in 58 patients (72.5%) with a median time to resolution of 10.4 weeks (range:0.3+-171.4+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of pneumonitisincluding interstitial lung disease was 5.6% (18/320). Grade 2 and Grade 3 cases were reported in1.9% (6/320) and 1.6% (5/320) of patients, respectively. Median time to onset was 26.9 weeks(range: 12.3-74.3 weeks). Resolution occurred in 14 patients (77.8%) with a median time to resolutionof 7.5 weeks (range: 2.1-60.7+ weeks).

In patients treated with nivolumab monotherapy, the incidence of diarrhoea, colitis, or frequent bowelmovements was 15.4% (716/4646). The majority of cases were Grade 1 or 2 in severity reported in9.9% (462/4646) and 4.0% (186/4646) of patients respectively. Grade 3 and 4 cases were reportedin 1.4% (67/4646) and <0.1% (1/4646) of patients respectively. Median time to onset was 8.3 weeks(range: 0.1-115.6). Resolution occurred in 639 patients (90.3%) with a median time to resolution of2.9 weeks (range: 0.1-124.4+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of diarrhoea or colitis was 26.0% (682/2626). Grade 2, Grade 3, and Grade 4 cases werereported in 8.1% (212/2626), 6.4% (167/2626), and 0.2% (4/2626), of patients, respectively. Twopatients (<0.1%) had a fatal outcome. Median time to onset was 1.4 months (range: 0.0-48.9).

Resolution occurred in 618 patients (91%) with a median time to resolution of 2.9 weeks(range: 0.1-170.0+). Among patients treated with nivolumab 1 mg/kg in combination withipilimumab 3 mg/kg for melanoma, the incidence of diarrhoea or colitis was 46.7%, including Grade 2(13.6%), Grade 3 (15.8%), and Grade 4 (0.4%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of diarrhoea orcolitis was 22.5% (405/1800). Grade 2, Grade 3, and Grade 4 cases were reported in 7.2% (130/1800),3.1% (56/1800), and 0.3% (6/1800) of patients, respectively. One patient (< 0.1%) had a fataloutcome. Median time to onset was 4.4 weeks (range: 0.1-93.6). Resolution occurred in 357 patients(88.6%) with a median time to resolution of 1.6 weeks (range: 0.1-212.3+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of diarrhoea,colitis, frequent bowel movements or enteritis was 59.1% (189/320). Grade 2 and Grade 3 cases werereported in 25.6% (82/320) and 6.3% (20/320) of patients, respectively. Grade 4 were reported in 0.6%(2/320). Median time to onset was 12.9 weeks (range: 0.3-110.9 weeks). Resolution occurred in143 patients (76.1%) with a median time to resolution of 12.9 weeks (range: 0.1-139.7+ weeks).

In patients treated with nivolumab monotherapy, the incidence of liver function test abnormalities was8.0% (371/4646). The majority of cases were Grade 1 or 2 in severity reported in 4.3% (200/4646) and1.8% (82/4646) of patients respectively. Grade 3 and 4 cases were reported in 1.6% (74/4646) and0.3% (15/4646) of patients, respectively. Median time to onset was 10.6 weeks (range: 0.1-132.0).

Resolution occurred in 298 patients (81.4%) with a median time to resolution of 6.1 weeks(range: 0.1-126.4+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of liver function test abnormalities was 21.2% (556/2626). Grade 2, Grade 3, and

Grade 4 cases were reported in 5.0% (132/2626), 8.3% (218/2626), and 1.3% (34/2626) of patients,respectively. Seven patients (0.3%) had a fatal outcome. Median time to onset was 1.5 months(range: 0.0-36.6). Resolution occurred in 482 patients (87.0%) with a median time to resolution of5.9 weeks (range: 0.1-175.9+). Among patients treated with nivolumab 1 mg/kg in combination withipilimumab 3 mg/kg for melanoma, the incidence of liver function test abnormalities was 30.1%including Grade 2 (6.9%), Grade 3 (15.8%), and Grade 4 (1.8%). Among patients treated withnivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg for HCC, the incidence of liver functiontest abnormalities was 34.3% including Grade 2 (8.4%), Grade 3 (14.2%), and Grade 4 (2.7%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of liver functiontest abnormalities was 18% (322/1800). Grade 2, Grade 3 and Grade 4 cases were reported in 5.1%(92/1800), 2.6% (47/1800) and < 0.1% (1/1800) of patients, respectively. Median time to onset was7.0 weeks (range: 0.1-99.0). Resolution occurred in 258 patients (81.1%) with a median time toresolution of 7.4 weeks (range: 0.4-240.0+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of liver functiontest abnormalities was 41.6% (133/320). Grade 2, Grade 3, and Grade 4 cases were reported in 14.7%(47/320), 10.3% (33/320), and 0.6% (2/320) of patients, respectively. Median time to onset was8.3 weeks (range: 0.1-107.9 weeks). Resolution occurred in 101 patients (75.9%) with a median timeto resolution of 9.6 weeks (range: 0.1-89.3+ weeks).

In patients treated with nivolumab monotherapy, the incidence of nephritis or renal dysfunction was2.6% (121/4646). The majority of cases were Grade 1 or 2 in severity reported in 1.5% (69/4646) and0.7% (32/4646) of patients respectively. Grade 3 and 4 cases were reported in 0.4% (18/4646) and<0.1% (2/4646) of patients, respectively. Median time to onset was 12.1 weeks (range: 0.1-79.1).

Resolution occurred in 80 patients (69.0%) with a median time to resolution of 8.0 weeks(range: 0.3-79.1+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of nephritis or renal dysfunction was 5.4% (141/2626). Grade 2, Grade 3, and Grade 4cases were reported in 2.0% (52/2626), 0.8% (21/2626), and 0.4% (11/2626) of patients, respectively.

Two patients (< 0.1%) had a fatal outcome. Median time to onset was 2.6 months (range: 0.0-34.8).

Resolution occurred in 110 patients (78.0%) with a median time to resolution of 5.9 weeks(range: 0.1-172.1+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of nephritis orrenal dysfunction was 10.9% (196/1800). Grade 2, Grade 3, and Grade 4 cases were reported in3.7% (66/1800), 1.4% (25/1800), and 0.2% (3/1800) of patients, respectively. Two patients (0.1%) hada fatal outcome. Median time to onset was 6.7 weeks (range: 0.1-60.7). Resolution occurred in133 patients (67.9%) with a median time to resolution of 9.1 weeks (range: 0.1-226.0+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of nephritis,immune mediated nephritis, renal failure, acute kidney injury, blood creatinine increased or blood ureaincreased was 10.0% (32/320). Grade 2 and Grade 3 cases were reported in 3.4% (11/320), and 1.3%(4/320) of patients, respectively. Median time to onset was 14.2 weeks (range: 2.1-87.1 weeks).

Resolution occurred in 18 patients (58.1%) with a median time to resolution of 10.1 weeks(range: 0.6-90.9+ weeks).

In patients treated with nivolumab monotherapy, the incidence of thyroid disorders, includinghypothyroidism or hyperthyroidism, was 13.0% (603/4646). The majority of cases were Grade 1 or 2in severity reported in 6.6% (305/4646) and 6.2% (290/4646) of patients, respectively. Grade 3 thyroiddisorders were reported in 0.2% (8/4646) of patients. Hypophysitis (3 Grade 1, 7 Grade 2, 9 Grade 3,and 1 Grade 4), hypopituitarism (6 Grade 2 and 1 Grade 3), adrenal insufficiency (including secondaryadrenocortical insufficiency, adrenocortical insufficiency acute and blood corticotrophin decreased)(2 Grade 1, 23 Grade 2, and 11 Grade 3), diabetes mellitus (including Type 1 diabetes mellitus, anddiabetic ketoacidosis) (1 Grade 1, 3 Grade 2 and 8 Grade 3 and 2 Grade 4), were reported. Mediantime to onset of these endocrinopathies was 11.1 weeks (range: 0.1-126.7). Resolution occurred in323 patients (48.7%). Median time to resolution was 48.6 weeks (range: 0.4-204.4+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of thyroid disorders was 23.2% (608/2626). Grade 2 and Grade 3 thyroid disorders werereported in 12.7% (333/2626) and 1.0% (27/2626) of patients, respectively.

Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 1.9% (49/2626)and 1.5% (40/2626) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.6%(16/2626) and 0.5% (13/2626) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenalinsufficiency (including secondary adrenocortical insufficiency, adrenocortical insufficiency acute,blood corticotrophin decreased and immune-mediated adrenal insufficiency) occurred in 2.7%(72/2626), 1.6% (43/2626) and 0.2% (4/2626) of patients, respectively. Grade 1, Grade 2, Grade 3,and Grade 4 diabetes mellitus (including Type 1 diabetes mellitus, and diabetic ketoacidosis) occurredin < 0.1% (1/2626), 0.3% (8/2626), 0.3% (7/2626), and 0.2% (6/2626) of patients, respectively.

Median time to onset of these endocrinopathies was 2.1 months (range: 0.0-28.1). Resolution occurredin 297 patients (40.0%). Time to resolution ranged from 0.3 to 257.1+ weeks.

In patients treated with nivolumab in combination with chemotherapy, the incidence of thyroiddisorders was 12.8% (230/1800). Grade 2 and Grade 3 thyroid disorders were reported in 6.3%(114/1800) and 0.1% (2/1800) of patients, respectively. Grade 3 hypophysitis occurred in 0.1%(2/1800) of patients. Grade 2 and Grade 3 hypopituitarism occurred in 0.2% (4/1800) of patients, each.

Grade 2, Grade 3, and Grade 4 adrenal insufficiency occurred in 0.6% (11/1800), 0.2% (3/1800), and< 0.1% (1/1800) of patients, respectively. One patient (< 0.1%) had a fatal outcome due to adrenalinsufficiency. Diabetes mellitus including Type 1 diabetes mellitus and fulminant Type 1 diabetesmellitus (4 Grade 2, 2 Grade 3, and 1 Grade 4), and diabetic ketoacidosis (1 Grade 2 and 1 Grade 4)were reported. Median time to onset of these endocrinopathies was 15.3 weeks (range: 1.1-124.3).

Resolution occurred in 101 patients (40.1%). Time to resolution ranged from 0.3+ to 233.6+ weeks.

In patients treated with nivolumab in combination with cabozantinib, the incidence of thyroiddisorders was 43.1% (138/320). Grade 2 and Grade 3 thyroid disorders were reported in 23.1%(74/320) and 0.9% (3/320) of patients, respectively. Hypophysitis occurred in 0.6% (2/320) ofpatients, all Grade 2. Adrenal insufficiency (including secondary adrenocortical insufficiency)occurred in 4.7% (15/320) of patients. Grade 2 and Grade 3 adrenal insufficiency cases were reportedin 2.2% (7/320) and 1.9% (6/320) of patients, respectively. Median time to onset of theseendocrinopathies was 12.3 weeks (range: 2.0-89.7 weeks). Resolution occurred in 50 patients (35.2%).

Time to resolution ranged from 0.9 to 132.0+ weeks.

In patients treated with nivolumab monotherapy, the incidence of rash was 30.0% (1396/4646). Themajority of cases were Grade 1 in severity reported in 22.8% (1060/4646) of patients. Grade 2 and

Grade 3 cases were reported in 5.9% (274/4646) and 1.3% (62/4646) of patients respectively. Mediantime to onset was 6.7 weeks (range: 0.1-121.1). Resolution occurred in 896 patients (64.6%) with amedian time to resolution of 20.1 weeks (0.1-192.7+).

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of rash was 46.1% (1210/2626). Grade 2, Grade 3, and Grade 4 cases were reported in14.3% (375/2626), pct. 4.6% (120/2626), and 0.1% (3/2626) of patients, respectively. Median time toonset was 0.7 months (range: 0.0-33.8). Resolution occurred in 843 patients (70%) with a median timeto resolution of 12.1 weeks (range: 0.1-268.7+). Among patients treated with nivolumab 1 mg/kg incombination with ipilimumab 3 mg/kg for melanoma, the incidence of rash was 65.2%, including

Grade 2 (20.3%) and Grade 3 (7.8%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of rash was25.4% (457/1800). Grade 2 and Grade 3 cases were reported in 6.2% (111/1800) and 2.3% (42/1800)of patients, respectively. Median time to onset was 6.4 weeks (range: 0.1-97.4). Resolution occurred in320 patients (70.2%) with a median time to resolution of 12.1 weeks (range: 0.1-258.7+).

In patients treated with nivolumab in combination with cabozantinib, the incidence of rash was62.8% (201/320). Grade 2 and Grade 3 cases were reported in 23.1% (74/320) and 10.6% (34/320) ofpatients, respectively. Median time to onset was 6.14 weeks (range: 0.1-104.4 weeks). Resolutionoccurred in 137 patients (68.2%) with a median time to resolution of 18.1 weeks(range: 0.1-130.6+ weeks).

Rare cases of SJS and TEN some of them with fatal outcome have been observed (see sections 4.2and 4.4).

Infusion reactions

In patients treated with nivolumab monotherapy, the incidence of hypersensitivity/infusion reactionswas 4.0% (188/4646), including 9 Grade 3 and 3 Grade 4 cases.

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the incidence of hypersensitivity/infusion reactions was 4.5% (118/2626). Grade 1, Grade 2, Grade 3,and Grade 4 cases were reported in 1.9% (49/2626), 2.4% (62/2626), 0.2% (6/2626), and < 0.1%(1/2626) of patients, respectively. Among patients with MPM treated with nivolumab 3 mg/kg incombination with ipilimumab 1 mg/kg, the incidence of hypersensitivity/infusion reactions was 12%.

In patients treated with nivolumab in combination with chemotherapy, the incidence ofhypersensitivity/infusion reactions was 8.2% (148/1800). Grade 2, Grade 3, and Grade 4 cases werereported in 4.6% (83/1800), 1.1% (20/1800), and 0.2% (3/1800) of patients, respectively.

In patients treated with nivolumab in combination with cabozantinib, the incidence ofhypersensitivity/infusion reactions was 2.5% (8/320). All 8 patients were Grade 1 or 2 in severity.

Grade 2 cases were reported in 0.3% (1/320) of patients.

Complications of allogeneic HSCT in classical Hodgkin lymphoma

Rapid onset of GVHD has been reported with nivolumab use before and after allogeneic HSCT (seesection 4.4).

In 62 evaluated patients from two cHL studies who underwent allogeneic HSCT after discontinuingnivolumab monotherapy, Grade 3 or 4 acute GVHD was reported in 17/62 patients (27.4%).

Hyperacute GVHD, defined as acute GVHD occurring within 14 days after stem cell infusion, wasreported in four patients (6%). A steroid-requiring febrile syndrome, without an identified infectiouscause, was reported in six patients (12%) within the first 6 weeks post-transplantation. Steroids wereused in four patients and three patients responded to steroids. Hepatic veno-occlusive disease occurredin two patients, one of whom died of GVHD and multi-organ failure. Nineteen of 62 patients (30.6%)died from complications of allogeneic HSCT after nivolumab. The 62 patients had a median follow-upfrom subsequent allogeneic HSCT of 38.5 months (range: 0-68 months).

Elevated liver enzymes when nivolumab is combined with cabozantinib in RCC

In a clinical study of previously untreated patients with RCC receiving nivolumab in combination withcabozantinib, a higher incidence of Grades 3 and 4 ALT increased (10.1%) and AST increased (8.2%)were observed relative to nivolumab monotherapy in patients with advanced RCC. In patients with

Grade ≥ 2 increased ALT or AST (n=85): median time to onset was 10.1 weeks (range: 2.0 to106.6 weeks), 26% received corticosteroids for median duration of 1.4 weeks (range: 0.9 to75.3 weeks), and resolution to Grades 0-1 occurred in 91% with median time to resolutionof 2.3 weeks (range: 0.4 to 108.1+ weeks). Among the 45 patients with Grade ≥ 2 increased ALT or

AST who were rechallenged with either nivolumab (n=10) or cabozantinib (n=10) administered as asingle agent or with both (n=25), recurrence of Grade ≥ 2 increased ALT or AST was observed in3 patients receiving OPDIVO, 4 patients receiving cabozantinib, and 8 patients receiving both

OPDIVO and cabozantinib.

In patients treated with nivolumab monotherapy, the proportion of patients who experienced a shiftfrom baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.4% for anaemia (all

Grade 3), 0.7% for thrombocytopaenia, 0.7% for leucopoenia, 8.7% for lymphopaenia, 0.9% forneutropaenia, 1.7% for increased alkaline phosphatase, 2.6% for increased AST, 2.3% for increased

ALT, 0.8% for increased total bilirubin, 0.7% for increased creatinine, 2.0% for hyperglycaemia, 0.7%for hypoglycaemia, 3.8% for increased amylase, 6.9% for increased lipase, 4.7% for hyponatraemia,1.6% for hyperkalaemia, 1.3% for hypokalaemia, 1.1% for hypercalcaemia, 0.6% forhypermagnesaemia, 0.4% for hypomagnesaemia, 0.6% for hypocalcaemia, 0.6% forhypoalbuminaemia, and <0.1% for hypernatraemia.

In patients treated with nivolumab in combination with ipilimumab (with or without chemotherapy),the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratoryabnormality was as follows: 4.8% for anaemia, 1.8% for thrombocytopaenia, 2.2% for leucopoenia,6.9% for lymphopaenia, 3.3% for neutropaenia, 2.7% for increased alkaline phosphatase, 9.8% forincreased AST, 9.3% for increased ALT, 2.3% for increased total bilirubin, 1.8% for increasedcreatinine, 1.4% for hypoalbuminaemia, 7.1% for hyperglycaemia, 0.7% for hypoglycaemia, 7.8% forincreased amylase, 16.3% for increased lipase, 0.8% for hypocalcaemia, 0.2% for hypernatraemia,0.8% for hypercalcaemia, 2.0% for hyperkalaemia, 0.8% for hypermagnesaemia, 0.4% forhypomagnesaemia, 3.0% for hypokalaemia, and 8.7% for hyponatraemia.

Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg formelanoma, a higher proportion of patients experienced a worsening from baseline to Grade 3 or 4increased ALT (15.3%).

In patients treated with nivolumab in combination with chemotherapy, the proportion of patients whoexperienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows:14.7% for anaemia, 6.2% for thrombocytopaenia, 11.7% leukopaenia, 13.6% for lymphopaenia, 26.3%neutropaenia, 2.0% for increased alkaline phosphatase, 3.3% for increased AST, 2.6% for increased

ALT, 1.9% for increased bilirubin, 1.3% for increased creatinine, 4.5% for increased amylase, pct. 5.2%for increased lipase, 0.4% for hypernatraemia, 8.1% for hyponatraemia, 1.8% for hyperkalaemia, 5.1%for hypokalaemia, 0.7% for hypercalcaemia, 1.8% for hypocalcaemia, 1.5% for hypermagnesaemia,2.9% for hypomagnesaemia, 3.7% for hyperglycaemia, and 0.6% for hypoglycaemia.

In patients treated with nivolumab in combination with cabozantinib, the proportion of patients whoexperienced a worsening from baseline to a Grade 3 or 4 laboratory abnormality was as follows:3.5% for anaemia (all Grade 3), 0.3% for thrombocytopaenia, 0.3% for leucopoenia, 7.5% forlymphopaenia, 3.5% for neutropaenia, 3.2% for increased alkaline phosphatase, 8.2% for increased

AST, 10.1% for increased ALT, 1.3% for increased total bilirubin, 1.3% for increased creatinine,11.9% for increased amylase, 15.6% for increased lipase, 3.5% for hyperglycaemia, 0.8% forhypoglycaemia, 2.2% for hypocalcaemia, 0.3% for hypercalcaemia, 5.4% for hyperkalaemia, 4.2% forhypermagnesaemia, 1.9% for hypomagnesaemia 3.2% for hypokalaemia, 12.3% for hyponatraemia,and 21.2% for hypophosphataemia.

Of the 3529 patients who were treated with nivolumab monotherapy 3 mg/kg or 240 mgevery 2 weeks and evaluable for the presence of anti-product-antibodies, 328 patients (9.3%) testedpositive for treatment-emergent anti-product-antibodies with 21 patients (0.6%) testing positive forneutralising antibodies.

Co-administration with chemotherapy did not affect nivolumab immunogenicity. Of the 1407 patientswho were treated with nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combinationwith chemotherapy and evaluable for the presence of anti-product-antibodies, 7.2% tested positive fortreatment emergent anti-product-antibodies with 0.5% tested positive for neutralising antibodies.

Of the patients who were treated with nivolumab in combination with ipilimumab and evaluable forthe presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26.0% withnivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 24.9% with nivolumab 3 mg/kgevery 2 weeks and ipilimumab 1 mg/kg every 6 weeks, and 37.8% with nivolumab 1 mg/kg andipilimumab 3 mg/kg every 3 weeks. The incidence of neutralising antibodies against nivolumab was0.8% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, 1.5% with nivolumab 3 mg/kgevery 2 weeks and ipilimumab 1 mg/kg every 6 weeks, and 4.6% with nivolumab 1 mg/kg andipilimumab 3 mg/kg every 3 weeks. Of patients evaluable for the presence of anti-ipilimumabantibodies, the incidence of anti-ipilimumab antibodies ranged from 6.3 to 13.7% and neutralisingantibodies against ipilimumab ranged from 0 to 0.4%.

Of the patients who were treated with nivolumab in combination with ipilimumab and chemotherapyand evaluable for the presence of anti-nivolumab antibodies or neutralising antibodies againstnivolumab, the incidence of anti-nivolumab antibodies was 33.8% and the incidence of neutralisingantibodies was 2.6%. Of the patients who were treated with nivolumab in combination withipilimumab and chemotherapy and evaluable for the presence of anti-ipilimumab antibodies orneutralising antibodies against ipilimumab, the incidence of anti-ipilimumab antibodies was 7.5%, andthe neutralising antibodies was 1.6%.

Although the clearance of nivolumab was increased by 20% when anti-nivolumab-antibodies werepresent, there was no evidence of loss of efficacy or altered toxicity profile in the presence ofnivolumab antibodies based on the pharmacokinetic and exposure-response analyses for bothmonotherapy and combination.

The safety of nivolumab as monotherapy (3 mg/kg every 2 weeks) and in combination withipilimumab (nivolumab 1 mg/kg or 3 mg/kg in combination with ipilimumab 1 mg/kg every 3 weeksfor the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks) was evaluated in97 paediatric patients aged ≥ 1 year to < 18 years (including 53 patients 12 to < 18 years) withrecurrent or refractory solid or haematological tumours, including advanced melanoma, in clinicalstudy CA209070. The safety profile in paediatric patients was generally similar to that seen in adultstreated with nivolumab as monotherapy or in combination with ipilimumab. No new safety signalswere observed. Long-term safety data is unavailable on the use of nivolumab in adolescents 12 yearsof age and older.

The most common adverse reactions (reported in at least 20% of paediatric patients) treated withnivolumab monotherapy were fatigue (35.9%) and decreased appetite (21.9%). The majority ofadverse reactions reported for nivolumab monotherapy were Grade 1 or 2 in severity. Twenty-onepatients (33%) had one or more Grades 3 to 4 adverse reactions.

The most common adverse reactions (reported in at least 20% of paediatric patients) treated withnivolumab in combination with ipilimumab were fatigue (33.3%) and rash maculo-papular (21.2%).

The majority of adverse reactions reported for nivolumab in combination with ipilimumab were

Grade 1 or 2 in severity. Ten patients (30%) had one or more Grades 3 to 4 adverse reactions.

No new safety signals were observed in clinical study CA209908 of 151 paediatric patients withhigh-grade primary central nervous system (CNS) malignancies (see section 5.1), relative to dataavailable in adult studies across indications.

No overall differences in safety were reported between elderly (≥ 65 years) and younger patients(< 65 years). Data from SCCHN, adjuvant melanoma, and adjuvant OC or GEJC patients 75 years ofage or older are too limited to draw conclusions on this population (see section 5.1). Data from dMMRor MSI-H CRC patients 75 years of age or older are limited (see section 5.1). Data from cHL patients65 years of age or older are too limited to draw conclusions on this population (see section 5.1).

In MPM patients, there was a higher rate of serious adverse reactions and discontinuation rate due toadverse reactions in patients 75 years of age or older (68% and 35%, respectively) relative to allpatients who received nivolumab in combination with ipilimumab (54% and 28%, respectively). In

HCC patients there were higher rates of serious adverse reactions and discontinuation due to adversereactions in patients aged 75 years or older (67% and 35%, respectively) relative to all patients whoreceived nivolumab with ipilimumab (53% and 27%, respectively).

For patients treated with nivolumab in combination with cabozantinib, data from RCC patients75 years of age or older are too limited to draw conclusions on this population (see section 5.1).

Hepatic or renal impairment

In the non-squamous NSCLC study (CA209057), the safety profile in patients with baseline renal orhepatic impairment was comparable to that in the overall population. These results should beinterpreted with caution due to the small sample size within the subgroups.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose have been reported in clinical trials. In case of overdose, patients should beclosely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatmentinstituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, PD-1/PDL-1 (Programmed cell death protein 1/ death ligand 1) inhibitors. ATC code:

L01FF01.

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds tothe programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of

T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which areexpressed in antigen presenting cells and may be expressed by tumours or other cells in the tumourmicroenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumabpotentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to

PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreasedtumour growth.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results inimproved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dualblockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.

Based on modelling of dose/exposure efficacy and safety relationships, there are no clinicallysignificant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significantdifferences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in adjuvanttreatment of melanoma, advanced melanoma and advanced RCC.

Treatment of advanced melanoma

Randomised phase 3 study vs. dacarbazine (CA209066)

The safety and efficacy of nivolumab 3 mg/kg for the treatment of advanced (unresectable ormetastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209066). Thestudy included adult patients (18 years or older) with confirmed, treatment-naive, Stage III or IV

BRAF wild-type melanoma and an ECOG performance-status score of 0 or 1. Patients with activeautoimmune disease, ocular melanoma, or active brain or leptomeningeal metastases were excludedfrom the study.

A total of 418 patients were randomised to receive either nivolumab (n = 210) administeredintravenously over 60 minutes at 3 mg/kg every 2 weeks or dacarbazine (n = 208) at 1000 mg/m2every 3 weeks. Randomisation was stratified by tumour PD-L1 status and M stage (M0/M1a/M1bversus M1c). Treatment was continued as long as clinical benefit was observed or until treatment wasno longer tolerated. Treatment after disease progression was permitted for patients who had a clinicalbenefit and did not have substantial adverse events with the study drug, as determined by theinvestigator. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours(RECIST), version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks forthe first year and then every 12 weeks thereafter. The primary efficacy outcome measure was OS. Keysecondary efficacy outcome measures were investigator-assessed PFS and objective response rate(ORR).

Baseline characteristics were balanced between the two groups. The median age was 65 years(range: 18-87), 59% were men, and 99.5% were white. Most patients had ECOG performance score of0 (64%) or 1 (34%). Sixty-one percent of patients had M1c stage disease at study entry. Seventy-fourpercent of patients had cutaneous melanoma, and 11% had mucosal melanoma; 35% of patients had

PD-L1 positive melanoma (≥ 5% tumour cell membrane expression). Sixteen percent of patients hadreceived prior adjuvant therapy; the most common adjuvant treatment was interferon (9%). Fourpercent of patients had a history of brain metastasis, and 37% of patients had a baseline LDH levelgreater than ULN at study entry.

The Kaplan-Meier curves for OS are shown in Figure 1.

Figure 1: Kaplan-Meier curves of OS (CA209066)

Overall survival (months)

Number of subjects at risk

Nivolumab210 185 150 105 45 8 0

Dacarbazine208 177 123 82 22 3 0 Nivolumab (events: 50/210), median and 95% CI: N.A.

- - -- - - Dacarbazine (events: 96/208), median and 95% CI: 10.84 (9.33, 12.09)

The observed OS benefit was consistently demonstrated across subgroups of patients includingbaseline ECOG performance status, M stage, history of brain metastases, and baseline LDH level.

Survival benefit was observed regardless of whether patients had tumours that were designated PD-L1negative or PD-L1 positive (tumour membrane expression cut off of 5% or 10%).

Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumababove chemotherapy may take 2-3 months.

Efficacy results are shown in Table 11.

Table 11: Efficacy results (CA209066)nivolumab dacarbazine(n = 210) (n = 208)

Overall survival

Events 50 (23.8%) 96 (46.2%)

Hazard ratio 0.4299.79% CI (0.25, 0.73)95% CI (0.30, 0.60)p-value < 0.0001

Median (95% CI) Not reached 10.8 (9.33, 12.09)

Rate (95% CI)

At 6 months 84.1 (78.3, 88.5) 71.8 (64.9, 77.6)

At 12 months 72.9 (65.5, 78.9) 42.1 (33.0, 50.9)

Probability of survivalnivolumab dacarbazine(n = 210) (n = 208)

Progression-free survival

Events 108 (51.4%) 163 (78.4%)

Hazard ratio 0.4395% CI (0.34, 0.56)p-value < 0.0001

Median (95% CI) 5.1 (3.48, 10.81) 2.2 (2.10, 2.40)

Rate (95% CI)

At 6 months 48.0 (40.8, 54.9) 18.5 (13.1, 24.6)

At 12 months 41.8 (34.0, 49.3) NA

Objective response 84 (40.0%) 29 (13.9%)(95% CI) (33.3, 47.0) (9.5, 19.4)

Odds ratio (95% CI) 4.06 (2.52, 6.54)p-value < 0.0001

Complete response (CR) 16 (7.6%) 2 (1.0%)

Partial response (PR) 68 (32.4%) 27 (13.0%)

Stable disease (SD) 35 (16.7%) 46 (22.1%)

Median duration of response

Months (range) Not reached (0+-12.5+) 6.0 (1.1-10.0+)

Median time to response

Months (range) 2.1 (1.2-7.6) 2.1 (1.8-3.6)“+” denotes a censored observation.

Randomised phase 3 study vs. chemotherapy (CA209037)

The safety and efficacy of nivolumab 3 mg/kg for the treatment of advanced (unresectable ormetastatic) melanoma were evaluated in a phase 3, randomised, open-label study (CA209037). Thestudy included adult patients who had progressed on or after ipilimumab and if BRAF V600 mutationpositive had also progressed on or after BRAF kinase inhibitor therapy. Patients with activeautoimmune disease, ocular melanoma, active brain or leptomeningeal metastases or a known historyof prior ipilimumab-related high-grade (Grade 4 per CTCAE v4.0) adverse reactions, except forresolved nausea, fatigue, infusion reactions, or endocrinopathies, were excluded from the study.

A total of 405 patients were randomised to receive either nivolumab (n = 272) administeredintravenously over 60 minutes at 3 mg/kg every 2 weeks or chemotherapy (n = 133) which consistedof the investigator’s choice of either dacarbazine (1000 mg/m2 every 3 weeks) or carboplatin(AUC 6 every 3 weeks) and paclitaxel (175 mg/m2 every 3 weeks). Randomisation was stratified by

BRAF and tumour PD-L1 status and best response to prior ipilimumab.

The co-primary efficacy outcome measures were confirmed ORR in the first 120 patients treated withnivolumab, as measured by independent radiology review committee (IRRC) using RECIST,version 1.1, and comparison of OS of nivolumab to chemotherapy. Additional outcome measuresincluded duration and timing of response.

The median age was 60 years (range: 23-88). Sixty-four percent of patients were men and 98% werewhite. ECOG performance scores were 0 for 61% of patients and 1 for 39% of patients. The majority(75%) of patients had M1c stage disease at study entry. Seventy-three percent of patients hadcutaneous melanoma and 10% had mucosal melanoma. The number of prior systemic regimenreceived was 1 for 27% of patients, 2 for 51% of patients, and > 2 for 21% of patients. Twenty-twopercent of patients had tumours that tested BRAF mutation positive and 50% of patients had tumoursthat were considered PD-L1 positive. Sixty-four percent of patients had no prior clinical benefit(CR/PR or SD) on ipilimumab. Baseline characteristics were balanced between groups except for theproportions of patients who had a history of brain metastasis (19% and 13% in the nivolumab groupand chemotherapy group, respectively) and patients with LDH greater than ULN at baseline(51% and 35%, respectively).

At the time of this final ORR analysis, results from 120 nivolumab-treated patients and47 chemotherapy-treated patients who had a minimum of 6 months of follow-up were analysed.

Efficacy results are presented in Table 12.

Table 12: Best overall response, time and duration of response (CA209037)nivolumab chemotherapy(n = 120) (n = 47)

Confirmed objective response (IRRC) 38 (31.7%) 5 (10.6%)(95% CI) (23.5, 40.8) (3.5, 23.1)

Complete response (CR) 4 (3.3%) 0

Partial response (PR) 34 (28.3%) 5 (10.6%)

Stable disease (SD) 28 (23.3%) 16 (34.0%)

Median duration of response

Months (range) Not reached 3.6 (Not available)

Median time to response

Months (range) 2.1 (1.6-7.4) 3.5 (2.1-6.1)

Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumababove chemotherapy may take 2-3 months.

Updated analysis (24-month follow-up)

Among all randomised patients, the ORR was 27.2% (95% CI: 22.0, 32.9) in the nivolumab group and9.8% (95% CI: 5.3, 16.1) in the chemotherapy group. Median durations of response were 31.9 months(range: 1.4+-31.9) and 12.8 months (range: 1.3+-13.6+), respectively. The PFS HR for nivolumab vs.chemotherapy was 1.03 (95% CI: 0.78, 1.36). The ORR and PFS were assessed by IRRC per RECISTversion 1.1.

There was no statistically significant difference between nivolumab and chemotherapy in the final OSanalysis. The primary OS analysis was not adjusted to account for subsequent therapies, with54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS maybe confounded by dropout, imbalance of subsequent therapies and differences in baseline factors.

More patients in the nivolumab arm had poor prognostic factors (elevated LDH and brain metastases)than in the chemotherapy arm.

Efficacy by BRAF status: Objective responses to nivolumab (according to the definition of theco-primary endpoint) were observed in patients with or without BRAF mutation-positive melanoma.

The ORRs in the BRAF mutation-positive subgroup were 17% (95% CI: 8.4, 29.0) for nivolumab and11% (95% CI: 2.4, 29.2) for chemotherapy, and in the BRAF wild-type subgroup were30% (95% CI: 24.0, 36.7) and 9% (95% CI: 4.6, 16.7), respectively.

The PFS HRs for nivolumab vs. chemotherapy were 1.58 (95% CI: 0.87, 2.87) for BRAFmutation-positive patients and 0.82 (95% CI: 0.60, 1.12) for BRAF wild-type patients. The OS HRsfor nivolumab vs. chemotherapy were 1.32 (95% CI: 0.75, 2.32) for BRAF mutation-positive patientsand 0.83 (95% CI: 0.62, 1.11) for BRAF wild-type patients.

Efficacy by tumour PD-L1 expression: Objective responses to nivolumab were observed regardless oftumour PD-L1 expression. However, the role of this biomarker (tumour PD-L1 expression) has notbeen fully elucidated.

In patients with tumour PD-L1 expression ≥ 1%, ORR was 33.5% for nivolumab(n = 179; 95% CI: 26.7, 40.9) and 13.5% for chemotherapy (n = 74; 95% CI: 6.7, 23.5). In patientswith tumour PD-L1 expression <1%, ORR per IRRC was 13.0% (n = 69; 95% CI: 6.1, 23.3) and12.0% (n = 25; 95% CI: 2.5, 31.2), respectively.

The PFS HRs for nivolumab vs. chemotherapy were 0.76 (95% CI: 0.54, 1.07) in patients with tumour

PD-L1 expression ≥ 1% and 1.92 (95% CI: 1.05, 3.5) in patients with tumour PD-L1 expression < 1%.

The OS HRs for nivolumab vs. chemotherapy were 0.69 (95% CI: 0.49, 0.96) in patients with tumour

PD-L1 expression ≥ 1% and 1.52 (95% CI: 0.89, 2.57) in patients with tumour PD-L1expression < 1%.

These subgroup analyses should be interpreted with caution given the small size of the subgroups andlack of statistically significant difference in OS in the all randomised population.

Open-label phase 1 dose-escalation study (MDX1106-03)

The safety and tolerability of nivolumab were investigated in a phase 1, open-label dose-escalationstudy in various tumour types, including malignant melanoma. Of the 306 previously treated patientsenrolled in the study, 107 had melanoma and received nivolumab at a dose of 0.1 mg/kg, 0.3 mg/kg,1 mg/kg, 3 mg/kg, or 10 mg/kg for a maximum of 2 years. In this patient population, objectiveresponse was reported in 33 patients (31%) with a median duration of response of 22.9 months(95% CI: 17.0, NR). The median PFS was 3.7 months (95% CI: 1.9, 9.3). The median OSwas 17.3 months (95% CI: 12.5, 37.8), and the estimated OS rates were 42%(95% CI: 32, 51) at 3 years, 35% (95% CI: 26, 44) at 4 years, and 34% (95% CI: 25, 43) at 5 years(minimum follow-up of 45 months).

Single-arm phase 2 study (CA209172)

Study CA209172 was a single-arm, open label study of nivolumab monotherapy in patients withstage III (unresectable) or stage IV metastatic melanoma after prior treatment containing ananti-CTLA-4 monoclonal antibody. Safety was the primary endpoint and efficacy was a secondaryendpoint. Of the 1008 treated patients, 103 (10%) had ocular/uveal melanoma, 66 (7%) had an ECOGperformance score of 2, 165 (16%) had asymptomatic treated and untreated CNS metastases,13 (1.3%) had treated leptomeningeal metastases, 25 (2%) had autoimmune disease, and 84 (8%) had

Grade 3-4 immune-related AEs with prior anti-CTLA-4 therapy. No new safety signals were identifiedin all treated patients and the overall safety profile of nivolumab was similar across subgroups.

Efficacy results based on investigator-assessed response rates at week 12 are presented in Table 13below.

Table 13: Response rate at week 12 - all response evaluable patients and by subgroup(CA209172)

Total Ocular/ ECOG PS 2 CNS Autoimmune Grade 3-4

Uveal metastasis disease irAEs withmelanoma anti-CTLA-4

N 161/588 4/61 4/20 20/73 3/16 13/46(%)a (27.4) (6.6) (20.0) (27.4) (18.8) (28.3)a Responses were assessed per RECIST 1.1 for 588/1008 (58.3%) of patients who continued treatment throughweek 12 and had a follow-up scan at week 12.

Randomised phase 3 study of nivolumab in combination with ipilimumab or nivolumab asmonotherapy vs. ipilimumab as monotherapy (CA209067)

The safety and efficacy of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg or nivolumab3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable ormetastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). Thedifferences between the two nivolumab-containing groups were evaluated descriptively. The studyincluded adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were tohave ECOG performance status score of 0 or 1. Patients who had not received prior systemicanticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant orneoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patientswith active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastaseswere excluded from the study.

A total of 945 patients were randomised to receive nivolumab in combination with ipilimumab(n = 314), nivolumab monotherapy (n = 316), or ipilimumab monotherapy (n = 315). Patients in thecombination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm receivednivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg andnivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membraneexpression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) stagingsystem. Treatment was continued as long as clinical benefit was observed or until treatment was nolonger tolerated. Tumour assessments were conducted 12 weeks after randomisation then every6 weeks for the first year, and every 12 weeks thereafter. The primary outcome measures wereprogression-free survival and OS. ORR and the duration of response were also assessed.

Baseline characteristics were balanced across the three treatment groups. The median age was 61 years(range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance statusscore was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58%had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy.

Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and36% of patients had a baseline LDH level greater than ULN at study entry. Among patients withquantifiable tumour PD-L1 expression, the distribution of patients was balanced across the threetreatment groups. Tumour PD-L1 expression was determined using the

PD-L1 IHC 28-8 pharmDx assay.

At primary analysis (minimum follow-up 9 months) the median PFS was 6.9 months in the nivolumabgroup as compared with 2.9 months in the ipilimumab group (HR = 0.57, 99.5% CI: 0.43, 0.76;p < 0.0001). The median PFS was 11.5 months in the nivolumab in combination with ipilimumabgroup, as compared with 2.9 months in the ipilimumab group (HR = 0.42, 99.5% CI: 0.31, 0.57;p < 0.0001).

PFS results from descriptive analysis (with minimum follow up of 90 months) are shown in Figure 2(all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour

PD-L1 1% cut off).

Figure 2: Progression-free survival (CA209067)

Progression-free survival per investigator (months)

Number of subjects at risk

Nivolumab + ipilimumab314 175 138 126 112 103 99 93 87 84 78 76 70 66 57 33 1 -

Nivolumab316 151 120 106 97 84 78 73 69 66 62 57 54 50 44 21 0 -

Ipilimumab315 78 46 34 31 28 21 18 16 15 12 11 10 9 9 7 1 -

- - -- - - Nivolumab+ipilimumab (events: 189/314), median and 95% CI: 11.50 (8.90, 20.04).

PFS rate at 12 months and 95% CI: 49% (44, 55), PFS rate at 60 months and 95% CI: 36% (32, 42), PFS rateat 90 months and 95% CI: 33% (27, 39) Nivolumab (events: 208/316), median and 95% CI: 6.93 (5.13, 10.18).

PFS rate at 12 months and 95% CI: 42% (36, 47), PFS rate at 60 months and 95% CI: 29% (24, 35), PFS rateat 90 months and 95% CI: 27% (22, 33)

- - -- - - Ipilimumab (events: 261/315), median and 95% CI: 2.86 (2.79, 3.09).

PFS rate at 12 months and 95% CI: 18% (14, 23), PFS rate at 60 months and 95% CI: 8% (5, 12), PFS rate at90 months and 95% CI: 7% (4, 11)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.35, 0.51)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.53 (0.44, 0.64)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.79 (0.65, 0.97)

Probability of progression-free survival

Figure 3: Progression-free survival by PD-L1 expression: 5% cut off (CA209067)

PD-L1 expression < 5%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab210 113 87 78 71 64 60 56 54 52 50 49 45 43 39 22 0 -

Nivolumab208 91 73 66 60 51 49 46 42 40 38 33 31 29 27 12 0 -

Ipilimumab202 45 26 19 18 16 14 13 11 10 7 6 5 4 4 3 0 -

- - -- - - Nivolumab+ipilimumab (events: 127/210), median and 95% CI: 11.17 (7.98, 17.51) Nivolumab (events: 139/208), median and 95% CI: 5.39 (2.96, 7.13)

- - -- - - Ipilimumab (events: 171/202), median and 95% CI: 2.79 (2.76, 3.02)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.33, 0.53)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.54 (0.43, 0.68)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.77 (0.61, 0.98)

Probability of progression-free survival

PD-L1 expression ≥ 5%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab68 45 37 35 30 29 29 27 24 23 20 19 17 15 13 8 1 -

Nivolumab80 52 41 36 33 29 26 24 24 23 21 21 20 18 14 7 0 -

Ipilimumab75 21 14 10 10 9 5 5 5 5 5 5 5 5 5 4 1 -

- - -- - - Nivolumab+ipilimumab (events: 36/68), median and 95% CI: 22.11 (9.72, 82.07)

- ------- Nivolumab (events: 48/80), median and 95% CI: 22.34 (9.46, 39.13)

- - -- - - Ipilimumab (events: 60/75), median and 95% CI: 3.94 (2.79, 4.21)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.38 (0.25, 0.58)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.43 (0.29, 0.64)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.89 (0.58, 1.35)

Probability of progression-free survival

Figure 4: Progression-free survival by PD-L1 expression: 1% cut off (CA209067)

PD-L1 expression < 1%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab123 65 51 46 41 38 36 33 31 29 29 28 25 24 21 13 0 -

Nivolumab117 44 35 33 30 26 24 21 19 17 15 11 11 9 9 5 0 -

Ipilimumab113 20 12 9 9 7 5 5 3 3 3 2 1 0 0 0 0 -

- - -- - - Nivolumab+ipilimumab (events: 76/123), median and 95% CI: 11.17 (6.93, 22.18) Nivolumab (events: 85/117), median and 95% CI: 2.83 (2.76, 5.62)

- - -- - - Ipilimumab (events: 94/113), median and 95% CI: 2.73 (2.66, 2.83)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.39 (0.28, 0.53)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.59 (0.44, 0.79)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.66 (0.48, 0.90)

Probability of progression-free survival

PD-L1 expression ≥ 1%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab155 93 73 67 60 55 53 50 47 46 41 40 37 34 31 17 1 -

Nivolumab171 99 79 69 63 54 51 49 47 46 44 43 40 38 32 14 0 -

Ipilimumab164 46 28 20 19 18 14 13 13 12 9 9 9 9 9 7 1 -

- - -- - - Nivolumab+ipilimumab (events: 90/155), median and 95% CI: 16.13 (8.90, 45.08)

- ------- Nivolumab (events: 102/171), median and 95% CI: 16.20 (8.11, 27.60)

- - -- - - Ipilimumab (events: 137/164), median and 95% CI: 3.48 (2.83, 4.17)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.32, 0.55)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.45 (0.35, 0.59)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.92 (0.69, 1.22)

The final (primary) OS analysis occurred when all patients had a minimum follow-up of 28 months.

At 28 months, median OS was not reached in the nivolumab group as compared with 19.98 months inthe ipilimumab group (HR = 0.63, 98% CI: 0.48, 0.81; p-value: < 0.0001). Median OS was notreached in the nivolumab in combination with ipilimumab group as compared with the ipilimumabgroup (HR = 0.55, 98% CI: 0.42, 0.72; p-value: < 0.0001).

OS results at an additional descriptive analysis undertaken at a minimum follow-up of 90 monthsshow outcomes consistent with the original primary analysis. OS results from this follow-up analysisare shown in Figure 5 (all randomised), Figure 6 and 7 (at the tumour PD-L1 5% and 1% cut off).

The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemictherapy was received by 36.0%, 49.1%, and 66.3% of patients in the combination, nivolumabmonotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 19.1%, 34.2%, and 48.3%of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively.

Probability of progression-free survival

Figure 5: Overall survival (CA209067) - Minimum follow-up of 90 months

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab314 265 227 210 199 187 179 169 163 158 156 153 147 144 141 129 7 -

Nivolumab316 266 231 201 181 171 158 145 141 137 134 130 126 123 120 107 4 -

Ipilimumab315 253 203 163 135 113 100 94 87 81 75 68 64 63 63 57 5 -

- - -- - - Nivolumab+ipilimumab (events: 162/314), median and 95% CI: 72.08 (38.18, N.A.)

OS rate and 95% CI at 12 months: 73% (68, 78), 24 months: 64% (59, 69), 36 months: 58% (52, 63),60 months: 52% (46, 57), and 90 months: 48% (42, 53) Nivolumab (events: 182/316), median and 95% CI: 36.93 months (28.25, 58.71)

OS rate and 95% CI at 12 months: 74% (69, 79), 24 months: 59% (53, 64), 36 months: 52% (46, 57),60 months: 44% (39, 50), and 90 months: 42% (36, 47)

- - -- - - Ipilimumab (events: 235/315), median and 95% CI: 19.94 months (16.85, 24.61)

OS rate and 95% CI at 12 months: 67% (61, 72), 24 months: 45% (39, 50), 36 months: 34% (29, 39),60 months: 26% (22, 31), and 90 months: 22% (18, 27)

Nivolumab+ipilimumab vs ipilimumab - HR (95% CI): 0.53 (0.44, 0.65)

Nivolumab vs ipilimumab - HR (95% CI): 0.63 (0.52, 0.77)

Nivolumab+ipilimumab vs nivolumab - HR (95% CI): 0.84 (0.68, 1.04)

Probability of overall survival

Figure 6: Overall survival by PD-L1 expression: 5% cut off (CA209067) - Minimumfollow-up of 90 months

PD-L1 expression < 5%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab210 178 146 139 130 123 116 109 106 104 102 100 98 96 96 88 6 -

Nivolumab208 169 144 123 112 108 102 92 90 88 86 84 83 80 79 70 3 -

Ipilimumab202 158 124 99 80 69 59 57 55 50 46 41 39 38 38 33 0 -

- - -- - - Nivolumab+ipilimumab (events: 109/210), median and 95% CI: 65.94 (32.72, N.A.) Nivolumab (events: 121/208), median and 95% CI: 35.94 months (23.06, 60.91)

- - -- - - Ipilimumab (events: 157/202), median and 95% CI: 18.40 months (13.70, 22.51)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.51 (0.40, 0.66)

Nivolumab vs. ipilimumab - HR (95% CI): 0.62 (0.49, 0.79)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.83 (0.64, 1.07)

Probability of overall survival

PD-L1 expression ≥ 5%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab68 56 52 45 45 43 43 41 40 37 37 36 33 32 30 27 1 -

Nivolumab80 76 69 61 57 53 47 44 43 41 41 40 38 38 36 33 1 -

Ipilimumab75 66 60 46 40 34 32 29 25 24 22 20 19 19 19 18 4 -

- - -- - - Nivolumab+ipilimumab (events: 33/68), median and 95% CI: N.A. (39.06, N.A.)

- ------- Nivolumab (events: 41/80), median and 95% CI: 64.28 months (33.64, N.A.)

- - -- - - Ipilimumab (events: 51/75), median and 95% CI: 28.88 months (18.10, 44.16)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.61 (0.39, 0.94)

Nivolumab vs. ipilimumab - HR (95% CI): 0.61 (0.41, 0.93)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.99 (0.63, 1.57)

Probability of overall survival

Figure 7: Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimumfollow-up of 90 months

PD-L1 expression < 1%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab123 102 82 79 74 70 65 63 62 62 62 60 59 57 56 50 5 -

Nivolumab117 86 73 62 57 53 49 43 43 42 41 41 40 38 37 33 2 -

Ipilimumab113 87 71 57 44 36 33 32 31 28 27 22 22 22 22 18 0 -

- - -- - - Nivolumab+ipilimumab (events: 66/123), median and 95% CI: 61.44 (26.45, N.A.) Nivolumab (events: 76/117), median and 95% CI: 23.46 months (13.01, 36.53)

- - -- - - Ipilimumab (events: 87/113), median and 95% CI: 18.56 months (13.67, 23.20)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.55 (0.40, 0.76)

Nivolumab vs. ipilimumab - HR (95% CI): 0.77 (0.57, 1.05)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.71 (0.51, 0.99)

Probability of overall survival

PD-L1 expression ≥ 1%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab155 132 116 105 101 96 94 87 84 79 79 77 74 72 70 65 2 -

Nivolumab171 159 140 122 112 108 100 93 90 87 86 83 81 80 78 70 2 -

Ipilimumab164 137 113 88 76 67 58 54 49 46 41 39 36 35 35 33 4 -

- - -- - - Nivolumab+ipilimumab (events: 76/155), median and 95% CI: 82.30 (39.06, N.A.)

- ------- Nivolumab (events: 86/171), median and 95% CI: 85.09 months (39.00, N.A.)

- - -- - - Ipilimumab (events: 121/164), median and 95% CI: 21.49 months (16.85, 29.08)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.52 (0.39, 0.70)

Nivolumab vs. ipilimumab - HR (95% CI): 0.52 (0.39, 0.69)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 1.01 (0.74, 1.37)

Probability of overall survival

Minimum follow-up for the analysis of ORR was 90 months. Responses are summarised in Table 14.

Table 14: Objective response (CA209067)nivolumab +ipilimumab nivolumab ipilimumab(n = 314) (n = 316) (n = 315)

Objective response 183 (58%) 142 (45%) 60 (19%)(95% CI) (52.6, 63.8) (39.4, 50.6) (14.9, 23.8)

Odds ratio (vs. ipilimumab) 6.35 3.5(95% CI) (4.38, 9.22) (2.49, 5.16)

Complete response (CR) 71(23%) 59 (19%) 19 (6%)

Partial response (PR) 112 (36%) 83 (26%) 41 (13%)

Stable disease (SD) 38 (12%) 29 (9%) 69 (22%)

Duration of response

Median (range), months N.A. 90.8 19.3(69.1-N.A.) (45.7-N.A.) (8.8-47.4)

Proportion ≥ 12 months induration 68% 73% 44%

Proportion ≥ 24 months induration 58% 63% 30%

ORR (95% CI) by tumour PD-L1 expression< 5% 56% (48.7, 62.5) 43% (36, 49.8) 18% (12.8, 23.8)n = 210 n = 208 n = 202≥ 5% 72% (59.9, 82.3) 59% (47.2, 69.6) 21% (12.7, 32.3)n = 68 n = 80 n = 75< 1% 54% (44.4, 62.7) 36% (27.2, 45.3) 18% (11.2, 26.0)n = 123 n = 117 n = 113≥ 1% 65% (56.4, 72) 55% (47.2, 62.6) 20% (13.7, 26.4)n = 155 n = 171 n = 164

Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORRcompared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and

OS results at 28 months of follow-up were consistently demonstrated across subgroups of patientsincluding baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases,and baseline LDH level. This observation was maintained with the OS results with a minimumfollow-up of 90 months.

Among 131 patients who discontinued the combination due to adverse reaction after 28 months offollow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median

OS was not reached.

Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumabregardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab andipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 14)after 90 months of follow-up, with a best overall response of complete response correlating to animproved survival rate.

After 90 months of follow-up, median durations of response for patients with tumour PD-L1expression level ≥ 5% were 78.19 months (range: 18.07-N.A.) in the combination arm,77.21 months(range: 26.25-N.A.) in the nivolumab monotherapy arm and 31.28 months (range: 6.08-N.A.) in theipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached(range: 61.93-N.A.) in the combination arm, were 90.84 months (range: 50.43-N.A.) in the nivolumabmonotherapy arm and 19.25 months (range: 5.32-47.44) in the ipilimumab monotherapy arm.

No clear cut off for PD-L1 expression can reliably be established when considering the relevantendpoints of tumour response and PFS and OS. Results from exploratory multivariate analysesidentified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH,

BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome.

Efficacy by BRAF status:

After 90 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patientsrandomised to nivolumab in combination with ipilimumab had a median PFS of 16.76 months(95% CI: 8.28, 32.0) and 11.7 months (95% CI: 7.0, 19.32), while those in the nivolumabmonotherapy arm had a median PFS of 5.62 months (95% CI: 2.79, 9.46) and 8.18 months(95% CI: 5.13, 19.55), respectively. BRAF[V600] mutation-positive and BRAF wild-type patientsrandomised to ipilimumab monotherapy had a median PFS of 3.09 months (95% CI: 2.79, 5.19) and2.83 months (95% CI: 2.76, 3.06), respectively.

After 90 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patientsrandomised to nivolumab in combination with ipilimumab had an ORR of 67.0% (95% CI: 57.0, 75.9;n = 103) and 54.0% (95% CI: 47.1, 60.9; n = 211), while those in the nivolumab monotherapy arm hadan ORR of 37.87% (95% CI: 28.2, 48.1; n = 98) and 48.2% (95% CI: 41.4, 55.0; n = 218),respectively. BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumabmonotherapy had an ORR of 23.0% (95% CI: 15.2, 32.5; n = 100) and 17.2% (95% CI: 12.4, 22.9;n = 215).

After 90 months of follow-up, in BRAF [V600] mutation-positive patients median OS was not reachedin the combination arm and 45.5 months in the nivolumab monotherapy arm. Median OS for BRAF[V600] mutation-positive patients in the ipilimumab monotherapy arm was 24.6 months. In BRAFwild-type patients median OS was 39.06 months in the combination arm, 34.37 months in thenivolumab monotherapy arm and 18.5 months in the ipilimumab monotherapy arm. The OS HRs fornivolumab in combination with ipilimumab vs. nivolumab monotherapy were 0.66(95% CI: 0.44, 0.98) for BRAF[V600] mutation-positive patients and 0.95 (95% CI: 0.74, 1.22) for

BRAF wild-type patients.

Randomised phase 2 study of nivolumab in combination with ipilimumab and ipilimumab (CA209069)

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination ofnivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable ormetastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis inpatients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for theipilimumab arm (n = 37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61%(95% CI: 49, 71), respectively, for the combination (n = 73) and 53% (95% CI: 36, 68) and 44%(95% CI: 28, 60), respectively, for ipilimumab (n = 37).

Randomised phase 3 study of nivolumab vs. placebo (CA20976K)

The safety and efficacy of nivolumab 480 mg monotherapy for the treatment of patients withcompletely resected melanoma were evaluated in a phase 3, randomised, double-blind study(CA20976K). The study included patients with an ECOG performance status score of 0 or 1 who had

Stage IIB or IIC American Joint Committee on Cancer (AJCC), 8th edition, histologically confirmedmelanoma that had been completely surgically resected. Enrolment required complete resection of theprimary melanoma with negative margins and a negative sentinel lymph node biopsy within 12 weeksprior to randomisation. Patients were enrolled regardless of their tumour PD-L1 status. The studyexcluded patients with ocular/uveal or mucosal melanoma, active autoimmune disease, any conditionrequiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) orother immunosuppressive medications, as well as patients with prior therapy for melanoma exceptsurgery.

A total of 790 patients were randomised (2:1) to receive either nivolumab (n = 526) administeredintravenously over 30 minutes at 480 mg every 4 weeks or placebo (n = 264) for up to 1 year or untildisease recurrence or unacceptable toxicity. Randomisation was stratified by AJCC 8th edition

T-category (T3b vs. T4a vs. T4b). Tumour assessments were conducted every 26 weeks duringyears 1-3 and every 52 weeks from 3 years to 5 years. The primary efficacy outcome measure wasrecurrence-free survival (RFS). RFS, assessed by the investigator, was defined as the time between thedate of randomisation and the date of first recurrence (local, regional, or distant metastasis), newprimary melanoma, or death from any cause, whichever occurred first. The secondary outcomemeasures included OS and distant metastasis-free survival (DMFS).

Baseline characteristics were generally balanced between the two groups. The median age was62 years (range: 19-92), 61% were men, and 98% were white. Baseline ECOG performance statusscore was 0 (94%) or 1 (6%). Sixty percent had stage IIB and 40% had stage IIC.

At a primary pre-specified interim analysis (minimum follow-up 7.8 months) a statistically significantimprovement in RFS was demonstrated with nivolumab compared to placebo with a HR of 0.42(95% CI: 0.30, 0.59; p < 0.0001). At an updated descriptive RFS analysis (minimum follow-up of15.6 months), nivolumab continued to demonstrate an RFS improvement with a HR of 0.53(95% CI: 0.40, 0.71). OS was not mature. Results reported from the analyses with minimum follow-upof 15.6 months are summarised in Table 15 and Figure 8.

Table 15: Efficacy results (CA20976K)nivolumab placebo(n = 526) (n = 264)

Recurrence-free survival with minimum follow-up 15.6 months

Recurrence-free survival

Events 102 (19.4%) 84 (31.8%)

Hazard ratioa 0.5395% CI (0.40, 0.71)

Median (95% CI) months NR 36.14 (24.77, NR)

Rate (95% CI) at 12 monthsb 88.8 (85.6, 91.2) 81.1 (75.7, 85.4)

Rate (95% CI) at 18 monthsb 83.9 (80.3, 86.9) 70.7 (64.5, 76.1)a Based on stratified Cox proportional hazard model.b Based on Kaplan-Meier estimates.

RFS benefit was consistent across key subgroups, including disease stage, T-category, and age.

Figure 8: Recurrence-free survival (CA20976K)

Recurrence-Free Survival per Investigator (months)

Number of subjects at risk

Nivolumab526 492 474 456 422 386 291 210 122 74 40 22 13 0

Placebo264 244 224 208 193 165 120 77 44 25 12 7 4 0 Nivolumab (events 102/526), median and 95% CI: NR

- - -- - - Placebo (events: 84/264), median and 95% CI: 36.14 (24.77, NR)

Nivolumab vs. Placebo - HR (95% CI): 0.53 (0.40, 0.71)

Based on data cut-off: 21-February-2023, minimum follow-up of 15.6 months

Tumour PD-L1 expression data were available for 302/790 (38.2%) randomised patients (36.3% and42.0% in the nivolumab and placebo arms, respectively), as PD-L1 expression was not a stratificationfactor for randomisation. The exploratory RFS analyses by PD-L1 expression showed a HR fornivolumab vs placebo of 0.43 (95% CI: 0.22, 0.84) in patients (N=167) with PD- L1 expression ≥ 1%,0.82 (95% CI: 0.44, 1.54) in patients (N=135) with PD-L1 expression < 1%, and 0.50 (95% CI: 0.34,0.73) in patients (N=488) with indeterminate/not reported/not evaluable PD-L1 expression.

Randomised phase 3 study of nivolumab vs ipilimumab 10 mg/kg (CA209238)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients withcompletely resected melanoma were evaluated in a phase 3, randomised, double-blind study(CA209238). The study included adult patients, who had an ECOG performance status score of 0 or 1,with Stage IIIB/C or Stage IV American Joint Committee on Cancer (AJCC), 7th edition, histologicallyconfirmed melanoma that is completely surgically resected. Per the AJCC 8th edition, this correspondsto patients with lymph node involvement or metastases. Patients were enrolled regardless of theirtumour PD-L1 status. Patients with prior autoimmune disease, and any condition requiring systemictreatment with either corticosteroids (≥ 10 mg daily prednisone or equivalent) or otherimmunosuppressive medications, as well as patients with prior therapy for melanoma (except patientswith surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervoussystem, and prior adjuvant interferon completed ≥ 6 months prior to randomisation) prior therapy with,anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody (including ipilimumab orany other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways), wereexcluded from the study.

Probability of Recurrence-Free Survival

A total of 906 patients were randomised to receive either nivolumab 3 mg/kg (n = 453) administeredevery 2 weeks or ipilimumab 10 mg/kg (n = 453) administered every 3 weeks for 4 doses then every12 weeks beginning at week 24 for up to 1 year. Randomisation was stratified by tumour PD-L1expression (≥ 5% vs. < 5%/indeterminate), and stage of disease per the AJCC staging system. Tumourassessments were conducted every 12 weeks for the first 2 years then every 6 months thereafter. Theprimary endpoint was recurrence-free survival (RFS). RFS, assessed by investigator, was defined asthe time between the date of randomisation and the date of first recurrence (local, regional, or distantmetastasis), new primary melanoma, or death due to any cause, whichever occurred first.

Baseline characteristics were generally balanced between the two groups. The median age was55 years (range: 18-86), 58% were men, and 95% were white. Baseline ECOG performance statusscore was 0 (90%) or 1 (10%). The majority of patients had AJCC Stage III disease (81%), and 19%had Stage IV disease. Forty-eight percent of patients had macroscopic lymph nodes and 32% hadtumour ulceration. Forty-two percent of patients were BRAF V600 mutation positive while 45% were

BRAF wild type and 13% BRAF were status unknown. For tumour PD-L1 expression, 34% ofpatients had PD-L1 expression ≥ 5% and 62% had < 5% as determined by clinical trial assay. Amongpatients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced acrossthe treatment groups. Tumour PD-L1 expression was determined using the

PD-L1 IHC 28-8 pharmDx assay.

At a primary pre-specified interim analysis (minimum follow-up 18 months) a statistically significantimprovement in RFS with nivolumab compared to ipilimumab with HR of 0.65 (97.56% CI: 0.51,0.83; stratified log-rank p<0.0001) was demonstrated. At an updated descriptive RFS analysis, withminimum follow-up of 24 months RFS improvement was confirmed with HR of 0.66 (95% Cl: 0.54,0.81; p<0.0001) and OS was not mature. Efficacy results with minimum follow-up of 36 months (RFSpre-specified final analysis) and 48 months (OS pre-specified final analysis) are shown in Table 16and Figure 9 and 10 (all randomised population).

Table 16: Efficacy results (CA209238)nivolumab ipilimumab 10 mg/kg(n = 453) (n = 453)

Final pre-specified analysis

Recurrence-free survival with minimum follow-up 36 months

Events 188 (41.5%) 239 (52.8%)

Hazard ratioa 0.6895% CI (0.56, 0.82)p-value p<0.0001

Median (95% CI) months NR (38.67, NR) 24.87 (16.62, 35.12)

Recurrence-free survival with minimum follow-up 48 months

Events 212 (46.8%) 253 (55.8%)

Hazard ratioa 0.7195% CI (0.60, 0.86)

Median (95% CI) months 52.37 (42.51, NR) 24.08 (16.56, 35.09)

Rate (95% CI) at 12 months 70.4 (65.9, 74.4) 60.0 (55.2, 64.5)

Rate (95% CI) at 18 months 65.8 (61.2, 70.0) 53.0 (48.1, 57.6)

Rate (95% CI) at 24 months 62.6 (57.9, 67.0) 50.2 (45.3, 54.8)

Rate (95% CI) at 36 months 57.6 (52.8, 62.1) 44.4 (39.6, 49.1)

Rate (95% CI) at 48 months 51.7 (46.8, 56.3) 41.2 (36.4, 45.9)nivolumab ipilimumab 10 mg/kg(n = 453) (n = 453)

Final pre-specified analysis

Overall survival with minimum follow-up 48 months

Events 100 (22.1%) 111 (24.5%)

Hazard ratioa 0.8795.03% CI (0.66, 1.14)p-value 0.3148

Median (95% CI) months Not Reached Not Reached

Rate (95% CI) at 12 months 96.2 (93.9, 97.6) 95.3 (92.8, 96.9)

Rate (95% CI) at 18 months 91.9 (88.9, 94.1) 91.8 (88.8, 94.0)

Rate (95% CI) at 24 months 88.0 (84.6, 90.7) 87.8 (84.4, 90.6)

Rate (95% CI) at 36 months 81.7 (77.8, 85.1) 81.6 (77.6, 85.0)

Rate (95% CI) at 48 months 77.9 (73.7, 81.5) 76.6 (72.2, 80.3)a Derived from a stratified proportional hazards model.

With a minimum follow-up of 36 months, the trial demonstrated a statistically significantimprovement in RFS for patients randomised to the nivolumab arm compared with the ipilimumab10 mg/kg arm. RFS benefit was consistently demonstrated across subgroups, including tumour

PD-L1 expression, BRAF status, and stage of disease. With a minimum follow up of 48 months,shown in Figure 9, the trial continued to demonstrate improvement in RFS in the nivolumab armcompared with the ipilimumab arm. RFS benefit was sustained across all subgroups.

Figure 9: Recurrence-free survival (CA209238)

Recurrence-free survival (months)

Number of subjects at risk

Nivolumab453 395 354 332 311 293 283 271 262 250 245 240 233 224 218 206 147 37 11 0

Ipilimumab453 366 316 273 253 234 220 208 201 191 185 177 171 168 163 154 113 32 10 0

- - -- - - Nivolumab  Ipilimumab

Probability of recurrence-free survival

Figure 10: Overall survival (CA209238)

Overall survival (months)

Number of subjects at risk

Nivolumab453 450 447 438 427 416 405 388 383 373 366 359 350 341 337 332 324 237 45 1 0

Ipilimumab453 447 442 430 416 407 395 382 373 363 350 345 340 333 322 316 315 218 40 0 0

- - -- - - Nivolumab  Ipilimumab

With a minimum follow-up of 48 months, shown in Figure 10, median OS was not reached in eithergroup (HR = 0.87, 95.03% CI: 0.66, 1.14; p-value: 0.3148). The overall survival data are confoundedby the effects of effective subsequent anti-cancer therapies. Subsequent systemic therapy was receivedby 33% and 42% of patients in the nivolumab and ipilimumab arms, respectively. Subsequentimmunotherapy (including anti-PD1 therapy, anti-CTLA-4 antibody, or other immunotherapy) wasreceived by 23% and 34% of patients in the nivolumab and ipilimumab arms, respectively.

Quality of life (QoL) with nivolumab remained stable and close to baseline values during treatment, asassessed by valid and reliable scales like the European Organisation for Research and Treatment of

Cancer (EORTC) QLQ-C30 and the EQ-5D utility index and visual analog scale (VAS).

Neoadjuvant treatment of NSCLC

Randomised, open-label, phase 3 study of nivolumab in combination with platinum-basedchemotherapy vs. platinum-based chemotherapy (CA209816)

The safety and efficacy of nivolumab in combination with platinum-based chemotherapy for 3 cycleswere evaluated in a phase 3, randomised, open-label study (CA209816). The study included patientswith ECOG performance status 0 or 1, measurable disease (per RECIST version 1.1), and whose

Probability of overall survivaltumours were resectable, histologically confirmed Stage IB (≥ 4 cm), II, or IIIA NSCLC (per the7th edition AJCC/Union for International Cancer Control (UICC) staging criteria).

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of a patient population with stage II-IIIA disease according tothe 7th edition AJCC/UICC staging criteria: any patient with a tumour size ≥5 cm; any patient with N1or N2 disease (regardless of primary tumour size); patients with multiple tumour nodules in either thesame lobe or different ipsilateral lobes; patients with tumours that are invasive of thoracic structures(directly invade visceral pleura, parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinalpleura, parietal pericardium, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve,oesophagus, vertebral body, carina); or tumours that involve the main bronchus; or tumours that areassociated with atelectasis or obstructive pneumonitis that extends to the hilar region or involves theentire lung.

The study did not include patients who had N2 status with tumours also invading the mediastinum,heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, or withseparate tumour nodule(s) in a different ipsilateral lobe.

Patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations(testing for EGFR mutations or ALK translocations was not mandatory at study entry), Grade 2 orgreater peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemicimmunosuppression were excluded from the study. Randomisation was stratified by tumour PD-L1expression level (≥ 1% vs. < 1% or non-quantifiable), disease stage (IB/II vs. IIIA), and gender (malevs. female). Patients were enrolled regardless of their tumour PD-L1 status. Tumour PD-L1 expressionwas determined using the PD-L1 IHC 28-8 pharmDx assay.

A total of 358 patients were randomised to receive either nivolumab in combination withplatinum-based chemotherapy (n = 179) or platinum-based chemotherapy (n = 179). Patients in thenivolumab in combination with chemotherapy arm received nivolumab 360 mg administeredintravenously over 30 minutes in combination with platinum-based chemotherapy every 3 weeks forup to 3 cycles. Patients in the chemotherapy arm received platinum-based chemotherapy administeredevery 3 weeks for up to 3 cycles. Platinum-based chemotherapy consisted of investigator’s choice ofpaclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or AUC 6 (any histology); pemetrexed500 mg/m2 and cisplatin 75 mg/m2 (non-squamous histology); or gemcitabine 1000 mg/m2 or1250 mg/m2 and cisplatin 75 mg/m2 (squamous histology). In the chemotherapy arm, two additionaltreatment regimen options included vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; ordocetaxel 60 mg/m2 or 75 mg/m2 and cisplatin 75 mg/m2 (any histology).

Tumour assessments were performed at baseline, within 14 days of surgery, every 12 weeks aftersurgery for 2 years, then every 6 months for 3 years, and every year for 5 years until diseaserecurrence or progression. The primary efficacy outcome measures were event-free survival (EFS)based on BICR assessment and pathological complete response rate (pCR) by blinded-independentpathology review (BIPR). OS was a key secondary efficacy outcome measure and exploratoryendpoints included feasibility of surgery.

Baseline characteristics in the ITT population were generally balanced across treatment groups. Themedian age was 65 years (range: 34-84) with 51% of patients ≥ 65 years and 7% of patients≥ 75 years; 50% of patients were Asian, 47% were white, and 71% were male. Baseline ECOGperformance status was 0 (67%) or 1 (33%); 50% of patients with PD-L1 ≥ 1% and 43% with

PD-L1 < 1%; 5% had Stage IB, 17% had Stage IIA, 13% had Stage IIB, and 64% had Stage IIIAdisease; 51% had squamous and 49% had non-squamous histology; and 89% were former/currentsmokers. Definitive surgery was performed on 83% of the patients in the nivolumab in combinationwith chemotherapy arm and on 75% of the patients in the chemotherapy arm. Adjuvant systemictreatment was received by 14.8% of patients in the nivolumab in combination with chemotherapy armand by 25% of patients in the chemotherapy arm.

At the final pCR analysis and pre-specified interim EFS analysis (minimum follow-up 21 months), inall randomised patients, a statistically significant improvement was demonstrated in pCR and EFS forpatients randomised to nivolumab in combination with chemotherapy as compared to chemotherapyalone. The pCR response rate was 24% in the nivolumab in combination with chemotherapy arm and2.2% in the chemotherapy arm (difference of pCR 21.6, 99% CI: 13.0, 30.3; odds ratio of pCR 13.9,99% CI: 3.49, 55.75; stratified p-value < 0.0001). Median EFS was 31.6 months in the nivolumab incombination with chemotherapy arm and 20.8 months in the chemotherapy arm (HR = 0.63,97.38% CI: 0.43, 0.91; stratified log-rank p-value 0.0052). The HR for OS was0.57 (99.67% CI: 0.30, 1.07) for nivolumab in combination with chemotherapy vs. chemotherapy.

Exploratory subgroup analysis by tumour PD-L1 expression and disease stage

The key efficacy results for the subgroup of patients with tumour PD-L1 expression ≥ 1% and diseasestage II-IIIA from an exploratory analysis with a minimum follow-up of 32.9 months are summarizedin Table 17.

Table 17: Efficacy results in patients with tumour PD-L1 ≥ 1% and stage II-IIIA disease*(CA209816)nivolumab + chemotherapy chemotherapy(n = 81) (n = 86)

Event-free survival per BICR

Events 22 (27.2%) 39 (45.3%)

Hazard ratioa 0.49(95% CI) (0.29, 0.83)

Median (months)b NR 26.71(95% CI) (44.42, NR) (13.40, NR)

Pathologic complete response per BIPR

Responses 26 (32.1%) 2 (2.3%)95% CIc (22.2, 43.4) (0.3, 8.1)

Difference of pCR (95% CI)d 29.8% (19.0, 40.7)a Based on an unstratified Cox proportional hazards model.b Kaplan-Meier estimate.c Based on Clopper and Pearson method.d Two-sided 95% confidence interval for unweighted difference was calculated using Newcombe method.

* 7th edition AJCC/UICC staging criteria.

Minimum follow-up for EFS was 32.9 months, data cut-off: 06-Sep-2022pCR data cut-off: 28-Jul-2020

The Kaplan-Meier curves for EFS for the subgroup of patients with tumour PD-L1 expression ≥ 1%and stage II-IIIA disease, with a minimum follow-up of 32.9 months, are shown in Figure 11.

Figure 11: Kaplan-Meier curves of EFS in patients with tumour PD-L1 ≥ 1% andstage II-IIIA disease (CA209816)

Event-Free Survival per BICR (Months)

Number of Subjects at Risk

Nivolumab + chemotherapy81 69 62 59 58 55 53 51 51 50 47 37 32 21 10 5 1 1 0

Chemotherapy86 71 60 52 44 40 38 36 34 31 30 23 18 14 7 6 1 1 0 Nivolumab + chemotherapy (events: 22/81), median and 95% CI: NR (44.42, NR)

- - -- - - Chemotherapy (events: 39/86), median and 95% CI: 26.71 (13.40, NR)

Based on data cut-off: 06-Sep-2022, minimum follow-up of 32.9 months

At the time of the updated EFS analysis, an interim analysis for OS was performed (minimum follow-up of 32.9 months). The exploratory, descriptive HR for OS in patients with tumour PD-L1 expression≥ 1% and stage II-IIIA disease was 0.43 (95% CI: 0.22, 0.83) for nivolumab in combination withchemotherapy vs. chemotherapy. The Kaplan-Meier curves for OS for the subgroup of patients withtumour PD-L1 expression ≥ 1% and stage II-IIIA disease, with a minimum follow-up of 32.9 months,are shown in Figure 12.

Probability of Event-Free Survival per BICR

Figure 12: Kaplan-Meier curves of OS in patients with tumour PD-L1 ≥ 1% andstage II-IIIA disease (CA209816)

Overall Survival (Months)

Number of Subjects at Risk

Nivolumab + chemotherapy81 80 76 76 74 73 71 69 69 69 68 67 59 50 33 22 11 6 3 1 0

Chemotherapy86 84 80 79 77 74 67 61 60 57 56 55 50 41 27 20 10 5 0 0 0 Nivolumab + chemotherapy (events: 13/81), median and 95% CI: NR

- - -- - - Chemotherapy (events: 29/86), median and 95% CI: NR

Based on data cut-off: 06-Sep-2022, minimum follow-up of 32.9 months

Neoadjuvant and adjuvant treatment of NSCLC

Randomised, double-blind, phase 3 study of neoadjuvant nivolumab in combination with platinum-based chemotherapy vs. platinum-based chemotherapy and adjuvant nivolumab monotherapy vs.placebo (CA20977T)

The safety and efficacy of nivolumab in combination with platinum-based chemotherapy for 4 cycles,followed by nivolumab monotherapy, were evaluated in a randomised, double-blind study(CA20977T). The study included patients with ECOG performance status 0 or 1 whose tumours wereresectable, suspected or histologically confirmed Stage IIA (> 4 cm) to IIIB (T3-T4 N2) NSCLC (perthe 8th edition American Joint Committee on Cancer (AJCC) Staging Manual). Patients were enrolledregardless of their tumour PD-L1 status.

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of a patient population with stage IIA-IIIB disease accordingto the 8th edition AJCC/UICC staging criteria: any patient with a tumour size > 4 cm; any patient with

N1 or N2 disease (regardless of primary tumour size); patients with multiple tumour nodules in eitherthe same lobe or different ipsilateral lobes; patients with tumours that are invasive of thoracic

Probability of Overall Survivalstructures (directly invade visceral pleura, parietal pleura, chest wall, diaphragm, phrenic nerve,mediastinal pleura, parietal pericardium, mediastinum, heart, great vessels, trachea, recurrent laryngealnerve, oesophagus, vertebral body, carina); or tumours that involve the main bronchus; or tumours thatare associated with atelectasis or obstructive pneumonitis that extends to the hilar region or involvesthe entire lung.

Patients with unresectable or metastatic NSCLC, EGFR mutations or known ALK translocations(testing for ALK translocations was not mandatory at study entry), brain metastasis, Grade 2 or greaterperipheral neuropathy, interstitial lung disease or active, non-infectious pneumonitis (symptomaticand/or requiring treatment), active autoimmune disease, or medical conditions requiring systemicimmunosuppression were excluded from the study.

A total of 461 patients were randomised to receive either nivolumab in combination with platinum-based chemotherapy followed by nivolumab monotherapy (n=229) or platinum-based chemotherapyfollowed by placebo (n=232). In the neoadjuvant phase, patients received either nivolumab 360 mgadministered intravenously over 30 minutes and platinum-doublet chemotherapy administered every3 weeks, or placebo and platinum-doublet chemotherapy administered every 3 weeks until diseaseprogression or unacceptable toxicity, for up to 4 cycles. Patients in both treatment arms could receivepost-operative radiation therapy (PORT) as standard of care. In the adjuvant phase, within 90 daysafter the surgery patients received either nivolumab 480 mg administered intravenously over30 minutes every 4 weeks, or placebo administered every 4 weeks for until disease progression,recurrence, or unacceptable toxicity, for up to 13 cycles. Platinum-based chemotherapy consisted ofpaclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or AUC 6 (any histology); pemetrexed500 mg/m2, and cisplatin 75 mg/m2 or carboplatin AUC 5 or AUC 6 (non-squamous histology); orcisplatin 75 mg/m2 and docetaxel 75 mg/m2 (squamous histology).

Stratification factors for randomisation were tumour PD-L1 expression level (≥ 1% versus < 1%versus indeterminate/not evaluable), disease stage (Stage II versus Stage III), and tumour histology(squamous versus nonsquamous). Tumour PD-L1 expression levels were assessed using the PD-L1

IHC 28-8 pharmDx test. Tumour assessments were performed at baseline, within 14 days after the lastdose of neoadjuvant treatment and before surgery, within 7 days prior to the start of adjuvant treatmentafter surgery, every 12 weeks after the first dose of adjuvant treatment for 2 years, then every24 weeks for up to 5 years until disease recurrence or progression was confirmed by BICR.

Among the 442 patients in CA20977T, 256 (58%) had tumour PD-L1 expression ≥1% based on the

PD-L1 IHC 28-8 pharmDx test. The median age was 66 years (range: 35 to 86) with 55% of patients≥ 65 years and 7% of patients ≥ 75 years, 69% were White, 28% were Asian, 2% were Black, and75% were male. Baseline ECOG performance status was 0 (59%) or 1 (41%); 36% had stage II and63% had stage III disease; 24% were N1 and 39% were N2; 25% were single-station and 14% weremultistation; 61% had tumours with squamous histology and 39% had tumours with non-squamoushistology; and 91% were former/current smokers.

Seventy-eight percent of patients in the neoadjuvant nivolumab in combination with platinum-doubletchemotherapy followed by adjuvant nivolumab arm had definitive surgery compared to 77% ofpatients in the neoadjuvant placebo and platinum-doublet chemotherapy followed by placebo arm.

Approximately 5% of patients in each treatment arm received PORT.

The primary efficacy outcome measure was event-free survival (EFS) based on BICR assessment.

Additional efficacy outcome measures included overall survival (OS), pathologic complete response(pCR) and major pathologic response as evaluated by blinded independent pathology review (BIPR).

In a pre-specified interim analysis in all randomised patients with a median follow-up of 25.4 months(range: 15.7-44.2 months), the study demonstrated statistically significant improvement of EFS.

Median EFS was not reached (95% CI: 28.94, NE) in the nivolumab in combination withchemotherapy/nivolumab arm and 18.43 months (95% CI: 13.63, 28.06) in the placebo withchemotherapy/placebo arm (HR = 0.58, 97.36% CI: 0.42, 0.81; stratified log-rank p-value 0.00025). Ina pre-specified interim analysis in all randomised patients with a median follow-up of 41 months(range: 31.3-59.8 months), median OS was not reached in both the nivolumab in combination withchemotherapy/nivolumab arm and in the placebo with chemotherapy/placebo arm (HR = 0.85, 97.63%

CI: 0.58, 1.25).

Exploratory subgroup analysis by tumour PD-L1 expression

EFS for the subgroup of patients with tumour PD-L1 expression ≥ 1%, with a median follow-up of41 months (range: 31.3-59.8 months), are presented in Table 18 and Figure 13.

Table 18: Efficacy results in patients with tumour PD-L1 ≥ 1% (CA20977T)nivolumab with chemotherapy/ placebo with chemotherapy/nivolumab placebo(n=128) (n=128)

Event-free survival (EFS) per BICR

Events (%) 47 (37%) 70 (55%)

Median (months)a 46.55 15.08(95% CI) (35.81, NE) (9.33, 31.41)

Hazard Ratiob 0.53(95% CI) (0.36, 0.76)

NE = non-estimable

Minimum follow-up for EFS was 31.3 months; data cut-off: 11-Nov-2024.a Kaplan-Meier estimate.b Based on an unstratified Cox proportional hazard model.

Figure 13: Kaplan-Meier curves of EFS in patients with tumour PD-L1 ≥1% (CA20977T)

Event Free Survival per BICR (Months)

Number of Subjects at Risk

Nivolumab + chemotherapy/Nivolumab128 119 95 89 83 80 78 75 73 70 61 55 44 35 17 11 2 1 1 1 0

Placebo + chemotherapy/Placebo128 110 87 68 57 54 46 44 42 42 40 36 23 20 9 8 2 1 0 0 0Nivolumab + chemotherapy/Nivolumab (events: 47/128), median and 95% CI:46.55 (35.81, NE)

- - -- - -Placebo + Chemotherapy/Placebo (events: 70/128), median and 95% CI: 15.08 (9.33, 31.41)

Based on data cut-off 11-Nov-2024, minimum follow-up of 31.3 months

Probability of Event Free Survival per BICR

At the time of the updated EFS analysis, an interim analysis for OS was performed (minimum follow-up of 31.3 months). The exploratory, descriptive HR for OS in patients with tumour PD-L1 expression≥ 1% was 0.61 (95% CI: 0.39, 0.97) for the nivolumab in combination with chemotherapy/nivolumabarm vs. the placebo with chemotherapy/placebo arm. The Kaplan-Meier curves for OS for thesubgroup of patients with tumour PD-L1 expression ≥ 1% are shown in Figure 14.

Figure 14: Kaplan-Meier curves of OS in patients with tumour PD-L1 ≥ 1% (CA20977T)

Overall Survival (Months)

Number of Subjects at Risk

Nivolumab + chemotherapy/Nivolumab128 123 114 108 103 99 96 94 92 90 90 80 67 55 42 26 15 4 2 1 0

Placebo + chemotherapy/Placebo128 126 116 106 101 96 88 86 77 77 73 65 54 36 25 17 10 5 4 0 0Nivolumab + chemotherapy/Nivolumab (events: 31/128), median and 95% CI: NR

- - -- - -Placebo + Chemotherapy/Placebo (events: 46/128), median and 95% CI: NR (38.08, NE)

Based on data cut-off 11-Nov-2024, minimum follow-up of 31.3 months

First-line treatment of NSCLC

Randomised phase 3 study of nivolumab in combination with ipilimumab and 2 cycles ofplatinum-based chemotherapy vs. 4 cycles of platinum-based chemotherapy (CA2099LA)

The safety and efficacy of nivolumab 360 mg every 3 weeks in combination with ipilimumab 1 mg/kgevery 6 weeks and 2 cycles of platinum-based chemotherapy were evaluated in a phase 3, randomised,open-label study (CA2099LA). The study included patients (18 years or older) with histologicallyconfirmed non-squamous or squamous Stage IV or recurrent NSCLC (per the 7th International

Association for the Study of Lung Cancer classification), ECOG performance status 0 or 1, and noprior anticancer therapy (including EGFR and ALK inhibitors). Patients were enrolled regardless oftheir tumour PD-L1 status.

Patients with sensitising EGFR mutations or ALK translocations, active (untreated) brain metastases,carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemicimmunosuppression were excluded from the study. Patients with treated brain metastases were eligibleif neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids,or on a stable or decreasing dose of < 10 mg daily prednisone equivalents. Randomisation wasstratified by histology (squamous vs non-squamous), tumour PD-L1 expression level (≥ 1% vs < 1%),and gender (male vs female).

Probability of Overall Survival

A total of 719 patients were randomised to receive either nivolumab in combination with ipilimumaband platinum-based chemotherapy (n = 361) or platinum-based chemotherapy (n = 358). Patients inthe nivolumab in combination with ipilimumab and platinum-based chemotherapy arm receivednivolumab 360 mg administered intravenously over 30 minutes every 3 weeks in combination withipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks and platinum-basedchemotherapy administered every 3 weeks for 2 cycles. Patients in the chemotherapy arm receivedplatinum-based chemotherapy administered every 3 weeks for 4 cycles; non-squamous patients couldreceive optional pemetrexed maintenance therapy.

Platinum-based chemotherapy consisted of carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2; orcisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6)and paclitaxel 200 mg/m2 for squamous NSCLC.

Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

Treatment could continue beyond disease progression if the patient was clinically stable and wasconsidered to be deriving clinical benefit by the investigator. Patients who discontinued combinationtherapy because of an adverse event attributed to ipilimumab were permitted to continue nivolumabmonotherapy. Tumour assessments were performed every 6 weeks after first dose of study treatmentfor the first 12 months, then every 12 weeks until disease progression or study treatment wasdiscontinued.

CA2099LA baseline characteristics were generally balanced across all treatment groups. The medianage was 65 years (range: 26-86) with 51% ≥ 65 years of age and 10% ≥ 75 years of age. The majorityof patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or1 (68%), 57% of patients with PD-L1 ≥ 1% and 37% with PD-L1 < 1%, 31% had squamous and 69%had non-squamous histology, 17% had brain metastases, and 86% were former/current smokers. Nopatients received prior immunotherapy.

CA2099LA primary efficacy outcome measure was OS. Additional efficacy endpoints were PFS,

ORR, and duration of response as assessed by BICR.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR for patientsrandomised to nivolumab in combination with ipilimumab and platinum-based chemotherapy ascompared to platinum-based chemotherapy alone at the prespecified interim analysis when 351 eventswere observed (87% of the planned number of events for final analysis). Minimum follow-up for OSwas 8.1 months.

Efficacy results are shown in Figure 15 (updated OS analysis with a minimum follow-up of12.7 months) and Table 19 (primary analysis with a minimum follow-up of 8.1 months).

An updated efficacy analysis was performed when all patients had a minimum follow-up of12.7 months (see Figure 15). At the time of this analysis, the hazard ratio for OS was 0.66 (95% CI:0.55, 0.80) and the hazard ratio for PFS was 0.68 (95% CI: 0.57, 0.82).

Figure 15: Kaplan-Meier plot of OS (CA2099LA)

Overall Survival (Months)

Number of subjects at risk

Nivolumab + ipilimumab + chemotherapy361 326 292 250 227 153 86 33 10 1 0

Chemotherapy358 319 260 208 166 116 67 26 11 0 0 Nivolumab + ipilimumab + chemotherapy (events: 190/361), median and 95% CI: 15.64(13.93, 19.98)

- - -- - - Chemotherapy (events: 242/358), median and 95% CI: 10.91 (9.46, 12.55)

Table 19: Efficacy results (CA2099LA)nivolumab + ipilimumab +chemotherapy chemotherapy(n = 361) (n = 358)

Overall survival

Events 156 (43.2%) 195 (54.5%)

Hazard ratio 0.69(96.71% CI)a (0.55, 0.87)

Stratified log-rank p-valueb 0.0006

Median (months) 14.1 10.7(95% CI) (13.24, 16.16) (9.46, 12.45)

Rate (95% CI) at 6 months 80.9 (76.4,84.6) 72.3 (67.4,76.7)

Probability of Survivalnivolumab + ipilimumab +chemotherapy chemotherapy(n = 361) (n = 358)

Progression-free survival

Events 232 (64.3%) 249 (69.6%)

Hazard ratio 0.70(97.48% CI)a (0.57, 0.86)

Stratified log-rank p-valuec 0.0001

Median (months)d 6.83 4.96(95% CI) (5.55, 7.66) (4.27, 5.55)

Rate (95% CI) at 6 months 51.7 (46.2, 56.8) 35.9 (30.5, 41.3)

Overall response ratee 136 (37.7%) 90 (25.1%)(95% CI) (32.7, 42.9) (20.7, 30.0)

Stratified CMH test p-valuef 0.0003

Complete response (CR) 7 (1.9%) 3 (0.8%)

Partial response (PR) 129 (35.7%) 87 (24.3%)

Duration of response

Median (months) 10.02 5.09(95% CI)d (8.21, 13.01) (4.34, 7.00)% with duration ≥ 6 monthsg 74 41a Based on a stratified Cox proportional hazard model.b p-value is compared with the allocated alpha of 0.0329 for this interim analysis.c p-value is compared with the allocated alpha of 0.0252 for this interim analysis.d Kaplan-Meier estimate.e Proportion with complete or partial response; CI based on the Clopper and Pearson Method.f p-value is compared with the allocated alpha of 0.025 for this interim analysis.g Based on Kaplan-Meier estimates of duration of response.

CMH = Cochran-Mantel-Haenszel

Subsequent systemic therapy was received by 28.8% and 41.1% of patients in the combination andchemotherapy arms, respectively. Subsequent immunotherapy (including anti-PD-1, anti-PD-L1, andanti-CTLA4) was received by 3.9% and 27.9% of patients in the combination and chemotherapy arms,respectively.

In study CA2099LA, subgroup descriptive analysis relative to chemotherapy, OS benefit was shownin patients treated with nivolumab in combination with ipilimumab and chemotherapy with squamoushistology (HR [95% CI] 0.65 [0.46, 0.93], n = 227) and in patients with non-squamous histology (HR[95% CI] 0.72 [0.55, 0.93], n = 492).

Table 20 summarises efficacy results of OS, PFS, and ORR by tumour PD-L1 expression inpre-specified subgroup analyses.

Table 20: Efficacy results by tumour PD-L1 expression (CA2099LA)nivolumab nivolumab nivolumab nivolumab+ + + +ipilimumab chemo- ipilimumab chemo- ipilimumab chemo- ipilimumab chemo-+ therapy + therapy + therapy + therapychemo- chemo- chemo- chemo-therapy therapy therapy therapy

PD-L1 < 1% PD-L1 ≥ 1% PD-L1 ≥ 1% to 49% PD-L1 ≥ 50%(n = 264) (n = 406) (n = 233) (n = 173)

OS hazardratio 0.65 0.67 0.69 0.64(95% CI)a (0.46, 0.92) (0.51, 0.89) (0.48, 0.98) (0.41, 1.02)

PFShazard 0.77 0.67 0.71 0.59ratio (0.57, 1.03) (0.53, 0.85) (0.52, 0.97) (0.40, 0.86)(95% CI)a

ORR % 31.1 20.9 41.9 27.6 37.8 24.5 48.7 30.9a Hazard ratio based on unstratified Cox proportional hazards model.

A total of 70 NSCLC patients aged ≥ 75 years were enrolled in study CA2099LA (37 patients in thenivolumab in combination with ipilimumab and chemotherapy arm and 33 patients in thechemotherapy arm). A HR of 1.36 (95% CI: 0.74, 2.52) in OS and a HR of 1.12 (95% CI: 0.64, 1.96)in PFS was observed for nivolumab in combination with ipilimumab and chemotherapy vs.chemotherapy within this study subgroup. ORR was 27.0% in the nivolumab in combination withipilimumab and chemotherapy arm and 15.2% in the chemotherapy arm. Forty-three percent ofpatients aged ≥ 75 years discontinued treatment with nivolumab in combination with ipilimumab andchemotherapy. Efficacy and safety data of nivolumab in combination with ipilimumab andchemotherapy are limited in this patient population.

In a subgroup analysis, a reduced survival benefit for nivolumab in combination with ipilimumab andchemotherapy compared to chemotherapy was observed in patients who were never smokers.

However, due to the small numbers of patients, no definitive conclusions can be drawn from thesedata.

Treatment of NSCLC after prior chemotherapy

Squamous NSCLC

Randomised phase 3 study vs. docetaxel (CA209017)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced ormetastatic squamous NSCLC were evaluated in a phase 3, randomised, open-label study (CA209017).

The study included patients (18 years or older) who have experienced disease progression during orafter one prior platinum doublet-based chemotherapy regimen and an ECOG performance status scoreof 0 or 1. Patients were enrolled regardless of their tumour PD-L1 status. Patients with activeautoimmune disease, symptomatic interstitial lung disease, or active brain metastases were excludedfrom the study. Patients with treated brain metastases were eligible if neurologically returned tobaseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasingdose of < 10 mg daily prednisone equivalents.

A total of 272 patients were randomised to receive either nivolumab 3 mg/kg (n = 135) administeredintravenously over 60 minutes every 2 weeks or docetaxel (n = 137) 75 mg/m2 every 3 weeks.

Treatment was continued as long as clinical benefit was observed or until treatment was no longertolerated. Tumour assessments, according to the RECIST, version 1.1, were conducted 9 weeks afterrandomisation and continued every 6 weeks thereafter. The primary efficacy outcome measure was

OS. Key secondary efficacy outcome measures were investigator-assessed ORR and PFS. In addition,symptom improvement and overall health status were assessed using the Lung cancer symptom score(LCSS) average symptom burden index and the EQ-5D Visual Analogue Scale (EQ-VAS),respectively.

Baseline characteristics were generally balanced between the two groups. The median agewas 63 years (range: 39-85) with 44% ≥ 65 years of age and 11% ≥ 75 years of age. The majority ofpatients were white (93%) and male (76%). Thirty-one percent had progressive disease reported as thebest response to their most recent prior regimen and 45% received nivolumab within 3 months ofcompleting their most recent prior regimen. Baseline ECOG performance status score was 0 (24%) or1 (76%).

The Kaplan-Meier curves for OS are shown in Figure 16.

Figure 16: Kaplan-Meier curves of OS (CA209017)

Overall survival (months)

Number of subjects at risk

Nivolumab 3 mg/kg135 113 86 69 52 31 15 7 0

Docetaxel137 103 68 45 30 14 7 2 0 Nivolumab 3 mg/kg (events: 86/135), median and 95% CI: 9.23 (7.33, 13.27)

- - -- - - Docetaxel (events: 113/137), median and 95% CI: 6.01 (5.13, 7.33)

The observed OS benefit was consistently demonstrated across subgroups of patients. Survival benefitwas observed regardless of whether patients had tumours that were designated PD-L1 negative or

PD-L1 positive (tumour membrane expression cut off of 1%, 5% or 10%). However, the role of thisbiomarker (tumour PD-L1 expression) has not been fully elucidated. With a minimum of 62.6 monthsfollow-up, OS benefit remains consistently demonstrated across subgroups.

Study CA209017 included a limited number of patients ≥ 75 years (11 in the nivolumab group and18 in the docetaxel group). Nivolumab showed numerically less effect on OS (HR 1.85; 95% CI: 0.76,4.51), PFS (HR = 1.76; 95%-CI: 0.77, 4.05) and ORR (9.1% vs. 16.7%). Because of the small samplesize, no definitive conclusions can be drawn from these data.

Efficacy results are shown in Table 21.

Probability of survival

Table 21: Efficacy results (CA209017)nivolumab docetaxel(n = 135) (n = 137)

Minimum follow-up: 10.6 months

Overall survival

Events 86 (63.7%) 113 (82.5%)

Hazard ratio 0.5996.85% CI (0.43, 0.81)p-value 0.0002

Median (95% CI) months 9.23 (7.33, 13.27) 6.01 (5.13, 7.33)

Rate (95% CI) at 12 months 42.1 (33.7, 50.3) 23.7 (16.9, 31.1)

Confirmed objective response 27 (20.0%) 12 (8.8%)(95% CI) (13.6, 27.7) (4.6, 14.8)

Odds ratio (95% CI) 2.64 (1.27, 5.49)p-value 0.0083

Complete response (CR) 1 (0.7%) 0

Partial response (PR) 26 (19.3%) 12 (8.8%)

Stable disease (SD) 39 (28.9%) 47 (34.3%)

Median duration of response

Months (range) Not reached (2.9-20.5+) 8.4 (1.4+-15.2+)

Median time to response

Months (range) 2.2 (1.6-11.8) 2.1 (1.8-9.5)

Progression-free survival

Events 105 (77.8%) 122 (89.1%)

Hazard ratio 0.6295% CI (0.47, 0.81)p-value < 0.0004

Median (95% CI) (months) 3.48 (2.14, pct. 4.86) 2.83 (2.10, 3.52)

Rate (95% CI) at 12 months 20.8 (14.0, 28.4) 6.4 (2.9, 11.8)

Updated analysis

Minimum follow-up: 24.2 months

Overall survivala

Events 110 (81.4%) 128 (93.4%)

Hazard ratio 0.6295% CI (0.47, 0.80)

Rate (95% CI) at 24 months 22.9 (16.2, 30.3) 8 (4.3, 13.3)

Confirmed objective response 20.0% 8.8%(95% CI) (13.6, 27.7) (4.6, 14.8)

Median duration of response

Months (range) 25.2 (2.9-30.4) 8.4 (1.4+-18.0+)nivolumab docetaxel(n = 135) (n = 137)

Progression-free survival

Rate (95% CI) at 24 months 15.6 (9.7, 22.7) All patients had either progressed,were censored, or lost to follow-up

Updated analysis

Minimum follow-up: 62.6 months

Overall survivala

Events 118 (87.4%) 133 (97.1%)

Hazard ratio 0.6295% CI (0.48, 0.79)

Rate (95% CI) at 60 months 12.3 (7.4, 18.5) 3.6 (1.4, 7.8)

Confirmed objective response 20.0% 8.8%(95% CI) (13.6, 27.7) (4.6, 14.8)

Median duration of response

Months (range) 25.2 (2.9-70.6+) 7.5 (0.0+-18.0+)

Progression-free survival

Rate (95% CI) at 60 months 9.4 (4.8, 15.8) All patients had either progressed,were censored, or lost to follow-upa Six patients (4%) randomised to docetaxel crossed over at any time to receive nivolumab treatment.“+” Denotes a censored observation.

The rate of disease-related symptom improvement, as measured by LCSS, was similar between thenivolumab group (18.5%) and the docetaxel group (21.2%). The average EQ-VAS increased over timefor both treatment groups, indicating better overall health status for patients remaining on treatment.

Single-arm phase 2 study (CA209063)

Study CA209063 was a single-arm, open-label study conducted in 117 patients with locally advancedor metastatic squamous NSCLC after two or more lines of therapy; otherwise similar inclusion criteriaas study CA209017 were applied. Nivolumab 3 mg/kg showed an ORR of 14.5% (95% CI: 8.7,22.2),a median OS of 8.21 months (95% CI: 6.05,10.9), and a median PFS of 1.87 months (95% CI1.77,3.15). The PFS was measured by RECIST, version 1.1. The estimated 1-year survival rate was41%.

Single-arm phase 2 study (CA209171)

Study CA209171 was a single-arm, open label study of nivolumab monotherapy in patients withpreviously treated advanced or metastatic squamous NSCLC. Safety was the primary endpoint andefficacy was a secondary endpoint. Of the 811 treated patients, 103 (13%) had an ECOG performancescore of 2, 686 (85%) were < 75 years old and 125 (15%) were ≥ 75 years old. No new safety signalswere identified in all treated patients and the overall safety profile of nivolumab was similar acrosssubgroups. Efficacy results based on investigator-assessed ORR are presented in Table 22 below.

Table 22: ORR based on response evaluable patients - total and by subgroup (CA209171)

Results Total ECOG PS 2 < 75 years ≥ 75 years

N responders/ N evaluablea 66/671 1/64 55/568 11/103(%) (9.8) (6.1) (9.7) (10.7)95% CIb (7.7, 12.3) (0.0, 8.4) (7.4, 12.4) (5.5, 18.3)a includes confirmed and unconfirmed responses, scans were mandatory only at week 8/9 and week 52.b CR+PR, confidence interval based on the Clopper and Pearson method

Non-squamous NSCLC

Randomised phase 3 study vs. docetaxel (CA209057)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced ormetastatic non-squamous NSCLC were evaluated in a phase 3, randomised, open-label study(CA209057). The study included patients (18 years or older) who have experienced diseaseprogression during or after one prior platinum doublet-based chemotherapy regimen which may haveincluded maintenance therapy and who had an ECOG performance status score of 0 or 1. Anadditional line of TKI therapy was allowed for patients with known EGFR mutation or ALKtranslocation. Patients were enrolled regardless of their tumour PD-L1 status. Patients with activeautoimmune disease, symptomatic interstitial lung disease, or active brain metastases were excludedfrom the study. Patients with treated brain metastases were eligible if neurologically returned tobaseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasingdose of < 10 mg daily prednisone equivalents.

A total of 582 patients were randomised to receive either nivolumab 3 mg/kg administeredintravenously over 60 minutes every 2 weeks (n = 292) or docetaxel 75 mg/m2 every 3 weeks(n = 290). Treatment was continued as long as clinical benefit was observed or until treatment was nolonger tolerated. Tumour assessments were conducted according to the RECIST version 1.1. Theprimary efficacy outcome measure was OS. Key secondary efficacy outcome measures wereinvestigator-assessed ORR and PFS. Additional prespecified subgroup analyses were conducted toevaluate the efficacy of tumour PD-L1 expression at predefined levels of 1%, 5% and 10%.

Assessment according to discrete PD-L1 expression intervals were not included in the prespecifiedanalyses due to the small sample sizes within the intervals.

Pre-study tumour tissue specimens were systematically collected prior to randomisation in order toconduct pre-planned analyses of efficacy according to tumour PD-L1 expression. Tumour PD-L1expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

The median age was 62 years (range: 21 to 85) with 34% ≥ 65 years of age and 7% ≥ 75 years of age.

The majority of patients were white (92%) and male (55%). Baseline ECOG performance status was0 (31%) or 1 (69%). Seventy-nine percent of patients were former/current smokers.

The Kaplan-Meier curves for OS are shown in Figure 17.

Figure 17: Kaplan-Meier curves of OS (CA209057)

Overall survival (months)

Number of subjects at risk

Nivolumab 3 mg/kg292 232 194 169 146 123 62 32 9 0

Docetaxel290 244 194 150 111 88 34 10 5 0 Nivolumab 3 mg/kg (events: 190/292), median and 95% CI: 12.19 (9.66, 14.98)

- - -- - - Docetaxel (events: 223/290), median and 95% CI: 9.36 (8.05, 10.68)

The trial demonstrated a statistically significant improvement in OS for patients randomised tonivolumab as compared with docetaxel at the prespecified interim analysis when 413 events wereobserved (93% of the planned number of events for final analysis). Efficacy results are shown in

Table 23.

Table 23: Efficacy results (CA209057)nivolumab docetaxel(n = 292) (n = 290)

Prespecified interim analysis

Minimum follow-up: 13.2 months

Overall survival

Events 190 (65.1%) 223 (76.9%)

Hazard ratioa 0.73(95.92% CI) (0.59, 0.89)p-valueb 0.0015

Median (95% CI) months 12.19 (9.66, 14.98) 9.36 (8.05, 10.68)

Rate (95% CI) at 12 months 50.5 (44.6, 56.1) 39.0 (33.3, 44.6)

Probability of survivalnivolumab docetaxel(n = 292) (n = 290)

Confirmed objective response 56 (19.2%) 36 (12.4%)(95% CI) (14.8, 24.2) (8.8, 16.8)

Odds ratio (95% CI) 1.68 (1.07, 2.64)p-value 0.0246

Complete response (CR) 4 (1.4%) 1 (0.3%)

Partial response (PR) 52 (17.8%) 35 (12.1%)

Stable disease (SD) 74 (25.3%) 122 (42.1%)

Median duration of response

Months (range) 17.15 (1.8-22.6+) 5.55 (1.2+-15.2+)

Median time to response

Months (range) 2.10 (1.2-8.6) 2.61 (1.4-6.3)

Progression-free survival

Events 234 (80.1%) 245 (84.5%)

Hazard ratio 0.9295% CI (0.77, 1.11)p-value 0.3932

Median (95% CI) (months) 2.33 (2.17, 3.32) 4.21 (3.45, pct. 4.86)

Rate (95% CI) at 12 months 18.5 (14.1, 23.4) 8.1 (5.1, 12.0)

Updated analysis

Minimum follow-up: 24.2 months

Overall survivalc

Events 228 (78.1%) 247 (85.1%)

Hazard ratioa 0.75(95% CI) (0.63, 0.91)

Rate (95% CI) at 24 months 28.7 (23.6, 34.0) 15.8 (11.9, 20.3)

Confirmed objective response 19.2% 12.4%(95% CI) (14.8, 24.2) (8.8, 16.8)

Median duration of response

Months (range) 17.2 (1.8-33.7+) 5.6 (1.2+-16.8)

Progression-free survival

Rate (95% CI) at 24 months 11.9 (8.3, 16.2) 1.0 (0.2, 3.3)nivolumab docetaxel(n = 292) (n = 290)

Updated analysis

Minimum follow-up: 62.7 months

Overall survivald

Events 250 (85.6%) 279 (96.2%)

Hazard ratioa 0.70(95% CI) (0.58, 0.83)

Rate (95% CI) at 60 months 14.0 (10.2, 18.3) 2.1 (0.9, pct. 4.4)

Confirmed objective response 19.5% 12.4%(95% CI) (15.1, 24.5) (8.8, 16.8)

Median duration of response

Months (range) 17.2 (1.8-70.4+) 5.6 (0.0+-33.4)

Progression-free survival

Rate (95% CI) at 60 months 7.5 (4.5, 11.4) All patients had either progressed,were censored, or lost to follow-upa Derived from a stratified proportional hazards model.b P-value is derived from a log-rank test stratified by prior maintenance therapy and line of therapy; the corresponding

O’Brien-Fleming efficacy boundary significance level is 0.0408.c Sixteen patients (6%) randomised to docetaxel crossed over at any time to receive nivolumab treatment.d Seventeen patients (6%) randomised to docetaxel crossed over at any time to receive nivolumab treatment.“+” Denotes a censored observation.

Quantifiable tumour PD-L1 expression was measured in 79% of patients in the nivolumab group and77% of patients in the docetaxel group. Tumour PD-L1 expression levels were balanced between thetwo treatment groups (nivolumab vs. docetaxel) at each of the predefined tumour PD-L1 expressionlevels of ≥ 1% (53% vs. 55%), ≥ 5% (41% vs. 38%), or ≥ 10% (37% vs. 35%).

Patients with tumour PD-L1 expression by all predefined expression levels in the nivolumab groupdemonstrated greater likelihood of improved survival compared to docetaxel, whereas survival wassimilar to docetaxel in patients with low or no tumour PD-L1 expression. In terms of ORR, increasing

PD-L1 expression was associated with larger ORR. Comparable to the overall population, medianduration of response was increased with nivolumab vs. docetaxel for patients with no PD-L1expression (18.3 months vs. 5.6 months) and for patients with PD-L1 expression (16.0 months vs.5.6 months).

Table 24 summarises results of ORR and OS by tumour PD-L1 expression.

Table 24: ORR and OS by tumour PD-L1 expression (CA209057)

PD-L1 expression nivolumab docetaxel

ORR by tumour PD-L1 expression

Minimum follow-up: 13.2 months

Odds ratio (95% CI)< 1% 10/108 (9.3%) 15/101 (14.9%) 0.59 (0.22, 1.48)95% CI: 4.5, 16.4 95% CI: 8.6, 23.3≥ 1% 38/123 (30.9%) 15/123 (12.2%) 3.22 (1.60, 6.71)95% CI: 22.9, 39.9 95% CI: 7.0, 19.3≥ 1% to < 10%a 6/37 (16.2%) 5/44 (11.4%) 1.51 (0.35, 6.85)95% CI: 6.2, 32.0 95% CI: 3.8, 24.6≥ 10% to < 50%a 5/20 (25.0%) 7/33 (21.2%) 1.24 (0.26, 5.48)95% CI: 8.7, 49.1 95% CI: 9.0, 38.9≥ 50%a 27/66 (40.9%) 3/46 (6.5%) 9.92 (2.68, 54.09)95% CI: 29.0, 53.7 95% CI: 1.4, 17.9

PD-L1 expression nivolumab docetaxel

OS by tumour PD-L1 expression

Minimum follow-up: 13.2 months

Number of events (number of patients) Unstratified hazardratio (95% CI)< 1% 77 (108) 75 (101) 0.90 (0.66, 1.24)≥ 1% 68 (123) 93 (123) 0.59 (0.43, 0.82)≥ 1% to < 10%a 27 (37) 30 (44) 1.33 (0.79, 2.24)≥ 10% to < 50%a 11 (20) 26 (33) 0.61 (0.30, 1.23)≥ 50%a 30 (66) 37 (46) 0.32 (0.20, 0.53)

Updated analysis

Minimum follow-up: 24.2 months< 1% 91 (108) 86 (101) 0.91 (0.67, 1.22)≥ 1% 87 (123) 103 (123) 0.62 (0.47, 0.83)

Updated analysis

Minimum follow-up: 62.7 months< 1% 100 (109) 96 (101) 0.87 (0.66, 1.16)≥1% 96 (122) 119 (123) 0.55 (0.42, 0.73)a Post-hoc analysis; results should be interpreted with caution as the subgroup samples sizes are small and, at the time of theanalysis, the PD-L1 IHC 28-8 pharmDx assay was not analytically validated at the 10% or 50% expression levels.

A higher proportion of patients experienced death within the first 3 months in the nivolumab arm(59/292, 20.2%) as compared to the docetaxel arm (44/290, 15.2%). Results of a post-hoc, exploratorymultivariate analysis indicated that nivolumab-treated patients with poorer prognostic features and/oraggressive disease when combined with lower (e.g., < 50%) or no tumour PD-L1 expression may be athigher risk of death within the first 3 months.

In subgroup analyses, survival benefit compared to docetaxel was not shown for patients who werenever-smokers or whose tumours harboured EGFR activating mutations; however, due to the smallnumbers of patients, no definitive conclusions can be drawn from these data.

Malignant pleural mesothelioma

Randomised phase 3 study of nivolumab in combination with ipilimumab vs. chemotherapy(CA209743)

The safety and efficacy of nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kgevery 6 weeks were evaluated in a phase 3, randomised, open-label study (CA209743). The studyincluded patients (18 years or older) with histologically confirmed and previously untreated malignantpleural mesothelioma of epithelioid or non-epithelioid histology, ECOG performance status 0 or 1,and no palliative radiotherapy within 14 days of first study therapy. Patients were enrolled regardlessof their tumour PD-L1 status.

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lungdisease, active autoimmune disease, medical conditions requiring systemic immunosuppression, andbrain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolutionwithin 3 months prior to inclusion in the study) were excluded from the trial. Randomisation wasstratified by histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and gender (male vs.female).

A total of 605 patients were randomised to receive either nivolumab in combination with ipilimumab(n = 303) or chemotherapy (n = 302). Patients in the nivolumab in combination with ipilimumab armreceived nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks in combinationwith ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years.

Patients in the chemotherapy arm received chemotherapy for up to 6 cycles (each cycle was 21 days).

Chemotherapy consisted of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 or carboplatin 5 AUC andpemetrexed 500 mg/m2.

Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

Treatment could continue beyond disease progression if the patient was clinically stable and wasconsidered to be deriving clinical benefit by the investigator. Patients who discontinued combinationtherapy because of an adverse reaction attributed to ipilimumab were permitted to continue nivolumabmonotherapy. Tumour assessments were performed every 6 weeks after first dose of study treatmentfor the first 12 months, then every 12 weeks until disease progression or study treatment wasdiscontinued.

CA209743 baseline characteristics were generally balanced across all treatment groups. The medianage was 69 years (range: 25-89) with 72% ≥ 65 years of age and 26% ≥ 75 years of age. The majorityof patients were white (85%) and male (77%). Baseline ECOG performance status was 0 (40%) or1 (60%), 80% of patients with PD-L1 ≥ 1% and 20% with PD-L1 < 1%, 75% had epithelioid and 25%had non-epithelioid histology.

CA209743 primary efficacy outcome measure was OS. Key secondary efficacy endpoints were PFS,

ORR, and duration of response as assessed by Blinded Independent Central Review (BICR) utilisingmodified RECIST criteria for pleural mesothelioma. Descriptive analyses for these secondaryendpoints are presented in Table 25.

The study demonstrated a statistically significant improvement in OS for patients randomised tonivolumab in combination with ipilimumab as compared to chemotherapy at the prespecified interimanalysis when 419 events were observed (89% of the planned number of events for final analysis).

Minimum follow-up for OS was 22 months.

Efficacy results are shown in Figure 18 and Table 25.

Figure 18: Kaplan-Meier curves of OS (CA209743)

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab303 273 251 226 200 173 143 124 101 65 30 11 2 0

Chemotherapy302 268 233 190 162 136 113 95 62 38 20 11 1 0

- - -- - - Nivolumab + ipilimumab (events: 200/303), median and 95% CI: 18.07 (16.82, 21.45)

- - -- - - Chemotherapy (events: 219/302), median and 95% CI: 14.09 (12.45, 16.23)

Table 25: Efficacy results (CA209743)nivolumab + ipilimumab chemotherapy(n = 303) (n = 302)

Overall survival

Events 200 (66%) 219 (73%)

Hazard ratio 0.74(96.6% CI)a (0.60, 0.91)

Stratified log-rank p-valueb 0.002

Median (months)c 18.1 14.1(95% CI) (16.8, 21.5) (12.5, 16.2)

Rate (95% CI) at 24 monthsc 41% (35.1, 46.5) 27% (21.9, 32.4)

Progression-free survival

Events 218 (72%) 209 (69%)

Hazard ratio 1.0(95% CI)a (0.82, 1.21)

Median (months)c 6.8 7.2(95% CI) (5.6, 7.4) (6.9, 8.1)

Probability of survivalnivolumab + ipilimumab chemotherapy(n = 303) (n = 302)

Overall response rate 40% 43%(95% CI) (34.1, 45.4) (37.1, 48.5)

Complete response (CR) 1.7% 0

Partial response (PR) 38% 43%

Duration of response

Median (months)c 11.0 6.7(95% CI) (8.1, 16.5) (5.3, 7.1)a Stratified Cox proportional hazard model.b p-value is compared with the allocated alpha of 0.0345 for this interim analysis.c Kaplan-Meier estimate.

Subsequent systemic therapy was received by 44.2% and 40.7% of patients in the combination andchemotherapy arms, respectively. Subsequent immunotherapy (including anti-PD-1, anti-PD-L1, andanti-CTLA-4) was received by 3.3% and 20.2% of patients in the combination and chemotherapyarms, respectively.

Table 26 summarises efficacy results of OS, PFS, and ORR by histology in prespecified subgroupanalyses.

Table 26: Efficacy results by histology (CA209743)

Epithelioid Non-epithelioid(n = 471) (n = 134)nivolumab chemotherapy nivolumab chemotherapy+ (n = 235) + (n = 67)ipilimumab ipilimumab(n = 236) (n = 67)

Overall survival

Events 157 164 43 55

Hazard ratio 0.85 0.46(95% CI)a (0.68, 1.06) (0.31, 0.70)

Median (months) 18.73 16.23 16.89 8.80(95% CI) (17.05, 21.72) (14.09, 19.15) (11.83, 25.20) (7.62, 11.76)

Rate (95% CI) at 41.2 31.8 39.5 9.724 months (34.7, 47.6) (25.7, 38.1) (27.5, 51.2) (3.8, 18.9)

Progression-free survival

Hazard ratio 1.14 0.58(95% CI)a (0.92, 1.41) (0.38, 0.90)

Median (months) 6.18 7.66 8.31 5.59(95% CI) (5.49, 7.03) (7.03, 8.31) (3.84, 11.01) (5.13, 7.16)

Overall response rate 38.6% 47.2% 43.3% 26.9%(95% CI)b (32.3, 45.1) (40.7, 53.8) (31.2, 56.0) (16.8, 39.1)

Duration of response 8.44 6.83 24.02 4.21

Median (months)(95% CI)c (7.16, 14.59) (5.59, 7.13) (8.31, N.A.) (2.79, 7.03)a Hazard ratio based on unstratified Cox proportional hazards model.b Confidence interval based on the Clopper and Pearson methodc Median computed using Kaplan-Meier method

Table 27 summarises efficacy results of OS, PFS, and ORR by baseline tumour PD-L1 expression inprespecified subgroup analyses.

Table 27: Efficacy results by tumour PD-L1 expression (CA209743)

PD-L1 < 1% PD-L1 ≥ 1%(n = 135) (n = 451)nivolumab chemotherapy nivolumab chemotherapy+ (n = 78) + (n = 219)ipilimumab ipilimumab(n = 57) (n = 232)

Overall survival

Events 40 58 150 157

Hazard ratio 0.94 0.69(95% CI)a (0.62, 1.40) (0.55, 0.87)

Median (months) 17.3 16.5 18.0 13.3(95% CI)b (10.1, 24.3) (13.4, 20.5) (16.8, 21.5) (11.6, 15.4)

Rate (95% CI) at 38.7 24.6 40.8 28.324 months (25.9, 51.3) (15.5, 35.0) (34.3, 47.2) (22.1, 34.7)

Progression-free survival

Hazard ratio 1.79 0.81(95% CI)a (1.21, 2.64) (0.64, 1.01)

Median (months) 4.1 8.3 7.0 7.1(95% CI)b (2.7, 5.6) (7.0, 11.1) (5.8, 8.5) (6.2, 7.6)

Overall response rate 21.1% 38.5% 43.5% 44.3%(95% CI)c (11.4, 33.9) (27.7, 50.2) (37.1, 50.2) (37.6, 51.1)a Hazard ratio based on unstratified Cox proportional hazards model.b Median computed using Kaplan-Meier method.c Confidence interval based on the Clopper and Pearson method.

A total of 157 MPM patients aged ≥ 75 years were enrolled in study CA209743 (78 in the nivolumabin combination with ipilimumab arm and 79 in the chemotherapy arm). A

HR of 1.02 (95% CI: 0.70, 1.48) in OS was observed for nivolumab in combination with ipilimumabvs. chemotherapy within this study subgroup. A higher rate of serious adverse reactions anddiscontinuation rate due to adverse reactions in patients 75 years of age or older relative to all patientswho received nivolumab in combination with ipilimumab was shown (see section 4.8). However, dueto the exploratory nature of this subgroup analysis, no definitive conclusions can be drawn.

Randomised phase 3 study of nivolumab as monotherapy vs. everolimus (CA209025)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced RCCwith a clear cell component was evaluated in a Phase 3, randomised, open-label study (CA209025).

The study included patients (18 years or older) who have experienced disease progression during orafter 1 or 2 prior anti-angiogenic therapy regimens and no more than 3 total prior systemic treatmentregimens. Patients had to have a Karnofsky Performance Score (KPS) ≥ 70%. This study includedpatients regardless of their tumour PD-L1 status. Patients with any history of or concurrent brainmetastases, prior treatment with an mammalian target of rapamycin (mTOR) inhibitor, activeautoimmune disease, or medical conditions requiring systemic immunosuppression were excludedfrom the study.

A total of 821 patients were randomised to receive either nivolumab 3 mg/kg (n = 410) administeredintravenously over 60 minutes every 2 weeks or everolimus (n = 411) 10 mg daily, administeredorally. Treatment was continued as long as clinical benefit was observed or until treatment was nolonger tolerated. The first tumour assessments were conducted 8 weeks after randomisation andcontinued every 8 weeks thereafter for the first year and then every 12 weeks until progression ortreatment discontinuation, whichever occurred later. Tumour assessments were continued aftertreatment discontinuation in patients who discontinued treatment for reasons other than progression.

Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression waspermitted if the patient had a clinical benefit and was tolerating study drug as determined by theinvestigator. The primary efficacy outcome measure was OS. Secondary efficacy assessmentsincluded investigator-assessed ORR and PFS.

Baseline characteristics were generally balanced between the two groups. The median age was62 years (range: 18-88) with 40% ≥ 65 years of age and 9% ≥ 75 years of age. The majority of patientswere male (75%) and white (88%), all Memorial Sloan Kettering Cancer Center (MSKCC) risk groupswere represented, and 34% and 66% of patients had a baseline KPS of 70 to 80% and 90 to 100%,respectively. The majority of patients (72%) were treated with one prior anti-angiogenic therapy. Themedian duration of time from initial diagnosis to randomisation was 2.6 years in both the nivolumaband everolimus groups. The median duration of treatment was 5.5 months (range: 0-29.6+ months) innivolumab-treated patients and was 3.7 months (range: 6 days-25.7+ months) in everolimus-treatedpatients.

Nivolumab was continued beyond progression in 44% of patients.

The Kaplan-Meier curves for OS are shown in Figure 19.

Figure 19: Kaplan-Meier curves of OS (CA209025)

Overall survival (months)

Number of subjects at risk

Nivolumab410 389 359 337 305 275 213 139 73 29 3 0

Everolimus411 366 324 287 265 241 187 115 61 20 2 0 Nivolumab 3 mg/kg (events: 183/410), median and 95% CI: 25.00 (21.75, N.A.)

- - -- - - Everolimus 10 mg (events: 215/411), median and 95% CI: 19.55 (17.64, 23.06)

The trial demonstrated a statistically significant improvement in OS for patients randomised tonivolumab as compared with everolimus at the prespecified interim analysis when 398 events wereobserved (70% of the planned number of events for final analysis) (Table 28 and Figure 19). OSbenefit was observed regardless of tumour PD-L1 expression level.

Efficacy results are shown in Table 28.

Probability of survival

Table 28: Efficacy results (CA209025)nivolumab everolimus(n = 410) (n = 411)

Overall survival

Events 183 (45%) 215 (52%)

Hazard ratio 0.7398.52% CI (0.57, 0.93)p-value 0.0018

Median (95% CI) 25.0 (21.7, NE) 19.6 (17.6, 23.1)

Rate (95% CI)

At 6 months 89.2 (85.7, 91.8) 81.2 (77.0, 84.7)

At 12 months 76.0 (71.5, 79.9) 66.7 (61.8, 71.0)

Objective response 103 (25.1%) 22 (5.4%)(95% CI) (21.0, 29.6) (3.4, 8.0)

Odds ratio (95% CI) 5.98 (3.68, 9.72)p-value < 0.0001

Complete response (CR) 4 (1.0%) 2 (0.5%)

Partial response (PR) 99 (24.1%) 20 (4.9%)

Stable disease (SD) 141 (34.4%) 227 (55.2%)

Median duration of response

Months (range) 11.99 (0.0-27.6+) 11.99 (0.0+-22.2+)

Median time to response

Months (range) 3.5 (1.4-24.8) 3.7 (1.5-11.2)

Progression-free survival

Events 318 (77.6%) 322 (78.3%)

Hazard ratio 0.8895% CI (0.75, 1.03)p-value 0.1135

Median (95% CI) 4.6 (3.71, 5.39) 4.4 (3.71, 5.52)“+” denotes a censored observation.

NE = non-estimable

The median time to onset of objective response was 3.5 months (range: 1.4-24.8 months) after the startof nivolumab treatment. Forty-nine (47.6%) responders had ongoing responses with a duration rangingfrom 0.0-27.6+ months.

Overall survival could be accompanied by an improvement over time in disease related symptoms andnon-disease specific QoL as assessed using valid and reliable scales in the Functional Assessment of

Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and the EuroQoL

EQ-5D. Apparently meaningful symptom improvement (MID = 2 point change in FKSI-DRS score;p < 0.001) and time to improvement (HR = 1.66 (1.33, 2.08), p < 0.001) were significantly better forpatients on the nivolumab arm. While both arms of the study received active therapy, the QoL datashould be interpreted in the context of the open-label study design and therefore cautiously taken.

Phase 3b/4 safety study (CA209374)

Additional safety and descriptive efficacy data are available from study CA209374, an open-label

Phase 3b/4 safety study of nivolumab monotherapy (treated with 240 mg every 2 weeks) for thetreatment of patients with advanced or metastatic RCC (n = 142), including 44 patients with non-clearcell histology.

In subjects with non-clear cell histology, at a minimum follow-up of approximately 16.7 months ORRand median duration of response were 13.6% and 10.2 months, respectively. Clinical activity wasobserved regardless of tumour PD-L1 expression status.

Randomised phase 3 study of nivolumab in combination with ipilimumab vs. sunitinib (CA209214)

The safety and efficacy of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for thetreatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study(CA209214). The study included patients (18 years or older) with previously untreated, advanced ormetastatic renal cell carcinoma with a clear-cell component. The primary efficacy population includedthose intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the

International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time ofinitial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status <80%,haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, plateletcount greater than the upper limit of normal, and absolute neutrophil count greater than the upper limitof normal). This study included patients regardless of their tumour PD-L1 status. Patients with

Karnofsky performance status < 70% and patients with any history of or concurrent brain metastases,active autoimmune disease, or medical conditions requiring systemic immunosuppression wereexcluded from the study. Patients were stratified by IMDC prognostic score and region.

A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk

RCC and received either nivolumab 3 mg/kg (n = 425) administered intravenously over 60 minutes incombination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 3 weeks for4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n = 422) 50 mgdaily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continuedas long as clinical benefit was observed or until treatment was no longer tolerated. The first tumourassessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter forthe first year and then every 12 weeks until progression or treatment discontinuation, whicheveroccurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-definedprogression was permitted if the patient had a clinical benefit and was tolerating study drug asdetermined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS asdetermined by a BICR in intermediate/poor risk patients.

Baseline characteristics were generally balanced between the two groups. The median age was61 years (range: 21-85) with 38% ≥ 65 years of age and 8% ≥ 75 years of age. The majority of patientswere male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was0.4 years in both the nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg and sunitinibgroups. The median duration of treatment was 7.9 months (range: 1 day-21.4+ months) in nivolumabwith ipilimumab-treated patients and was 7.8 months (range: 1 days-20.2+ months) in sunitinib-treatedpatients. Nivolumab with ipilimumab was continued beyond progression in 29% of patients.

Efficacy results for the intermediate/poor risk patients are shown in Table 29 (primary analysis with aminimum follow-up of 17.5 months and with a minimum follow-up of 60 months) and in Figure 20(minimum follow-up of 60 months).

OS results at an additional descriptive analysis undertaken at a minimum follow-up of 60 monthsshow outcomes consistent with the original primary analysis.

Table 29: Efficacy results in intermediate/poor risk patients (CA209214)nivolumab + ipilimumab sunitinib(n = 425) (n = 422)

Primary analysisminimum follow-up: 17.5 months

Overall survival

Events 140 (33%) 188 (45%)

Hazard ratioa 0.6399.8% CI (0.44, 0.89)p-valueb, c < 0.0001

Median (95% CI) NE (28.2, NE) 25.9 (22.1, NE)

Rate (95% CI)

At 6 months 89.5 (86.1, 92.1) 86.2 (82.4, 89.1)

At 12 months 80.1 (75.9, 83.6) 72.1 (67.4, 76.2)

Progression-free survival

Events 228 (53.6%) 228 (54.0%)

Hazard ratioa 0.8299.1% CI (0.64, 1.05)p-valueb,h 0.0331

Median (95% CI) 11.6 (8.71, 15.51) 8.4 (7.03, 10.81)

Confirmed objective response 177 (41.6%) 112 (26.5%)(BICR)(95% CI) (36.9, 46.5) (22.4, 31.0)

Difference in ORR (95% CI)d 16.0 (9.8, 22.2)p-valuee,f < 0.0001

Complete response (CR) 40 (9.4%) 5 (1.2%)

Partial response (PR) 137 (32.2%) 107 (25.4%)

Stable disease (SD) 133 (31.3%) 188 (44.5%)

Median duration of responseg

Months (range) NE (1.4+-25.5+) 18.17 (1.3+-23.6+)

Median time to response

Months (range) 2.8 (0.9-11.3) 3.0 (0.6-15.0)

Updated analysis*minimum follow-up: 60 months

Overall survival

Events 242 (57%) 282 (67%)

Hazard ratioa 0.6895% CI (0.58, 0.81)

Median (95% CI) 46.95 (35.35, 57.43) 26.64 (22.08, 33.54)

Rate (95% CI)

At 24 months 66.3 (61.5, 70.6) 52.4 (47.4, 57.1)

At 36 months 54.6 (49.7, 59.3) 43.7 (38.7, 48.5)

At 48 months 49.9 (44.9, 54.6) 35.8 (31.1, 40.5)

At 60 months 43.0 (38.1, 47.7) 31.3 (26.8, 35.9)nivolumab + ipilimumab sunitinib(n = 425) (n = 422)

Progression-free survival

Events 245 (57.6%) 253 (60.0%)

Hazard ratioa 0.7395% CI (0.61, 0.87)

Median (95% CI) 11.6 (8.44, 16.63) 8.3 (7.03, 10.41)

Confirmed objective response 179 (42.1%) 113 (26.8%)(BICR)(95% CI) (37.4, 47.0) (22.6, 31.3)

Difference in ORR (95% CI)d,e 16.2 (10.0, 22.5)

Complete response (CR) 48 (11.3%) 9 (2.1%)

Partial response (PR) 131 (30.8%) 104 (24.6%)

Stable disease (SD) 131 (30.8%) 187 (44.3%)

Median duration of responseg

Months (range) NE (50.89-NE) 19.38 (15.38-25.10)

Median time to response

Months (range) 2.8 (0.9-35.0) 3.1 (0.6-23.6)a Based on a stratified proportional hazards model.b Based on a stratified log-rank test.c p-value is compared to alpha 0.002 in order to achieve statistical significance.d Strata adjusted difference.e Based on the stratified DerSimonian-Laird test.f p-value is compared to alpha 0.001 in order to achieve statistical significance.g Computed using Kaplan-Meier method.h p-value is compared to alpha 0.009 in order to achieve statistical significance.“+” denotes a censored observation.

NE = non-estimable

* Descriptive analysis based on data cut-off: 26-Feb-2021.

Figure 20: Kaplan-Meier curves of OS in intermediate/poor risk patients(CA209214) - Minimum follow-up of 60 months

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab425 372 332 306 270 241 220 207 196 181 163 79 2 0

Sunitinib422 353 291 237 206 184 169 151 137 125 112 58 3 0 Nivolumab + ipilimumab (events: 242/425), median and 95.0% CI: 46.95 (35.35, 57.43)

- - -- - - Sunitinib (events: 282/422), median and 95.0% CI: 26.64 (22.08, 33.54)

An updated descriptive OS analysis was performed when all patients had a minimum follow-up of24 months. At the time of this analysis, the hazard ratio was 0.66 (99.8% CI 0.48-0.91) with 166/425events in the combination arm and 209/422 events in the sunitinib arm. In intermediate/poor-riskpatients, OS benefit was observed in the nivolumab in combination with ipilimumab arm vs. sunitinibregardless of tumour PD-L1 expression. Median OS for tumour PD-L1 expression ≥ 1% was notreached for nivolumab in combination with ipilimumab, and was 19.61 months in the sunitinib arm(HR = 0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 expression < 1%, the median OS was34.7 months for the nivolumab in combination with ipilimumab, and was 32.2 months in the sunitinibarm (HR = 0.70; 95% CI: 0.54, 0.92).

CA209214 also randomised 249 favourable risk patients as per IMDC criteria to nivolumab plusipilimumab (n = 125) or to sunitinib (n = 124). These patients were not evaluated as part of theprimary efficacy population. At a minimum of 24 months follow-up, OS in favourable risk patientsreceiving nivolumab plus ipilimumab compared to sunitinib had a hazard ratio of 1.13(95% CI: 0.64, 1.99; p = 0.6710). With 60 months minimum follow-up, the HR for OS was 0.94 (95%

CI: 0.65, 1.37).

There are no data on the use of nivolumab in combination with ipilimumab in patients with only a nonclear-cell histology in first-line RCC.

Probability of survival

Patients ≥ 75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and thecombination of nivolumab and ipilimumab showed numerically less effect on OS (HR 0.97, 95% CI:0.48, 1.95) in this subgroup versus the overall population at a minimum follow-up of 17.5 months.

Because of the small size of this subgroup, no definitive conclusions can be drawn from these data.

Randomised phase 3 study of nivolumab in combination with cabozantinib vs. sunitinib (CA2099ER)

The safety and efficacy of nivolumab 240 mg in combination with cabozantinib 40 mg for thefirst-line treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-labelstudy (CA2099ER). The study included patients (18 years or older) with advanced or metastatic RCCwith a clear cell component, Karnofsky Performance Status (KPS) ≥ 70%, and measurable disease asper RECIST v1.1 regardless of their PD-L1 status or IMDC risk group. The study excluded patientswith autoimmune disease or other medical conditions requiring systemic immunosuppression, patientswho had prior treatment with an anti-PD-1, anti PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4antibody, poorly controlled hypertension despite antihypertensive therapy, active brain metastases anduncontrolled adrenal insufficiency. Patients were stratified by IMDC prognostic score, PD-L1 tumourexpression, and region.

A total of 651 patients were randomised to receive either nivolumab 240 mg (n = 323) administeredintravenously every 2 weeks in combination with cabozantinib 40 mg once daily orally or sunitinib(n = 328) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off. Treatment continueduntil disease progression or unacceptable toxicity with nivolumab administration for up to 24 months.

Treatment beyond initial investigator-assessed RECIST version 1.1-defined progression was permittedif the patient had a clinical benefit and was tolerating study drug, as determined by the investigator.

First tumour assessment post-baseline was performed at 12 weeks (± 7 days) following randomisation.

Subsequent tumour assessments occurred at every 6 weeks (± 7 days) until Week 60, then every12 weeks (± 14 days) until radiographic progression, confirmed by the BICR. The primary efficacyoutcome measure was PFS as determined by a BICR. Additional efficacy measures included OS and

ORR as key secondary endpoints.

Baseline characteristics were generally balanced between the two groups. The median age was61 years (range: 28-90) with 38.4% ≥ 65 years of age and 9.5% ≥ 75 years of age. The majority ofpatients were male (73.9%) and white (81.9%). Eight percent of patients were Asian, 23.2% and76.5% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. Patient distributionby IMDC risk categories was 22.6% favourable, 57.6% intermediate, and 19.7% poor. For tumour

PD-L1 expression, 72.5% of patients had PD-L1 expression < 1% or indeterminate and 24.9% ofpatients had PD-L1 expression ≥ 1%. 11.5% of patients had tumours with sarcomatoid features. Themedian duration of treatment was 14.26 months (range: 0.2-27.3 months) in nivolumab withcabozantinib-treated patients and was 9.23 months (range: 0.8-27.6 months) in sunitinib-treatedpatients.

The study demonstrated a statistically significant benefit in PFS, OS, and ORR for patientsrandomised to nivolumab in combination with cabozantinib as compared to sunitinib. Efficacy resultsfrom the primary analysis (minimum follow-up 10.6 months; median follow-up 18.1 months) areshown in Table 30.

Table 30: Efficacy results (CA2099ER)nivolumab + cabozantinib sunitinib(n = 323) (n = 328)

Progression-free survival

Events 144 (44.6%) 191 (58.2%)

Hazard ratioa 0.5195% CI (0.41, 0.64)p-valueb, c < 0.0001

Median (95% CI)d 16.59 (12.45, 24.94) 8.31 (6.97, 9.69)nivolumab + cabozantinib sunitinib(n = 323) (n = 328)

Overall survival

Events 67 (20.7%) 99 (30.2%)

Hazard ratioa 0.6098.89% CI (0.40, 0.89)p-valueb,c,e 0.0010

Median (95% CI) N.E. N.E. (22.6, N.E.)

Rate (95% CI)

At 6 months 93.1 (89.7, 95.4) 86.2 (81.9, 89.5)

Confirmed objective response 180 (55.7%) 89 (27.1%)(BICR)(95% CI)f (50.1, 61.2) (22.4, 32.3)

Difference in ORR (95% CI) g 28.6 (21.7, 35.6)p-valueh < 0.0001

Complete response (CR) 26 (8.0%) 15 (4.6%)

Partial response (PR) 154 (47.7%) 74 (22.6%)

Stable disease (SD) 104 (32.2%) 138 (42.1%)

Median duration of responsed

Months (range) 20.17 (17.31, N.E.) 11.47 (8.31, 18.43)

Median time to response

Months (range) 2.83 (1.0-19.4) 4.17 (1.7-12.3)a Stratified Cox proportional hazards model. Hazard ratio is nivolumab and cabozantinib over sunitinib.b Log-rank test stratified by IMDC prognostic risk score (0, 1-2, 3-6), PD-L1 tumour expression (≥ 1% versus < 1% orindeterminate) and region (US/Canada/W Europe/N Europe, ROW) as entered in the IRT.c 2-sided p-values from stratified regular log-rank test.d Based on Kaplan-Meier estimates.e Boundary for statistical significance p-value <0.0111.f CI based on the Clopper and Pearson method.g Strata adjusted difference in objective response rate (nivolumab + cabozantinib - sunitinib) based on DerSimonianand Laird.h 2-sided p-value from CMH test.

NE = non-estimable

The primary analysis of PFS included censoring for new anti-cancer treatment (Table 30). Results for

PFS with and without censoring for new anti-cancer treatment were consistent.

PFS benefit was observed in the nivolumab in combination with cabozantinib arm vs. suntinibregardless of the IMDC risk category. Median PFS for the favourable risk group was not reached fornivolumab in combination with cabozantinib, and was 12.81 months in the sunitinib arm (HR = 0.60;95% CI: 0.37, 0.98). Median PFS for the intermediate risk group was 17.71 months for nivolumab incombination with cabozantinib and was 8.38 months in the sunitinib arm (HR = 0.54; 95% CI: 0.41,0.73). Median PFS for the poor risk group was 12.29 months for nivolumab in combination withcabozantinib and was 4.21 months in the sunitinib arm (HR = 0.36; 95% CI: 0.23, 0.58).

PFS benefit was observed in the nivolumab in combination with cabozantinib arm vs. sunitinibregardless of tumour PD-L1 expression. Median PFS for tumour PD-L1 expression ≥ 1% was13.08 months for nivolumab in combination with cabozantinib, and was 4.67 months in the sunitinibarm (HR = 0.45; 95% CI: 0.29, 0.68). For tumour PD-L1 expression < 1%, the median PFS was19.84 months for nivolumab in combination with cabozantinib, and 9.26 months in the sunitinib arm(HR = 0.50; 95% CI: 0.38, 0.65).

An updated PFS and OS analysis were performed when all patients had a minimum follow-up of16.0 months and a median follow-up of 23.5 months (see Figures 21 and 22). The PFS hazard ratiowas 0.52 (95% CI: 0.43, 0.64). The OS hazard ratio was 0.66 (95% CI: 0.50, 0.87). Updated efficacydata (PFS and OS) in subgroups for the IMDC risk categories and PD-L1 expression levels confirmedthe original results. With the updated analysis, median PFS is reached for the favourable risk group.

Figure 21: Kaplan-Meier curves of PFS (CA2099ER)

Progression-free Survival per BICR (months)

Number of subjects at risk

Nivolumab + cabozantinib323 280 236 201 166 145 102 56 26 5 2 0

Sunitinib328 230 160 122 87 61 37 17 7 2 1 0 Nivolumab + cabozantinib (events: 175/323), median and 95.0% CI: 16.95 (12.58, 19.38)

- - -- - - Sunitinib (events: 206/328), median and 95.0% CI: 8.31 (6.93, 9.69)

Probability of progression-free survival

Figure 22: Kaplan-Meier curves of OS (CA2099ER)

Overall Survival (Months)

Number of subjects at risk

Nivolumab + cabozantinib323 308 295 283 269 255 220 147 84 40 10 0

Sunitinib328 295 272 254 236 217 189 118 62 22 4 0 Nivolumab + cabozantinib (events: 86/323), median and 95% CI: NE

- - -- - - Sunitinib (events: 116/328), median and 95% CI: 29.47 (28.35, NE)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of relapsed orrefractory cHL following ASCT was evaluated in two multi-centre, open-label, single-arm studies(CA209205 and CA209039).

CA209205 is a Phase 2, open-label, multi-cohort, single-arm study of nivolumab in cHL. It includes243 patients who had ASCT; Cohort A included 63 (26%) patients who were brentuximab vedotinnaïve; Cohort B included 80 (33%) patients who had received brentuximab vedotin after ASCTfailure; and Cohort C included 100 (41%) patients who had received brentuximab vedotin beforeand/or after ASCT out of which 33 (14%) patients received brentuximab vedotin only prior to ASCT.

All patients received nivolumab 3 mg/kg monotherapy intravenously over 60 minutes every 2 weeks.

The first tumour assessments were conducted 9 weeks after the start of treatment and continuedthereafter until disease progression or treatment discontinuation. The primary efficacy outcomemeasure was ORR as determined by an IRRC. Additional efficacy measures included duration ofresponse, PFS and OS.

CA209039 is a Phase 1b open-label, multi-centre, dose-escalation, and multidose study of nivolumabin relapsed/refractory hematologic malignancies, including 23 patients with cHL treated withnivolumab 3 mg/kg monotherapy; amongst which, 15 patients received prior brentuximab vedotintreatment as a salvage therapy following ASCT, similar to Cohort B of study CA209205. The firsttumour assessments were conducted 4 weeks after the start of treatment and continued thereafter until

Probability of survivaldisease progression or treatment discontinuation. Efficacy assessments included investigator-assessed

ORR, retrospectively evaluated by an IRRC, and duration of response.

Data from the 80 patients from CA209205 Cohort B and from the 15 patients from CA209039 whoreceived prior brentuximab vedotin treatment following ASCT were integrated. Additional data from100 patients from CA209205 Cohort C who received brentuximab before and/or after ASCT are alsopresented. Baseline characteristics were similar across the two studies and cohorts (see Table 31below).

Table 31: Baseline patient characteristics in CA209205 Cohort B, Cohort C and CA209039

CA209205 CA209205 CA209039 CA209205

Cohort B and Cohort Ba Cohort Cb

CA209039(n = 95) (n = 80) (n = 15) (n = 100)

Median age, years (range) 37.0 (18-72) 37.0 (18-72) 40.0 (24-54) 32.0 (19-69)

Gender 61 (64%) M 51 (64%) M 10 (67%) M 56 (56%) M34 (36%) F 29 (36%) F 5 (33%) F 44 (44%) F

ECOG status0 49 (52%) 42 (52.5%) 7 (47%) 50 (50%)1 46 (48%) 38 (47.5%) 8 (53%) 50 (50%)≥ 5 prior lines of systemic 49 (52%) 39 (49%) 10 (67%) 30 (30%)therapy

Prior radiation therapy 72 (76%) 59 (74%) 13 (87%) 69 (69%)

Prior ASCT1 87 (92%) 74 (92.5%) 13 (87%) 100 (100%)≥ 2 8 (8%) 6 (7.5%) 2 (13%) 0 (0%)

Years from most recent 3.5 (0.2-19.0) 3.4 (0.2-19.0) 5.6 (0.5-15.0) 1.7 (0.2-17.0)transplant to first dose of studytherapy, median (min-max)a 18/80 (22.5%) of the patients in CA209205 Cohort B presented B-Symptoms at baseline.b 25/100 (25%) of the patients in CA209205 Cohort C presented B-Symptoms at baseline.

Efficacy from both studies was evaluated by the same IRRC. Results are shown in Table 32.

Table 32: Efficacy results in patients with relapsed/refractory classical Hodgkin lymphoma

CA209205 Cohort Ba CA209205 Cohort Ba CA209039and CA209039

Number (n)/ minimum follow-up (months) (n = 95/12.0) (n = 80/12.0) (n = 15/12.0)

Objective response, n (%); (95% CI) 63 (66%); (56, 76) 54 (68%); (56, 78) 9 (60%); (32, 84)

Complete remission (CR), n (%); (95% CI) 6 (6%); (2, 13) 6 (8%); (3, 16) 0 (0%); (0, 22)

Partial remission (PR), n (%); (95% CI) 57 (60%); (49, 70) 48 (60%); (48, 71) 9 (60%); (32, 84)

Stable disease, n (%) 22 (23) 17 (21) 5 (33)

Duration of response (months)b

Median (95% CI) 13.1 (9.5, NE) 13.1 (8.7, NE) 12.0 (1.8, NE)

Range 0.0+-23.1+ 0.0+-14.2+ 1.8-23.1+

Median time to response

Months (range) 2.0 (0.7-11.1) 2.1 (1.6-11.1) 0.8 (0.7-4.1)

Median duration of follow-up

Months (range) 15.8 (1.9-27.6) 15.4 (1.9-18.5) 21.9 (11.2-27.6)

Progression-free survival

Rate (95% CI) at 12 months 57 (45, 68) 55 (41, 66) 69 (37, 88)“+” denotes a censored observation.a Follow-up was ongoing at the time of data submission.b Data unstable due to the limited duration of response for Cohort B resulting from censoring.

NE = non-estimable

Updated efficacy results from longer follow-up data of Cohort B (minimum 68.7 months) and

Cohort C (minimum 61.9 months) from CA209205 are presented below in Table 33.

Table 33: Updated efficacy results in patients with relapsed/refractory classical Hodgkinlymphoma from longer follow-up of study CA209205

CA209205 Cohort B CA209205 Cohort C

Number (n)/ minimum follow-up (months) (n = 80/68.7) (n = 100/61.9)a

Objective response, n (%); (95% CI) 57 (71%); (60, 81) 75 (75%); (65, 83)

Complete remission (CR), n (%); (95% CI) 11 (14%); (7, 23) 21 (21%); (14, 30)

Partial remission (PR), n (%); (95% CI) 46 (58%); (46, 69) 54 (54%); (44, 64)

Stable disease, n (%) 14 (18%) 12 (12%)

Duration of response in all responders (months)b

Median (95% CI) 16.6 (9.3, 25.7) 18.2 (11.6, 30.9)

Range 0.0+-71.0+ 0.0+-59.8+

Duration of response in CR (months)

Median (95% CI) 30.3 (2.4, NE) 26.4 (7.1, NE)

Range 0.7+-50.0+ 0.0+-55.7+

Duration of response in PR (months)

Median (95% CI) 10.6 (7.5, 25.3) 14.7 (9.4, 30.4)

Range 0.0+-67.9+ 0.0+-55.9+

Median time to response

Months (range) 2.2 (1.6-11.1) 2.1 (0.8, 17.9)

Median duration of follow-up

Months (range) 58.5 (1.9-74.3) 53.5 (1.4-70.4)

Progression-free survival

Median (95% CI) 14.8 (11.0, 19.8) 15.1 (11.1, 19.1)

Rate (95% CI) at 12 months 52 (39, 63) 53 (42, 64)

Rate (95% CI) at 24 months 36 (24, 48) 37 (25, 48)

Rate (95% CI) at 60 months 16 (6, 29) 15 (6, 28)

Overall survival

Median Not reached Not reached

Rate (95% CI) at 12 months 95 (87, 98) 90 (82, 94)

Rate (95% CI) at 24 months 87 (77, 93) 86 (77, 91)

Rate (95% CI) at 60 months 72 (60, 81) 67 (56, 75)“+” denotes a censored observation.a Patients in Cohort C (n = 33) who have received brentuximab vedotin only prior to ASCT had ORR of 73% (95% CI:

55, 87), CR of 21% (95% CI: 9, 39), PR of 52% (95% CI: 34, 69). Median duration of response was 13.5 months(95% CI: 9.4, 30.9).

b Determined for subjects with CR or PR.

NE = non-estimable

B-symptoms were present in 22% (53/243) of the patients in CA209205 at baseline. Nivolumabtreatment resulted in rapid resolution of B-symptoms in 88.7% (47/53) of the patients, with a mediantime to resolution of 1.9 months.

In a post-hoc analysis of the 80 patients in CA209205 Cohort B, 37 had no response to priorbrentuximab vedotin treatment. Among these 37 patients, treatment with nivolumab resulted in an

ORR of 62.2% (23/37). The median duration of response is 25.6 months (10.6, 56.5) for the23 responders to nivolumab who had failed to achieve response with prior brentuximab vedotintreatment.

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of metastatic orrecurrent SCCHN were evaluated in a phase 3, randomised, open-label study (CA209141). The studyincluded patients (18 years or older), with histologically confirmed recurrent or metastatic SCCHN(oral cavity, pharynx, larynx), stage III/IV and not amenable to local therapy with curative intent(surgery or radiation therapy with or without chemotherapy) and who have experienced diseaseprogression during or within 6 months of receiving platinum-based therapy regimen and had an ECOGperformance status score of 0 or 1. Prior platinum-based therapy was administered in either theadjuvant, neo-adjuvant, primary, recurrent, or metastatic setting. Patients were enrolled regardless oftheir tumour PD-L1 or human papilloma virus (HPV) status. Patients with active autoimmune disease,medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of thenasopharynx, squamous cell carcinoma of unknown primary, salivary gland or non-squamoushistologies (e.g., mucosal melanoma), or active brain or leptomeningeal metastases were excludedfrom the study. Patients with treated brain metastases were eligible if neurologically returned tobaseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasingdose of < 10 mg daily prednisone equivalents.

A total of 361 patients were randomised to receive either nivolumab 3 mg/kg (n = 240) administeredintravenously over 60 minutes every 2 weeks or investigator’s choice of either cetuximab (n = 15),400 mg/m2 loading dose followed by 250 mg/m2 weekly or methotrexate (n = 52) 40 to 60 mg/m2weekly, or docetaxel (n = 54) 30 to 40 mg/m2 weekly. Randomisation was stratified by priorcetuximab treatment. Treatment was continued as long as clinical benefit was observed or untiltreatment was no longer tolerated. Tumour assessments, according to RECIST version 1.1, wereconducted 9 weeks after randomisation and continued every 6 weeks thereafter. Treatment beyondinitial investigator-assessed RECIST version 1.1-defined progression was permitted in patientsreceiving nivolumab, if the patient had a clinical benefit and was tolerating study drug, as determinedby the investigator. The primary efficacy outcome measure was OS. Key secondary efficacy outcomemeasures were investigator-assessed PFS and ORR. Additional prespecified subgroup analyses wereconducted to evaluate the efficacy by tumour PD-L1 expression at predefined levels of 1%, 5%, and10%.

Pre-study tumour tissue specimens were systematically collected prior to randomisation in order toconduct pre-planned analyses of efficacy according to tumour PD-L1 expression. Tumour PD-L1expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

Baseline characteristics were generally balanced between the two groups. The median agewas 60 years (range: 28-83) with 31% ≥ 65 years of age and 5% ≥ 75 years of age, 83% were male,and 83% were white. Baseline ECOG performance status score was 0 (20%) or 1 (78%), 77% wereformer/current smokers, 90% had Stage IV disease, 66% had two or more lesions, 45%, 34% and 20%received 1, 2, or 3 or more prior lines of systemic therapy, respectively, and 25% were HPV-16 statuspositive.

With a minimum follow-up of 11.4 months, the trial demonstrated a statistically significantimprovement in OS for patients randomised to nivolumab as compared with investigator’s choice. The

Kaplan-Meier curves for OS are shown in Figure 23. Efficacy results are shown in Table 34.

Figure 23: Kaplan-Meier curves of OS (CA209141)

Overall survival (months)

Number of subjects at risk

Nivolumab240 169 132 98 76 45 27 12 3

Investigator’s choice121 88 51 32 22 9 4 3 0 Nivolumab 3 mg/kg (events: 184/240), median and 95% CI: 7.72 (5.68, 8.77)

- - -- - - Investigator’s choice (events: 105/121), median and 95% CI: 5.06 (4.04, 6.24)

Table 34: Efficacy results (CA209141)nivolumab investigator’s choice(n = 240) (n = 121)

Overall survival

Events 184 (76.7%) 105 (86.8%)

Hazard ratioa 0.71(95% CI) (0.55, 0.90)p-valueb 0.0048

Median (95% CI) (months) 7.72 (5.68, 8.77) 5.06 (4.04, 6.24)

Rate (95% CI) at 6 months 56.5 (49.9, 62.5) 43.0 (34.0, 51.7)

Rate (95% CI) at 12 months 34.0 (28.0, 40.1) 19.7 (13.0, 27.3)

Rate (95% CI) at 18 months 21.5 (16.2, 27.4) 8.3 (3.6, 15.7)

Progression-free survival

Events 204 (85.0%) 104 (86.0%)

Hazard ratio 0.8795% CI (0.69, 1.11)p-value 0.2597

Median (95% CI) (months) 2.04 (1.91, 2.14) 2.33 (1.97, 3.12)

Rate (95% CI) at 6 months 21.0 (15.9, 26.6) 11.1 (5.9, 18.3)

Rate (95% CI) at 12 months 9.5 (6.0, 13.9) 2.5 (0.5, 7.8)

Probability of survivalnivolumab investigator’s choice(n = 240) (n = 121)

Confirmed objective responsec 32 (13.3%) 7 (5.8%)(95% CI) (9.3, 18.3) (2.4, 11.6)

Odds ratio (95% CI) 2.49 (1.07, 5.82)

Complete response (CR) 6 (2.5%) 1 (0.8%)

Partial response (PR) 26 (10.8%) 6 (5.0%)

Stable disease (SD) 55 (22.9%) 43 (35.5%)

Median time to response

Months (range) 2.1 (1.8-7.4) 2.0 (1.9-4.6)

Median duration of response

Months (range) 9.7 (2.8-20.3+) 4.0 (1.5+-8.5+)a Derived from a stratified proportional hazards model.b P-value is derived from a log-rank test stratified by prior cetuximab; the corresponding O’Brien-Fleming efficacyboundary significance level is 0.0227.c In the nivolumab group there were two patients with CRs and seven patients with PRs who had tumour PD-L1expression < 1%.

Quantifiable tumour PD-L1 expression was measured in 67% of patients in the nivolumab group and82% of patients in the investigator’s choice group. Tumour PD-L1 expression levels were balancedbetween the two treatment groups (nivolumab vs. investigator’s choice) at each of the predefinedtumour PD-L1 expression levels of ≥ 1% (55% vs. 62%), ≥ 5% (34% vs. 43%), or ≥ 10% (27% vs.34%).

Patients with tumour PD-L1 expression by all predefined expression levels in the nivolumab groupdemonstrated greater likelihood of improved survival compared to investigator’s choice. Themagnitude of OS benefit was consistent for ≥ 1%, ≥ 5% or ≥ 10% tumour PD-L1 expression levels(see Table 35).

Table 35: OS by tumour PD-L1 expression (CA209141)

PD-L1 Expression nivolumab investigator’s choice

OS by tumour PD-L1 expression

Number of events (number of patients) Unstratified hazardratio (95% CI)< 1% 56 (73) 32 (38) 0.83 (0.54, 1.29)≥ 1% 66 (88) 55 (61) 0.53 (0.37, 0.77)≥ 5% 39 (54) 40 (43) 0.51 (0.32, 0.80)≥ 10% 30 (43) 31 (34) 0.57 (0.34, 0.95)

In an exploratory post-hoc analysis using a non-validated assay, both tumour cell PD-L1 expressionand tumour-associated immune cell (TAIC) PD-L1 expression were analysed in relation to themagnitude of treatment effect of nivolumab compared to investigator’s choice. This analysis showedthat not only tumour cell PD-L1 expression but also TAIC PD-L1 expression appeared to beassociated with benefit from nivolumab relative to investigator’s choice (see Table 36). Due to thesmall numbers of patients in the subgroups, and exploratory nature of the analysis, no definitiveconclusions can be drawn from these data.

Table 36: Efficacy by tumour cell and TAIC PD-L1 expression (CA209141)

Median OSa (months) Median PFSa (months) ORR (%)

HRb (95% CI) HRb (95% CI) (95% CI)cnivolumab investigator’s nivolumab investigator’ nivolumab investigator’schoice s choice choice

PD-L1 ≥ 1%, 9.10 4.60 3.19 1.97 19.7 0

PD-L1+ TAIC 0.43 (0.28, 0.67) 0.48 (0.31, 0.75) (10.6, 31.8) (0, 7.5)abundantd(61 nivolumab,47 investigator’schoice)

PD-L1 ≥ 1%, 6.67 4.93 1.99 2.04 11.1 7.1

PD-L1+ TAIC 0.89 (0.44, 1.80) 0.93 (0.46, 1.88) (2.4, 29.2) (0.2, 33.9)rared(27 nivolumab,14 investigator’schoice)

PD-L1 < 1%, 11.73 6.51 2.10 2.73 18.6 12.0

PD-L1+ TAIC 0.67 (0.38, 1.18) 0.96 (0.55, 1.67) (8.4, 33.4) (2.5, 31.2)abundantd(43 nivolumab,25 investigator’schoice)

PD-L1 < 1%, 3.71 4.85 1.84 2.12 3.7 10.0

PD-L1+ TAIC 1.09 (0.50, 2.36) 1.91 (0.84, pct. 4.36) (< 0.1, 19.0) (0.3, 44.5)rared(27 nivolumab,10 investigator’schoice)a OS and PFS were estimated using Kaplan-Meier method.b Hazard ratio in each subgroup derived from a Cox proportional hazards model with treatment as the only covariate.c Confidence interval for ORR calculated using the Clopper-Pearson method.d PD-L1+ TAIC in the tumour microenvironment were qualitatively assessed, and characterised as “numerous”,“intermediate”, and “rare” based on pathologist assessments. “Numerous” and “intermediate” groups were combinedto define the “abundant” group.

Patients with investigator-assessed primary site of oropharyngeal cancer were tested for HPV(determined by p16 immunohistochemistry [IHC]). OS benefit was observed regardless of HPV status(HPV-positive: HR = 0.63; 95% CI: 0.38, 1.04, HPV-negative: HR = 0.64; 95% CI: 0.40, 1.03, and

HPV-unknown: HR = 0.78; 95% CI: 0.55, 1.10).

Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35,and 3-level EQ-5D. Over 15 weeks of follow-up, patients treated with nivolumab exhibited stable

PROs, while those assigned to investigator’s choice therapy exhibited significant declines infunctioning (e.g., physical, role, social) and health status as well as increased symptomatology (e.g.,fatigue, dyspnoea, appetite loss, pain, sensory problems, social contact problems). The PRO datashould be interpreted in the context of the open-label study design and therefore taken cautiously.

Advanced urothelial carcinoma

Randomised open-label phase 3 study of nivolumab in combination with chemotherapy vs.chemotherapy (CA209901)

The safety and efficacy of nivolumab in combination with cisplatin and gemcitabine followed bynivolumab monotherapy were evaluated in a randomised open-label study CA209901 in cisplatin-eligible patients with unresectable or metastatic urothelial carcinoma. The study included subjects(18 years or older) with histological or cytological evidence of metastatic or surgically unresectabletransitional cell carcinoma (TCC) of the urothelium involving the renal pelvis, ureter, bladder orurethra, who were eligible for cisplatin and gemcitabine. Minor histologic variants (< 50% overall)were acceptable (TCC must have been the dominant histology). All subjects were required to havemeasurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST1.1 criteria. No prior systemic anti-cancer therapy for metastatic or surgically unresectable urothelialcarcinoma was permitted. Prior neoadjuvant chemotherapy or prior adjuvant platinum-basedchemotherapy following radical cystectomy were permitted as long as the disease recurrence tookplace ≥ 12 months from completion of therapy. Prior intravesical therapy was permitted if completedat least 4 weeks prior to initiation of study treatment. Radiation therapy (with or withoutchemotherapy) with curative intent was permitted if treatment was completed ≥ 12 months beforeenrolment. Palliative radiotherapy was permitted as long as it was completed at least 2 weeks prior totherapy.

A total of 608 patients were randomised to receive either nivolumab in combination with cisplatin andgemcitabine (n = 304) or cisplatin and gemcitabine (n = 304). Randomisation was stratified by tumour

PD-L1 status (≥ 1% vs. < 1% or indeterminate) and liver metastasis (yes vs. no). The median age was65 years of age (range: 32 to 86) with 51% of patients ≥ 65 years of age and 12% of patients≥ 75 years of age, 23% were Asian, 72% were White, 0.3% were Black; 77% were male, 23% werefemale. Baseline ECOG performance status was 0 (53%) or 1 (46%). Patients in the nivolumab incombination with cisplatin and gemcitabine arm were treated with nivolumab 360 mg every threeweeks, in combination with cisplatin and gemcitabine for up to 6 cycles, after which patients receivednivolumab monotherapy 480 mg every 4 weeks for a total of up to 24 months. Patients receivedgemcitabine dosed at 1000 mg/m2 IV over 30-minutes on Days 1 and 8 of the 3 week treatment cycleand cisplatin dosed at 70 mg/m2 IV over 30 to 120-minutes on Day 1 of the 3 week treatment cycle. Atotal of 92 patients (49 in the nivolumab in combination with cisplatin and gemcitabine arm and 43 inthe cisplatin and gemcitabine arm) switched from cisplatin to carboplatin after at least one cycle ofcisplatin.

The study demonstrated a statistically significant benefit in OS and PFS for patients randomised tonivolumab in combination with cisplatin and gemcitabine compared to cisplatin and gemcitabinealone. Efficacy results are presented in Table 37 and Figures 24 and 25.

Table 37: Efficacy Results (CA209901)nivolumab and cisplatin- cisplatin- gemcitabinegemcitabine chemotherapy chemotherapy(n = 304) (n = 304)

Overall Survivala

Events 172 (56.6) 193 (63.5)

Median (months) 21.7 18.9(95% CI) (18.6, 26.4) (14.7, 22.4)

Hazard ratio (95% CI)b 0.78(0.63, 0.96)p-valuec 0.0171

Progression-free Survivala

Events 211 (69.4) 191 (62.8)

Median (months) 7.92 7.56(95% CI) (7.62, 9.49) (6.05, 7.75)

Hazard ratio (95% CI)b 0.72(0.59, 0.88)p-valuec 0.0012

Objective Response Rate

Responders 175 (57.6) 131 (43.1)(95% CI) (51.8, 63.2) (37.5, 48.9)a Based on Kaplan-Meier Estimatesb Stratified Cox proportional hazard model.c 2 sided p-value from stratified log-rank test.

Figure 24: Kaplan Meier curves of OS (CA209901)

Overall Survival (months)

Number of subjects at risk

Nivolumab + gemcitabine-cisplatin chemotherapy304 286 264 228 196 167 142 119 97 84 69 58 48 36 25 20 15 12 7 4 2 0

Gemcitabine-cisplatin chemotherapy304 277 242 208 166 140 122 102 82 65 49 39 33 24 17 16 13 9 4 4 1 0

- - -- - - Nivolumab + gemcitabine-cisplatin chemotherapy (events: 172/304), median and 95% CI: 21.72(18,63, 26.38)

- - -- - - Gemcitabine-cisplatin chemotherapy (events: 193/304), median and 95% CI: 18.85 (14.72, 22.44)

Based on clinical data cut-off: 09-May-2023, minimum follow-up of 7.4 months

Probability of survival

Figure 25: Kaplan Meier curves of PFS (CA209901)

Progression free Survival (months)

Number of subjects at risk

Nivolumab + gemcitabine-cisplatin chemotherapy304 253 179 116 82 65 57 49 41 36 31 26 19 14 11 10 10 6 5 1 0

Gemcitabine-cisplatin chemotherapy304 223 119 63 35 25 17 12 12 10 9 8 6 5 2 1 1 0 0 0 0

- - -- - - Nivolumab + gemcitabine-cisplatin chemotherapy (events: 211/304), median and 95% CI: 7.92(7.62, 9.49)

- - -- - - Gemcitabine-cisplatin chemotherapy (events: 191/304), median and 95% CI: 7.56 (6.05, 7.75)

Based on clinical data cut-off: 09-May-2023, minimum follow-up of 7.4 months

The primary analysis of PFS included censoring for new anti-cancer treatment before diseaseprogression (Table 37). Results for PFS with and without censoring for new anti-cancer treatmentbefore disease progression were consistent.

Open-label phase 2 study (CA209275)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients withlocally advanced or metastatic urothelial carcinoma was evaluated in a phase 2, multicentre,open-label, single-arm study (CA209275).

The study included patients (18 years or older) who had disease progression during or followingplatinum-containing chemotherapy for advanced or metastatic disease or had disease progressionwithin 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Patients had an ECOG performance status score of 0 or 1 and were enrolled regardless of their tumour

PD-L1 status. Patients with active brain metastases or leptomeningeal metastases, active autoimmunedisease, or medical conditions requiring systemic immunosuppression were excluded from the study.

Patients that received more than 2 prior lines of chemotherapy with liver metastases were excluded.

A total of 270 patients who received nivolumab 3 mg/kg administered intravenously over 60 minutesevery 2 weeks with a minimum follow-up of 8.3 months were evaluable for efficacy. Treatment was

Probability of Progression-free Survivalcontinued as long as clinical benefit was observed or until treatment was no longer tolerated. The firsttumour assessments were conducted 8 weeks after the start of treatment and continued every 8 weeksthereafter up to 48 weeks, then every 12 weeks until disease progression or treatment discontinuation,whichever occurred later. Tumour assessments were continued after treatment discontinuation inpatients who discontinued treatment for reasons other than progression. Treatment beyond initialinvestigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had aclinical benefit, did not have rapid disease progression, and was tolerating study drug as determined bythe investigator. The primary efficacy outcome measure was ORR as determined by BICR. Additionalefficacy measures included duration of response, PFS and OS.

The median age was 66 years (range: 38 to 90) with 55% ≥ 65 years of age and 14% ≥ 75 years of age.

The majority of patients were white (86%) and male (78%). Baseline ECOG performance status was0 (54%) or 1 (46%).

Table 38: Efficacy results (CA209275)anivolumab(n = 270)

Confirmed objective response 54 (20.0%)(95% CI) (15.4, 25.3)

Complete response (CR) 8 (3.0%)

Partial response (PR) 46 (17.0%)

Stable disease (SD) 60 (22.2%)

Median duration of responseb

Months (range) 10.4 (1.9+-12.0+)

Median time to response

Months (range) 1.9 (1.6, 7.2)

Progression-free survival

Events (%) 216 (80)

Median (95% CI) months 2.0 (1.9, 2.6)

Rate (95% CI) at 6 months 26.1 (20.9, 31.5)

Overall survivalc

Events (%) 154 (57)

Median (95% CI) months 8.6 (6.05, 11.27)

Rate (95% CI) at 12 months 41.0 (34.8, 47.1)

Tumour PD-L1 expression level< 1% ≥ 1%

Confirmed objective response(95% CI)16% (10.3, 22.7) 25% (17.7, 33.6)n = 146 n = 124

Median duration of response

Months (range)10.4 (3.7, 12.0+) Not Reached (1.9+, 12.0+)

Progression-free survival

Median (95% CI) months 1.9 (1.8, 2.0) 3.6 (1.9, 3.7)

Rate (95% CI) at 6 months 22.0 (15.6, 29.2) 30.8 (22.7, 39.3)

Overall survival

Median (95% CI) months 5.9 (4.37, 8.08) 11.6 (9.10, NE)

Rate (95% CI) at 12 months 34.0 (26.1, 42.1) 49.2 (39.6, 58.1)“+” denotes a censored observation.a median follow-up 11.5 months.b Data unstable due to the limited duration of response.

c included 4 drug-related deaths: 1 pneumonitis, 1 acute respiratory failure, 1 respiratory failure, and 1 cardiovascularfailure.

NE: non-estimable

Results from post-hoc, exploratory analyses indicate that in patients with low (e.g. <1%) to no tumour

PD-L1 expression, other patient characteristics (e.g. liver metastases, visceral metastases, baselinehaemoglobin <10g/dL and ECOG performance status = 1) might contribute to the clinical outcome.

Open-label phase 1/2 study (CA209032)

CA209032 was a Phase 1/2 open-label multi-cohort study which included a cohort of 78 patients(including 18 subjects who received planned crossover treatment with nivolumab 3 mg/kg plusipilimumab 1 mg/kg combination) with similar inclusion criteria to study CA209275 treated withnivolumab monotherapy 3 mg/kg for urothelial carcinoma. At a minimum follow-up of 9 months,investigator-assessed confirmed ORR was 24.4% (95% CI: 15.3, 35.4). The median duration ofresponse was not reached (range: 4.4-16.6+ months). The median OS was 9.7 months (95% CI: 7.26,16.16) and the estimated OS rates were 69.2% (CI: 57.7, 78.2) at 6 months and 45.6% (CI: 34.2, 56.3)at 12 months.

Adjuvant treatment of urothelial carcinoma

Randomised phase 3 study of adjuvant nivolumab vs. placebo (CA209274)

The safety and efficacy of nivolumab monotherapy for the adjuvant treatment of urothelial carcinomawas evaluated in a phase 3 multicentre, randomised, placebo-controlled, double-blinded study(CA209274). The study included patients (18 years or older) who have undergone radical resection ofmuscle invasive urothelial carcinoma (MIUC) originating in the bladder or upper urinary tract (renalpelvis or ureter) and are at high risk of recurrence. The MIUC pathologic staging criteria that defineshigh risk patients was ypT2-ypT4a or ypN+ for adult patients who received neoadjuvant cisplatinchemotherapy, and pT3-pT4a or pN+ for adult patients who did not receive neoadjuvant cisplatinchemotherapy and were not eligible or refused adjuvant cisplatin chemotherapy. The study includedpatients regardless of their PD-L1 status, who had an ECOG performance status score of 0 or 1 (an

ECOG PS of 2 was allowed for patients ineligible for neoadjuvant cisplatin chemotherapy). Tumourcell PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay. The study excludedpatients with active, known or suspected autoimmune disease, patients who had treatment with anychemotherapy, radiation therapy, biologics for cancer, intravesical therapy, or investigational therapywithin 28 days of first administration of study treatment.

A total of 709 patients were randomised to receive either nivolumab 240 mg (n = 353) every 2 weeksor placebo (n = 356) every 2 weeks until recurrence or unacceptable toxicity for a maximum treatmentduration of 1 year. Of these, 282 patients had tumour cell PD-L1 expression ≥ 1%; 140 in thenivolumab arm and 142 in the placebo arm. Randomisation was stratified by pathologic nodal status(N+ vs. N0/x with < 10 nodes removed vs. N0 with ≥ 10 nodes removed), tumour cell PD-L1expression (≥ 1% vs. < 1%/indeterminate), and use of cisplatin neoadjuvant chemotherapy. Tumourimaging assessments were to be performed every 12 weeks from the date of first dose to week 96, thenevery 16 weeks from week 96 to week 160, then every 24 weeks until non-urothelial tract recurrenceor treatment was discontinued (whichever occurred later) for a maximum of 5 years. The primaryefficacy outcome measures were disease-free survival (DFS) in all randomised patients and DFS inrandomised patients with tumour cell PD-L1 expression ≥ 1%. DFS was defined as the time betweenthe date of randomisation and the date of the first documented recurrence assessed by investigator(local urothelial tract, local non-urothelial tract or distant), or death (from any cause), whicheveroccurred first. Secondary efficacy outcome measures included overall survival (OS).

Baseline characteristics were generally balanced across treatment groups. In patients with tumour cell

PD-L1 expression ≥ 1%, the median age was 66 years (range: 34 - 92 years), 76% were male and 76%were white. Eighty two percent had muscle invasive bladder cancer (MIBC), 18% had upper tracturothelial carcinoma (UTUC) (renal pelvis and ureter), 42% of patients received prior cisplatin in theneoadjuvant setting, 45% of patients were N+ at radical resection, patients had ECOG performancestatus of 0 (61%), 1 (37%), or 2 (2%), and 7% of patients had a haemoglobin < 10 g/dL.

At the primary pre-specified interim analysis in patients with tumour cell PD-L1 expression ≥ 1%(minimum follow-up of 6.3 months and median follow-up of 22.1 months for the nivolumab arm), thestudy demonstrated a statistically significant improvement in DFS for patients randomised tonivolumab as compared to placebo. Median DFS as determined by the investigator was not reached(95% CI: 21.19, N.R.) for nivolumab versus 8.41 months (95% CI: 5.59, 21.19) for placebo, HR 0.55(98.72% CI: 0.35, 0.85), p-value = 0.0005. The primary analysis of DFS included censoring for newanti-cancer treatment. Results for DFS with and without censoring for new anti-cancer treatment wereconsistent.

In an updated descriptive DFS analysis in patients with tumour cell PD-L1 expression ≥ 1%(minimum follow-up of 11.4 months and median follow-up of 25.5 months for the nivolumab arm),

DFS improvement was confirmed.

Efficacy results from this descriptive updated analysis are shown in Table 39 and Figure 26.

Table 39: Efficacy results in patients with tumour cell PD-L1 ≥ 1% (CA209274)nivolumab placebo(n = 140) (n = 142)

Disease-Free Survival Minimum follow-up 11.4 months

Events (%) 56 (40.0) 85 (59.9)

Hazard ratio (95% CI)a 0.53 (0.38, 0.75)

Median (95% CI) (months)b NR (22.11, NE) 8.41 (5.59, 20.04)

Rate (95% CI) at 6 months 74.5 (66.2, 81.1) 55.7 (46.8, 63.6)

Rate (95% CI) at 12 months 67.6 (59.0, 74.9) 46.3 (37.6, 54.5)

Rate (95% CI) at 24 months 58.6 (49.3, 66.9) 37.4 (29.0, 45.8)

NR: not reached, NE: non-estimable.a Stratified Cox proportional hazard model. Hazard Ratio is nivolumab over placebo.b Based on Kaplan-Meier estimates.

Figure 26: Kaplan-Meier curves of DFS in patients with tumour cell PD-L1 expression ≥ 1%(CA209274)

Disease-Free Survival (Months)

Number of subjects at risk

Placebo142 90 74 62 57 53 49 44 36 29 23 21 18 14 9 5 3 2 1 0

Nivolumab140 113 99 96 85 75 67 58 50 38 33 30 29 22 19 8 3 1 0 0

- - -- - - Placebo (events: 85/142), median and 95% CI: 8.41 (5.59, 20.04) Nivolumab (events: 56/140), median and 95% CI: N.A. (22.11, N.A.)

Minimum follow-up of 11.4 months

Exploratory pre-specified subgroup descriptive analyses were performed in patients based on priorcisplatin treatment in the neoadjuvant setting.

In the subgroup of patients with tumour cell PD-L1 expression ≥ 1% who received prior cisplatin inthe neoadjuvant setting (n = 118), the DFS HR was 0.37 (95% CI: 0.22, 0.64) with median DFS notreached and 8.41 months for the nivolumab and placebo arms, respectively. In the subgroup of patientswith tumour cell PD-L1 expression ≥ 1% who did not receive prior cisplatin in the neoadjuvant setting(n = 164), the DFS HR was 0.69 (95% CI: 0.44, 1.08) with median DFS of 29.67 and 11.37 months forthe nivolumab and placebo arms, respectively.

dMMR or MSI-H colorectal cancer

Open-label study of nivolumab in combination with ipilimumab versus chemotherapy in dMMR or

MSI-H CRC patients naive to treatment in the metastatic setting

The safety and efficacy of nivolumab 240 mg in combination with ipilimumab 1 mg/kg every 3 weeks,for a maximum of 4 doses, followed by nivolumab monotherapy 480 mg every 4 weeks in thefirst-line treatment of unresectable or metastatic CRC with known tumour MSI-H or dMMR statuswere evaluated in a randomized, multi-arm, phase 3, open-label study (CA2098HW). Study treatmentarms included nivolumab monotherapy, nivolumab in combination with ipilimumab, or investigator’s

Probability of Disease-Free Survivalchoice of chemotherapy. MSI-H or dMMR tumour status was determined in accordance with localstandard of practice using PCR, NGS or IHC, assays. Central assessment of MSI-H status using PCR(Idylla MSI) test and dMMR status using IHC (Omnis MMR) test was conducted retrospectively onpatient tumour specimens used for local MSI-H/dMMR status determination. Patients with confirmed

MSI-H/dMMR status by either central test comprised the primary efficacy population. Patients withbrain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroidsor immunosuppressants, or had been treated with checkpoint inhibitors were excluded from the study.

Randomisation was stratified by tumour location (right vs left). Patients randomized to thechemotherapy arm could receive nivolumab plus ipilimumab combination upon progression assessedby BICR.

A total of 303 previously untreated patients, in the metastatic setting, were randomised to study,including 202 patients to nivolumab in combination with ipilimumab and 101 patients tochemotherapy. Among them 255 had centrally confirmed MSI-H/dMMR status, 171 in the nivolumabin combination with ipilimumab arm and 84 in the chemotherapy arm. Patients in the nivolumab plusipilimumab arm received nivolumab 240 mg every 3 weeks in combination with ipilimumab 1 mg/kgevery 3 weeks, for a maximum of 4 doses, followed by nivolumab monotherapy 480 mg every4 weeks. Patients in the chemotherapy arm received: mFOLFOX6 (oxaliplatin, leucovorin, andfluorouracil) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin400 mg/m2, and fluorouracil 400 mg/m2 bolus followed by fluorouracil 2400 mg/m2 over 46 hoursevery 2 weeks. Bevacizumab 5 mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6every 2 weeks; or FOLFIRI (irinotecan, leucovorin, and fluorouracil) with or without eitherbevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2bolus and fluorouracil 2400 mg/m2 over 46 hours every 2 weeks. Bevacizumab 5 mg/kg or cetuximab500 mg/m2 administered prior to FOLFIRI every 2 weeks. Treatment continued until diseaseprogression, unacceptable toxicity, or for nivolumab in combination with ipilimumab up to 24 months.

Patients who discontinued combination therapy because of an adverse reaction attributed toipilimumab were permitted to continue nivolumab as a single agent. Tumour assessments per

RECIST v1.1 were conducted every 6 weeks for the first 24 weeks, then every 8 weeks thereafter untilweek 96, then every 16 weeks thereafter until week 146, and then every 24 weeks.

The baseline characteristics of all randomised previously untreated for metastatic disease patientswere: the median age was 63 years (range: 21 to 87), with 46% ≥ 65 years of age and 18% ≥ 75 yearsof age; 46% were male and 86% were White. Baseline ECOG performance status was 0 (54%) and ≥ 1(46%); tumour location was right-sided or left-sided for 68% and 32% of patients, respectively; and39 patients had confirmed Lynch syndrome among the 223 patients with a known status. The baselinecharacteristics of previously untreated for metastatic disease patients with centrally confirmed MSI-

H/dMMR were consistent with all randomised previously untreated patients. Among the 101 patientsrandomised to receive chemotherapy, 88 received chemotherapy per protocol, including oxaliplatin-containing regimens (58%) and irinotecan-containing regimens (42%). Additionally, 66 patientsreceived a targeted agent, either bevacizumab (64%) or cetuximab (11%).

A primary efficacy outcome measure of the study was BICR-assessed PFS per RECIST 1.1.

Additional efficacy measures included ORR assessed by BICR, OS, and duration of response.

The study met the primary endpoint, at the planned interim analysis, demonstrating a statisticallysignificant improvement in BICR assessed-PFS for patients with centrally confirmed MSI-H/dMMRin the nivolumab in combination with ipilimumab arm compared with the chemotherapy arm. The

BICR-assessed PFS results are presented in Table 40 and Figure 27. At the time of this interimanalysis, the other endpoints, including the data from nivolumab monotherapy arm, were not tested,due to testing hierarchy.

Table 40: Efficacy results in first-line MSI-H/dMMR centrally confirmed CRC(CA2098HW)anivolumab + ipilimumab chemotherapy(n = 171) (n = 84)

Progression-free survival

Events 48 (28%) 52 (62%)

Hazard ratio 0.2195% CI (0.14, 0.32)p-valueb < 0.0001

Median (95% CI) (months) NR (38.4, NR) 5.9 (4.4, 7.8)a Median follow-up of 31.5 months (range: 6.1 to 48.4 months).b Based on stratified 2-sided log-rank test

Figure 27: Kaplan-Meier curve of PFS in first-line patients with MSI-H/dMMR centrallyconfirmed CRC (CA2098HW)

Progression free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab171 144 132 122 108 95 92 77 64 53 42 37 22 10 9 1 0

Chemotherapy84 53 29 20 10 6 5 5 3 2 0 0 0 0 0 0 0 Nivolumab + ipilimumab (events: 48/171), median and 95% CI: N.A. (38.44, N.A.)

- - -  - - - Chemotherapy (events: 52/84), median and 95% CI: 5.85 (4.37, 7.79)

Open-label study of nivolumab in combination with ipilimumab in dMMR or MSI-H CRC in patientswho received prior fluoropyrimidine-based combination chemotherapy

The safety and efficacy of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for thetreatment of dMMR or MSI-H metastatic CRC was evaluated in a Phase 2, multi-centre, open-label,single-arm study (CA209142).

The study included patients (18 years or older) with locally determined dMMR or MSI-H status, whohad disease progression during, after, or were intolerant to, prior therapy with fluoropyrimidine andoxaliplatin or irinotecan. Patients who had their most recent prior treatment in the adjuvant settingshould have progressed on or within 6 months of completion of adjuvant chemotherapy. Patients hadan ECOG performance status score of 0 or 1 and were enrolled regardless of their tumour PD-L1status. Patients with active brain metastases, active autoimmune disease, or medical conditionsrequiring systemic immunosuppression were excluded from the study.

Probability of progression-free survival

A total of 119 patients were treated with nivolumab 3 mg/kg administered intravenously over60 minutes in combination with ipilimumab 1 mg/kg administered intravenously over 90 minutesevery 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks. Treatmentwas continued as long as clinical benefit was observed or until treatment was no longer tolerated.

Tumour assessments according to RECIST version 1.1 were conducted every 6 weeks for the first24 weeks and every 12 weeks thereafter. The primary outcome measure was investigator-assessed

ORR. Secondary outcome measures were BICR-assessed ORR and disease control rate. Analysis of

ORR included duration of and time to response. Exploratory outcome measures included PFS and OS.

The median age was 58 years (range: 21-88) with 32% ≥ 65 years of age and 9% ≥ 75 years of age,59% were male and 92% were white. Baseline ECOG performance status was 0 (45%) or 1 (55%),25% of patients had BRAF mutations, 37% had KRAS mutations, and 12% were unknown. Of the119 treated patients, 109 had received prior fluoropyrimidine based chemotherapy in the metastaticsetting and 9 in the adjuvant setting. Before study enrolment, of the 119 treated patients, 118 (99%)had received fluorouracil, 111 (93%) had received oxaliplatin, 87 (73%) had received irinotecan aspart of prior therapies; 82 (69%) had received prior treatment with fluoropyrimidine, oxaliplatin, andirinotecan. Twenty three percent, 36%, 24%, and 16% received 1, 2, 3, or 4 or more prior therapiesrespectively, and 29% of patients had received an EGFR inhibitor.

Efficacy results (minimum follow-up 46.9 months; median follow-up 51.1 months) are shown in

Table 41.

Table 41: Efficacy results (CA209142)*nivolumab + ipilimumab(n = 119)

Confirmed objective response, n (%) 77 (64.7)(95% CI) (55.4, 73.2)

Complete response (CR), n (%) 15 (12.6)

Partial response (PR), n (%) 62 (52.1)

Stable disease (SD), n (%) 25 (21.0)

Duration of response

Median (range) months NR (1.4, 58.0+)

Median time to response

Months (range) 2.8 (1.1, 37.1)

* per investigator assessment“+” denotes a censored observation.

NR = not reached

The BICR-assessed ORR was 61.3% (95% CI: 52.0, 70.1), including CR rate of 20.2% (95% CI: 13.4,28.5), PR rate of 41.2% (95% CI: 32.2, 50.6) and stable disease reported in 22.7%. BICR assessmentswere generally consistent with the investigator assessment. Confirmed responses were observedregardless of BRAF or KRAS mutation status, and tumour PD-L1 expression levels.

Of 119 patients 11 (9.2%) patients were ≥ 75 years. The investigator assessed ORR in patients≥ 75 years was 45.5% (95% CI: 16.7, 76.6).

Oesophageal squamous cell carcinoma

Randomised phase 3 study of nivolumab monotherapy in previously treated patients (ONO-4538-24/

CA209473)

The safety and efficacy of nivolumab 240 mg monotherapy for the treatment of unresectableadvanced, recurrent or metastatic oesophageal squamous cell carcinoma (OSCC) was evaluated in aphase 3 randomised active-controlled, open-label study (ONO-4538-24/CA209473). The studyincluded adult patients (20 years or older) who were refractory or intolerant to at least onefluoropyrimidine- and platinum-based combination regimen, and patients were enrolled regardless oftumour PD-L1 expression level. Patients who were refractory or intolerant to taxane therapy, had brainmetastases that were symptomatic or required treatment, had active autoimmune disease, medicalconditions requiring systemic immunosuppression, and patients with apparent tumour invasion inorgans located adjacent to the oesophagus (e.g. the aorta or respiratory tract), were excluded from thestudy.

A total of 419 patients were randomised 1:1 to receive either nivolumab 240 mg administeredintravenously over 30 minutes every 2 weeks (n = 210) or investigator’s choice of taxanechemotherapy: either docetaxel (n = 65) 75 mg/m2 intravenously every 3 weeks, or paclitaxel(n = 144) 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off. Randomisationwas stratified by location (Japan vs. rest of world), number of organs with metastases (≤ 1 vs. ≥ 2) andtumour PD-L1 expression (≥ 1% vs. <1% or indeterminate). Treatment continued until diseaseprogression, assessed by the investigator per RECIST version 1.1, or unacceptable toxicity. Tumourassessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter. Treatmentbeyond initial investigator-assessed progression was permitted in patients receiving nivolumab with norapid progression, investigator-assessed benefit, tolerance to treatment, stable performance status, andfor whom treatment beyond progression would not delay an imminent intervention to prevent seriouscomplications associated with disease progression (e.g. brain metastasis). The primary efficacyoutcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed ORRand PFS. Additional prespecified subgroup analyses were conducted to evaluate the efficacy bytumour PD-L1 expression at a predefined level of 1%. Tumour PD-L1 expression was determinedusing the PD-L1 IHC 28-8 pharmDx assay.

Baseline characteristics were generally balanced between the two groups. The median age was65 years (range: 33-87), 53% were ≥ 65 years of age, 10% were aged ≥ 75 years, 87% were male, 96%were Asian and 4% were white. Baseline ECOG performance status was 0 (50%) or 1 (50%).

With a minimum follow-up of 17.6 months, the study demonstrated a statistically significantimprovement in OS for patients randomised to nivolumab as compared with investigator’s choicetaxane chemotherapy. Efficacy results are shown in Table 42 and Figure 28.

A higher proportion of patients experienced death within the first 2.5 months in the nivolumab arm(32/210, 15.2%) as compared to the chemotherapy arm (15/209, 7.2%). No specific factor(s)associated with early deaths could be identified.

Table 42: Efficacy results (ONO-4538-24/CA209473)nivolumab investigator’s choice(n = 210) (n = 209)

Overall Survivala

Events 160 (76%) 173 (83%)

Hazard ratio (95% CI)b 0.77 (0.62, 0.96)p-valuec 0.0189

Median (95% CI) (months) 10.9 (9.2, 13.3) 8.4 (7.2, 9.9)

Objective Response Rated,e 33 (19.3%) 34 (21.5%)(95% CI) (13.7, 26.0) (15.4, 28.8)

Complete response 1 (0.6%) 2 (1.3%)

Partial response 32 (18.7%) 32 (20.3%)

Stable disease 31 (18.1%) 65 (41.1%)

Median duration of response (95% CI) (months) 6.9 (5.4, 11.1) 3.9 (2.8, 4.2)

Progression-Free Survivala

Events 187 (89%) 176 (84%)

Median (95% CI) (months) 1.7 (1.5, 2.7) 3.4 (3.0, 4.2)

Hazard ratio (95% CI)b 1.1 (0.9, 1.3)a Based on ITT analysis.b Based on a stratified proportional hazards model.c Based on a stratified log-rank test.

d Based on Response Evaluable Set (RES) analysis, n=171 in nivolumab group and n=158 in investigator’s choicegroup.

e Not significant, p-value 0.6323.

Figure 28: Kaplan-Meier curves of OS (ONO-4538-24/CA209473)

Overall Survival (Months)

Number of subjects at risk

Nivolumab210 182 167 147 126 111 95 82 70 60 43 25 17 13 7 4 3 0 0

Investigator’s choice209 196 169 126 105 84 68 57 49 40 27 17 12 6 2 1 1 1 0 Nivolumab - - - - - - Investigator’s choice

Of the 419 patients, 48% had tumour PD-L1 expression ≥ 1%. The remaining 52% of patients hadtumour PD-L1 expression <1%. The hazard ratio (HR) for OS was 0.69 (95% CI: 0.51, 0.94) withmedian survivals of 10.9 and 8.1 months for the nivolumab and investigator’s choice taxanechemotherapy arms, respectively, in the tumour PD-L1 positive subgroup. In the tumour PD-L1negative OSCC subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9and 9.3 months for the nivolumab and chemotherapy arms, respectively.

Randomised phase 3 study of nivolumab in combination with ipilimumab vs. chemotherapy andnivolumab in combination with chemotherapy vs. chemotherapy as first-line treatment (CA209648)

The safety and efficacy of nivolumab in combination with ipilimumab and nivolumab in combinationwith chemotherapy were evaluated in a randomised, active-controlled, open-label study (CA209648).

The study included adult patients (18 years or older) with previously untreated, unresectable advanced,recurrent or metastatic OSCC. Patients were enrolled regardless of their tumour PD-L1 status, andtumour cell PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay. Patientswere required to have squamous cell carcinoma or adenosquamous cell carcinoma of oesophagus, notamenable to chemoradiation and/or surgery. Prior adjuvant, neoadjuvant, or definitive chemotherapy,radiotherapy or chemoradiotherapy was permitted if given as part of curative intent regimen prior totrial enrollment. Patients who had a baseline performance score ≥ 2, had brain metastases that weresymptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants,or patients at high risk of bleeding or fistula due to apparent invasion of tumour to organs adjacent tothe oesophageal tumour were excluded from the study. Randomisation was stratified by tumour cell

Probability of Overall Survival (%)

PD-L1 status (≥ 1% vs. < 1% or indeterminate), region (East Asia vs. rest of Asia vs. rest of world),

ECOG performance status (0 vs. 1), and number of organs with metastases (≤ 1 vs. ≥ 2).

A total of 970 patients were randomised to receive either nivolumab in combination with ipilimumab,(n = 325), nivolumab in combination with chemotherapy (n = 321), or chemotherapy (n = 324). Ofthese, 473 patients had tumour cell PD-L1 expression ≥ 1%,158 in the nivolumab plus ipilimumabarm, 158 in the nivolumab plus chemotherapy arm, and 157 in the chemotherapy arm. Patients in thenivolumab plus ipilimumab arm received nivolumab 3 mg/kg every 2 weeks in combination withipilimumab 1 mg/kg every 6 weeks, and patients in the nivolumab plus chemotherapy arm receivednivolumab 240 mg every 2 weeks on days 1 and 15, fluorouracil 800 mg/m2/day intravenously ondays 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).

Patients in the chemotherapy arm received fluorouracil 800 mg/m2/day intravenously on days 1through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle). Treatmentcontinued until disease progression, unacceptable toxicity, or up to 24 months. Patients in thenivolumab plus ipilimumab arm who discontinued combination therapy because of an adverse reactionattributed to ipilimumab were permitted to continue nivolumab as a single agent. Patients in thenivolumab plus chemotherapy arm in whom either fluorouracil and/or cisplatin were discontinued,other components of the treatment regimen were allowed to be continued.

Baseline characteristics were generally balanced across treatment groups. In patients with tumour cell

PD-L1 expression ≥ 1%, the median age was 63 years (range: 26-85), 8.2% were ≥ 75 years of age,81.8% were male, 73.1% were Asian, and 23.3% were white. Patients had histological confirmation ofsquamous cell carcinoma (98.9%) or adenosquamous cell carcinoma (1.1%) in the oesophagus.

Baseline ECOG performance status was 0 (45.2%) or 1 (54.8%).

Nivolumab in combination with ipilimumab vs. chemotherapy

The primary efficacy outcome measures were PFS (by BICR) and OS assessed in patients with tumourcell PD-L1 expression ≥ 1%. Secondary endpoints per the pre-specified hierarchical testing included

OS, PFS (by BICR), and ORR (by BICR) in all randomised patients. The tumour assessments per

RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeksthereafter.

At the primary pre-specified analysis, with a minimum follow-up of 13.1 months, the studydemonstrated a statistically significant improvement in OS in patients with tumour cell PD-L1expression ≥ 1%. Efficacy results are shown in Table 43.

Table 43: Efficacy results in patients with tumour cell PD-L1 ≥ 1% (CA209648)nivolumab + ipilimumab chemotherapya(n = 158) (n = 157)

Overall survival

Events 106 (67.1%) 121 (77.1%)

Hazard ratio (98.6% CI)b 0.64 (0.46, 0.90)p-valuec 0.0010

Median (95% CI) (months)d 13.70 (11.24, 17.02) 9.07 (7.69, 9.95)

Rate (95% CI) at 12 monthsd 57.1 (49.0, 64.4) 37.1 (29.2, 44.9)

Progression-free survivale

Events 123 (77.8%) 100 (63.7%)

Hazard ratio (98.5% CI)b 1.02 (0.73, 1.43)p-valuec 0.8958

Median (95% CI) (months)d 4.04 (2.40, 4.93) 4.44 (2.89, 5.82)

Rate (95% CI) at 12 monthsd 26.4 (19.5, 33.9) 10.5 (4.7, 18.8)nivolumab + ipilimumab chemotherapya(n = 158) (n = 157)

Overall response rate, n (%)e 56 (35.4) 31 (19.7)(95% CI) (28.0, 43.4) (13.8, 26.8)

Complete response 28 (17.7) 8 (5.1)

Partial response 28 (17.7) 23 (14.6)

Duration of responsee

Median (95% CI) (months)d 11.83 (7.10, 27.43) 5.68 (4.40, 8.67)

Range 1.4+, 34.5+ 1.4+, 31.8+a Fluorouracil and cisplatin.b Based on stratified Cox proportional hazard model.c Based on stratified 2-sided log-rank test.d Based on Kaplan-Meier estimates.e Assessed by BICR.

At an updated descriptive analysis with a minimum follow-up of 20 months, OS improvements wereconsistent with the primary analysis. Median OS was 13.70 months (95% CI: 11.24, 17.41) fornivolumab plus ipilimumab vs. 9.07 months (95% CI: 7.69, 10.02) for chemotherapy (HR = 0.63;95% CI: 0.49, 0.82). Median PFS was 4.04 months (95% CI: 2.40, 4.93) for nivolumab plusipilimumab vs. 4.44 months (95% CI: 2.89, 5.82) for chemotherapy (HR = 1.02; 95% CI: 0.77, 1.34).

The ORR was 35.4% (95% CI: 28.0, 43.4) for nivolumab plus ipilimumab vs. 19.7% (95% CI:13.8, 26.8) for chemotherapy.

The Kaplan-Meier curves for OS with a minimum follow-up of 20 months are shown in Figure 29.

Figure 29: Kaplan-Meier curves of OS in patients with tumour cell PD-L1 ≥ 1% (CA209648)

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab158 136 116 98 89 72 63 55 43 31 20 16 10 9 4 2 0

Chemotherapy157 137 107 73 53 40 30 21 15 12 8 6 3 2 1 0 0 Nivolumab + ipilimumab (events: 119/158), median and 95% CI: 13.70 (11.24, 17.41)

- - -  - - - Chemotherapy (events: 130/157), median and 95% CI: 9.07 (7.69, 10.02)

Based on data cut-off: 23-Aug-2021, minimum follow-up of 20 months

Nivolumab in combination with chemotherapy vs. chemotherapy

The primary efficacy outcome measures were PFS (by BICR) and OS in patients with tumour cell

PD-L1 expression ≥ 1%. Secondary endpoints per the pre-specified hierarchical testing included OS,

PFS (by BICR), and ORR (by BICR) in all randomised patients. The tumour assessments per

RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeksthereafter.

At the primary pre-specified analysis, with a minimum follow-up of 12.9 months the studydemonstrated a statistically significant improvement in OS and PFS in patients with tumour cell

PD-L1 expression ≥ 1%. Efficacy results are shown in Table 44.

Table 44: Efficacy results in patients with tumour cell PD-L1 ≥ 1% (CA209648)nivolumab + chemotherapy chemotherapya(n = 158) (n = 157)

Overall survival

Events 98 (62.0%) 121 (77.1%)

Hazard ratio (99.5% CI)b 0.54 (0.37, 0.80)p-valuec <0.0001

Median (95% CI) (months)d 15.44 (11.93, 19.52) 9.07 (7.69, 9.95)

Rate (95% CI) at 12 monthsd 58.0 (49.8, 65.3) 37.1 (29.2, 44.9)

Probability of survivalnivolumab + chemotherapy chemotherapya(n = 158) (n = 157)

Progression-free survivale

Events 117 (74.1%) 100 (63.7%)

Hazard ratio (98.5% CI)b 0.65 (0.46, 0.92)p-valuec 0.0023

Median (95% CI) (months)d 6.93 (5.68, 8.34) 4.44 (2.89, 5.82)

Rate (95% CI) at 12 monthsd 25.4 (18.2, 33.2) 10.5 (4.7, 18.8)

Overall response rate, n (%)e 84 (53.2) 31 (19.7)(95% CI) (45.1, 61.1) (13.8, 26.8)

Complete response 26 (16.5) 8 (5.1)

Partial response 58 (36.7) 23 (14.6)

Duration of responsee

Median (95% CI) (months)d 8.38 (6.90, 12.35) 5.68 (4.40, 8.67)

Range 1.4+, 34.6 1.4+, 31.8+a Fluorouracil and cisplatin.b Based on stratified Cox proportional hazard model.c Based on stratified 2-sided log-rank test.d Based on Kaplan-Meier estimates.e Assessed by BICR.

At an updated descriptive analysis with a minimum follow-up of 20 months, OS improvements wereconsistent with the primary analysis. Median OS was 15.05 months (95% CI: 11.93, 18.63) fornivolumab plus chemotherapy vs. 9.07 months (95% CI: 7.69, 10.02) for chemotherapy (HR = 0.59;95% CI: 0.46, 0.76). Median PFS was 6.93 months (95% CI: 5.68, 8.35) for nivolumab pluschemotherapy vs. 4.44 months (95% CI: 2.89, 5.82) for chemotherapy (HR = 0.66; 95% CI: 0.50,0.87). The ORR was 53.2% (95% CI: 45.1, 61.1) for nivolumab plus chemotherapy vs. 19.7%(95% CI: 13.8, 26.8) for chemotherapy.

The Kaplan-Meier curves for OS and PFS with a minimum follow-up of 20 months are shown in

Figures 30 and 31.

Figure 30: Kaplan-Meier curves of OS in patients with tumour cell PD-L1 ≥ 1% (CA209648)

Overall survival (months)

Number of subjects at risk

Nivolumab + chemotherapy158 143 129 105 88 76 66 52 38 32 19 15 5 1 0 0

Chemotherapy157 137 107 73 53 40 30 21 15 12 8 6 3 2 1 0

- - -- - - Nivolumab + chemotherapy (events: 118/158), median and 95% CI: 15.05 (11.93, 18.63)

- - -- - - Chemotherapy (events: 130/157), median and 95% CI: 9.07 (7.69, 10.02)

Based on data cut-off: 23-Aug-2021, minimum follow-up of 20 months

Probability of survival

Figure 31: Kaplan-Meier curves of PFS in patients with tumour cell PD-L1 ≥ 1%(CA209648)

Progression-free survival (months)

Number of subjects at risk

Nivolumab + chemotherapy158 107 75 47 30 22 16 10 10 7 6 4 0 0 0

Chemotherapy157 68 36 17 5 1 1 1 1 1 1 1 1 1 0

- - -- - - Nivolumab + chemotherapy (events: 123/158), median and 95% CI: 6.93 (5.65, 8.35)

- - -- - - Chemotherapy (events: 101/157), median and 95% CI: 4.44 (2.89, 5.82)

Based on data cut-off: 23-Aug-2021, minimum follow-up of 20 months

Adjuvant treatment of oesophageal or gastro-oesophageal junction cancer

The safety and efficacy of nivolumab monotherapy for the adjuvant treatment of oesophageal orgastro-oesophageal junction cancer was evaluated in a phase 3 multicentre, randomised,placebo-controlled, double-blinded study (CA209577). The study included adult patients who hadreceived CRT, followed by complete surgical resection of carcinoma within 16 weeks prior torandomisation, and who had residual pathologic disease as confirmed by the investigator, with at leastypN1 or ypT1. Patients with a baseline performance score ≥ 2, who did not receive concurrent CRTprior to surgery, with stage IV resectable disease, active autoimmune disease, or medical conditionsrequiring systemic immunosuppression were excluded from the study. Patients were enrolledregardless of tumour PD-L1 expression level.

A total of 794 patients were randomised 2:1 to receive either nivolumab 240 mg (n = 532) or placebo(n = 262). Patients were administered nivolumab intravenously over 30 minutes every 2 weeks for16 weeks followed by 480 mg infused over 30 minutes every 4 weeks beginning at week 17. Patientswere administered placebo over 30 minutes with the same dosing schedule as nivolumab.

Randomisation was stratified by tumour PD-L1 status (≥1% vs. <1% or indeterminate ornon-evaluable), pathologic lymph node status (positive ≥ ypN1 vs. negative ypN0), and histology(squamous vs. adenocarcinoma). Treatment continued until disease recurrence, unacceptable toxicity,or for up to 1 year in total duration. The primary efficacy outcome measure was disease-free survival(DFS), as assessed by the investigator, defined as the time between the date of randomisation and thedate of first recurrence (local, regional, or distant from the primary resected site) or death from anycause, whichever occurred first. Patients on treatment underwent imaging for tumour recurrence every12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5.

Probability of progression-free survival

Baseline characteristics were generally balanced between the two groups. The median age was62 years (range: 26-86) with 36% ≥ 65 years of age and 5% ≥ 75 years of years. The majority ofpatients were white (82%) and male (85 %). Baseline ECOG performance status was 0 (58%) or1 (42%).

At the primary pre-specified interim analysis (minimum of 6.2 months and a median of 24.4 monthsfollow-up), the study demonstrated a statistically significant improvement in DFS for patientsrandomised to nivolumab compared with placebo. Median DFS as determined by the investigator was22.41 months (95% CI: 16.62, 34.00) for nivolumab versus 11.04 months (95% CI: 8.34, 14.32) forplacebo, HR 0.69 (96.4% CI: 0.56, 0.86), p-value < 0.0003. The primary analysis of DFS includedcensoring for new anti-cancer treatment. Results for DFS with and without censoring for newanti-cancer treatment were consistent. In an updated descriptive DFS analysis with minimum of14 months and median of 32.2 months follow-up, DFS improvement was confirmed. Efficacy resultsfrom this descriptive secondary analysis are shown in Table 45 and Figure 32.

Table 45: Efficacy results (CA209577)nivolumab placebo(n = 532) (n = 262)

Disease-free Survivala with minimum follow-up 14 monthsc

Events (%) 268 (50) 171 (65)

Hazard ratio (95% CI)b 0.67 (0.55, 0.81)

Median (95% CI) (months) 22.4 (17.0, 33.6) 10.4 (8.3, 13.9)

Rate (95% CI) at 6 months 72.6 (68.5, 76.3) 61.5 (55.3, 67.1)

Rate (95% CI) at 12 months 61.8 (57.4, 65.8) 45.5 (39.3, 51.4)

Rate (95% CI) at 24 months 48.3 (43.7, 52.8) 36.0 (29.9, 42.0)a Based on all randomised patients.b Based on a stratified cox proportional hazards model.c Descriptive analysis based on data cut-off: 18-Feb-2021.

Figure 32: Kaplan-Meier curves of DFS (CA209577)

Disease-free Survival (months)

Number of subjects at risk

Nivolumab532 433 371 342 307 272 228 194 160 137 106 84 57 34 19 4 4 0

Placebo262 211 158 134 114 107 88 73 62 50 33 30 18 11 5 3 1 0 Nivolumab (events: 268/532), median and 95% CI: 22.41 (16.95, 33.64)

- - -- - - Placebo (events: 171/262), median and 95% CI: 10.35 (8.31, 13.93)

Based on data cut-off: 18-Feb-2021, minimum follow-up of 14 months

DFS benefit was observed regardless of histology and PD-L1 expression.

Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma

The safety and efficacy of nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combinationwith chemotherapy (dose and schedule of nivolumab selected depending on the chemotherapy regimenused, see below) was evaluated in a phase 3, randomised, open-label study (CA209649). The studyincluded adult patients (18 years or older) with previously untreated advanced or metastatic gastric,gastro-oesophageal junction (GEJ) or oesophageal adenocarcinoma, no prior systemic treatment(including HER2 inhibitors), and ECOG performance status score 0 or 1. Patients were enrolledregardless of their tumour cell PD-L1 status, and tumour cell PD-L1 expression was determined usingthe PD-L1 IHC 28-8 pharmDx assay. A retrospective re-scoring of a patient’s tumour PD-L1 statususing CPS was conducted using the PD-L1-stained tumour specimens used for randomisation. Patientswith known HER2-positive tumours, who had baseline ECOG performance score ≥ 2, untreatedcentral nervous system metastases, or who had active, known, or suspected autoimmune disease, ormedical conditions requiring systemic immunosuppression were excluded from the study. A total of643 patients with HER2-undetermined status (40.3% of the study population) were included in thestudy. Randomisation was stratified by tumour cell PD-L1 status (≥ 1% vs. < 1% or indeterminate),region (Asia vs. US vs. rest of world), ECOG performance status (0 vs. 1), and chemotherapy regimen.

Chemotherapy consisted of FOLFOX (fluorouracil, leucovorin and oxaliplatin) or CapeOX(capecitabine and oxaliplatin).

Probability of Disease-Free Survival

A total of 1581 patients were randomised to receive either nivolumab in combination withchemotherapy or chemotherapy. Of these, 955 patients had PD-L1 CPS ≥ 5; 473 in the nivolumab pluschemotherapy arm and 482 in the chemotherapy arm. Patients in the nivolumab plus chemotherapyarm received either nivolumab 240 mg by intravenous infusion over 30 minutes in combination with

FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 400 mg/m2 intravenously onday 1 and fluorouracil 1200 mg/m2 intravenously by continuous infusion over 24 hours daily or perlocal standard on days 1 and 2) every 2 weeks, or nivolumab 360 mg by intravenous infusion over30 minutes in combination with CapeOX (oxaliplatin 130 mg/m2 intravenously on day 1 andcapecitabine 1000 mg/m2 orally twice daily on days 1-14) every 3 weeks. Treatment continued untildisease progression, unacceptable toxicity, or for up to 24 months for nivolumab only. In patients whoreceived nivolumab plus chemotherapy and in whom chemotherapy was discontinued, nivolumabmonotherapy was allowed to be given at 240 mg every 2 weeks, 360 mg every 3 weeks or 480 mgevery 4 weeks up to 24 months after treatment initiation. Tumour assessments were performed every6 weeks up to and including week 48, then every 12 weeks thereafter.

Baseline characteristics were generally balanced across treatment groups. In patients with PD-L1

CPS ≥ 5, the median age was 62 years (range: 18-90), 11% were ≥ 75 years of age, 71% were male,25% were Asian and 69% were white. Baseline ECOG performance status was 0 (42%) or 1 (58%).

Tumour locations were distributed as gastric (70%), GEJ (18%) and oesophagus (12%).

Primary efficacy outcome measures were PFS (by BICR) and OS assessed in patients with PD-L1

CPS ≥ 5 based on the PD-L1 IHC 28-8 pharmDX. Secondary endpoints per the pre-specifiedhierarchical testing were OS in patients with PD-L1 CPS ≥ 1 and in all randomised patients; furtherendpoints included ORR (BICR) in PD-L1 CPS ≥ 5 and all randomised patients. At the primary pre-specified analysis, with a minimum follow-up of 12.1 months, the study demonstrated a statisticallysignificant improvement in OS and PFS in patients with PD-L1 CPS ≥ 5. Median OS was 14.4 months(95% CI: 13.1, 16.2) for nivolumab in combination with chemotherapy vs. 11.1 months (95% CI: 10.0,12.1) for chemotherapy (HR = 0.71; 98.4% CI: 0.59, 0.86; p-value <0.0001). Median PFS was7.69 months (95% CI: 7.03, 9.17) for nivolumab in combination with chemotherapy vs. 6.05 months(95% CI: 5.55, 6.90) for chemotherapy (HR = 0.68; 98% CI: 0.56, 0.81; p-value <0.0001). The ORRwas 60% (95% CI: 55, 65) for nivolumab in combination with chemotherapy vs. 45%(95% CI: 40, 50) for chemotherapy.

At an updated descriptive analysis with a minimum follow-up of 19.4 months, OS improvements wereconsistent with the primary analysis. Efficacy results are shown in Table 46, and Figures 33, and 34.

Table 46: Efficacy results in patients with PD-L1 CPS ≥ 5 (CA209649)nivolumab + chemotherapy chemotherapy(n = 473) (n = 482)

Minimum follow-up 19.4 monthsa

Overall survival

Events 344 (73%) 397 (82%)

Hazard ratio (95% CI)b 0.69 (0.60, 0.81)

Median (95% CI) (months)c 14.4 (13.1, 16.3) 11.1 (10.0, 12.1)

Rate (95% CI) at 12 months 57.3 (52.6, 61.6) 46.4 (41.8, 50.8)

Progression-free survivald

Events 342 (72.3%) 366 (75.9%)

Hazard ratio (95% CI)b 0.68 (0.59, 0.79)

Median (95% CI) (months)c 8.31 (7.03, 9.26) 6.05 (5.55, 6.90)

Rate (95% CI) at 12 months 36.3 (31.7, 41.0) 21.9 (17.8, 26.1)nivolumab + chemotherapy chemotherapy(n = 473) (n = 482)

Objective response rate, nd,e 227/378 (60%) 176/390 (45%)(95% CI) (54.9, 65.0) (40.1, 50.2)

Complete response 12.2% 6.7%

Partial response 47.9% 38.5%

Duration of responsed,e

Median (95% CI) (months)c 9.69 (8.25, 12.22) 6.97 (5.62, 7.85)a Descriptive analysis based on data cut-off: 04-Jan-2021.b Based on stratified long Cox proportional hazard model.c Kaplan-Meier estimate.d Confirmed by BICR.e Based on patients with measurable disease at baseline.

Figure 33: Kaplan-Meier curves of OS in patients with PD-L1 CPS ≥ 5 (CA209649)

Overall survival (months)

Number of subjects at risk

Nivolumab + chemotherapy473 439 378 314 263 223 187 155 118 78 56 37 23 13 4 0

Chemotherapy482 421 350 272 213 152 122 92 68 44 28 16 8 2 0 0 Nivolumab + chemotherapy (events: 344/473), median and 95% CI: 14.42 (13.14, 16.26)

- - -- - - Chemotherapy (events: 397/482), median and 95% CI: 11.10 (10.02, 12.09)

Minimum follow-up of 19.4 months

Probability of survival

Figure 34: Kaplan-Meier curves of PFS in patients with PD-L1 CPS ≥ 5 (CA209649)

Progression free survival (months)

Number of subjects at risk

Nivolumab + chemotherapy473 386 259 186 143 115 88 67 47 31 20 11 4 1 0

Chemotherapy482 328 202 114 81 58 46 30 20 16 12 7 3 0 0 Nivolumab + chemotherapy (events: 342/473), median and 95% CI: 8.31 (7.03, 9.26)

- - -- - - Chemotherapy (events: 397/482), median and 95% CI: 6.05 (5.55, 6.90)

Minimum follow-up of 19.4 months

Hepatocellular carcinoma

The safety and efficacy of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg every3 weeks, for a maximum of 4 doses, followed by nivolumab monotherapy 480 mg every 4 weeks inthe first-line treatment of unresectable or advanced hepatocellular carcinoma (HCC) were evaluated ina phase 3, randomised, active-controlled, open-label study (CA2099DW). The study included adultpatients (18 years or older) with histologically confirmed HCC, Child Pugh Class A, ECOGperformance status 0 or 1, and no prior systemic therapy for advanced disease.

Esophagogastroduodenoscopy was not mandated prior to enrolment. The study enrolled adults whosedisease was not amenable to or progressed after surgical and/or locoregional therapies. Priorneo-adjuvant or adjuvant systemic therapy was permitted. Patients with active autoimmune disease,brain or leptomeningeal metastases, prior liver transplant, a history of hepatic encephalopathy (within12 months of randomisation), clinically significant ascites, medical conditions requiring systemicimmunosuppression, infection with HIV, or active co infection with hepatitis B virus (HBV) andhepatitis C virus (HCV) or HBV and hepatitis D virus (HDV) were excluded from the study.

Randomisation was stratified by aetiology (HBV vs. HCV vs. non-viral), macrovascular invasionand/or extrahepatic spread (present or absent), and alpha-fetoprotein levels (≥ 400 or < 400 ng/mL).

Probability of progression-free survival

A total of 668 patients were randomised to receive nivolumab in combination with ipilimumab(n = 335) or investigator’s choice (n = 333) of lenvatinib or sorafenib. In the investigator’s choice arm,85% and 15% of treated patients received lenvatinib or sorafenib, respectively. Patients in thenivolumab plus ipilimumab arm received nivolumab 1 mg/kg every 3 weeks in combination withipilimumab 3 mg/kg every 3 weeks, for up to a maximum of 4 doses, followed by nivolumabmonotherapy 480 mg every 4 weeks. Patients in the investigators’ choice arm received eitherlenvatinib 8 mg orally daily (if body weight < 60 kg) or 12 mg orally daily (if body weight ≥ 60 kg),or sorafenib 400 mg orally twice daily. Treatment continued until disease progression, unacceptabletoxicity, or for up to 24 months. Patients who discontinued combination therapy because of an adversereaction attributed to ipilimumab were permitted to continue nivolumab as a single agent. Tumourassessments were conducted at baseline, after randomisation at week 9 and week 16, then every8 weeks up to 48 weeks, and then every 12 weeks thereafter until disease progression, treatmentdiscontinuation, or initiation of subsequent therapy.

Baseline characteristics were generally balanced across treatment groups. The median age was66 years (range: 20 to 89), with 53% ≥ 65 years and 16% ≥ 75 years, 53% were White, 44% were

Asian, 2.2% were Black, and 82% were male. Baseline ECOG performance status was 0 (71%) or 1(29%). Thirty-four percent (34%) of patients had HBV infection, 28% had HCV infection, and 36%had no evidence of HBV or HCV infection. Nineteen percent (19%) of patients had alcoholic liverdisease and 11% had non-alcoholic fatty liver disease. The majority of patients had BCLC stage C(73%) disease at baseline, 19% had stage B, and 6% had stage A. Patients with Child-Pugh scores of5, 6, and ≥ 7 were 77%, 20%, and 3%, respectively. A total of 54% of patients had extrahepaticspread; 25% had macrovascular invasion; and 33% had AFP levels ≥ 400 µg/L.

The study demonstrated a statistically significant benefit in OS and ORR for patients randomised tonivolumab in combination with ipilimumab compared to investigator’s choice of lenvatinib orsorafenib. Efficacy results are presented in Table 47 and Figure 35.

Table 47: Efficacy results in first-line HCC (CA2099DW)anivolumab + ipilimumab lenvatinib or sorafenib(n = 335) (n = 333)

Overall survival

Events 194 (58%) 228 (68%)

Median (months) 23.7 20.6(95% CI) (18.8, 29.4) (17.5, 22.5)

Hazard ratio (95% CI)b 0.79 (0.65, 0.96)p-valuec 0.0180

Overall Response Rate, n (%)d 121 (36.1) 44 (13.2)(95% CI) (31.0, 41.5) (9.8, 17.3)p-valuee < 0.0001

Complete response (%) 23 (6.9) 6 (1.8)

Partial response (%) 98 (29.3) 38 (11.4)

Duration of Response (months)d

Median 30.4 12.9(95% CI) (21.2, N.A.) (10.2, 31.2)a Minimum follow-up of 26.8 months. Median follow up of 35.2 months.b Based on stratified Cox proportional hazard model.c Based on a 2-sided stratified log-rank test. Boundary for statistical significance: p-value ≤ 0.0257.d Assessed by BICR using RECIST 1.1.e Based on a 2-sided stratified Cochran-Mantel-Haenszel test. Boundary for statistical significance: p-value ≤ 0.025.

Figure 35: Kaplan-Meier curve of OS in first-line patients with HCC (CA2099DW)

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab335 300 264 239 220 206 179 162 150 137 104 71 42 24 11 8 0 0

Investigator’s choice333 310 280 245 216 194 164 144 116 106 76 44 34 20 4 3 1 0--+---- Nivolumab + ipilimumab (events: 194/335), median and 95% CI: 23.66 (18.33, 29.44)

- - -+- - - Lenvatinib or sorafenib (events: 228/333), median and 95% CI: 20.63 (17.48, 22.54)

Open label phase 1/2 study (CA209070)

Study CA209070 was an open-label, single-arm, dose-confirmation and dose-expansion, phase 1/2study of nivolumab as a single agent and in combination with ipilimumab in paediatric and youngadult patients with recurrent or refractory solid or haematological tumours, including neuroblastoma,osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, advanced melanoma, cHL and non-Hodgkinlymphoma (NHL). Among the 126 treated patients, 97 were paediatric patients from 12 monthsto < 18 years of age. Of the 97 paediatric patients, 64 were treated with nivolumab monotherapy(3 mg/kg administered intravenously over 60 minutes every 2 weeks) and 33 were treated withnivolumab in combination with ipilimumab (nivolumab 1 mg/kg or 3 mg/kg administeredintravenously over 60 minutes in combination with ipilimumab 1 mg/kg administered intravenouslyover 90 minutes every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapyevery 2 weeks). Patients received either nivolumab as monotherapy for a median of 2 doses(range: 1, 89) or nivolumab in combination with ipilimumab for a median of 2 doses (range: 1, 24).

The main primary outcome measures were safety, tolerability and antitumour activity as evaluated bydescriptive ORR and OS.

Among the 64 paediatric patients treated with nivolumab monotherapy, 60 were response-evaluablepatients (melanoma n = 1, solid tumours n = 47 and haematological tumours n = 12). In the48 response-evaluable paediatric patients with melanoma or solid tumours, no objective responseswere observed. In the 12 response-evaluable paediatric patients with haematological tumours, ORRwas 25.0% (95% CI: 5.5, 57.2), including 1 complete response in cHL and 2 partial responses, one incHL and another one in NHL. In the descriptive analyses for the 64 paediatric patients treated withnivolumab monotherapy, the median OS was 6.67 months (95% CI: 5.98, NA); 6.14 months

Probability of overall survival(95% CI: 5.39, 24.67) for patients with melanoma or solid tumours, and not reached for patients withhaematological tumours.

Among the 30 response-evaluable paediatric patients treated with nivolumab in combination withipilimumab (solid tumours other than melanoma only), no objective responses were observed. For the33 paediatric patients treated with nivolumab in combination with ipilimumab, the median OS was8.25 months (95% CI: 5.45, 16.95) in a descriptive analysis.

Open label phase 1b/2 study (CA209908)

Study CA209908 was an open-label, sequential-arm, phase 1b/2 clinical study of nivolumabmonotherapy and nivolumab in combination with ipilimumab in paediatric and young adult patientswith high-grade primary CNS malignancies, including diffuse intrinsic pontine glioma (DIPG),high-grade glioma, medulloblastoma, ependymoma and other recurrent subtypes of high-grade CNSmalignancy (e.g., pineoblastoma, atypical teratoid/rhabdoid tumour, and embryonal CNS tumours). Ofthe 151 paediatric patients (from ≥ 6 months to < 18 years old) enrolled in the study, 77 were treatedwith nivolumab monotherapy (3 mg/kg every 2 weeks) and 74 were treated with nivolumab incombination with ipilimumab (3 mg/kg nivolumab followed by 1 mg/kg ipilimumab, every 3 weeksfor 4 doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks). The primary efficacyoutcome measures were OS in the DIPG cohort and investigator-assessed PFS, based on RANOcriteria, for all other tumour types. The median OS in the DIPG cohort was 10.97 months(80% CI: 9.92, 12.16) in patients treated with nivolumab monotherapy and 10.50 months(80% CI: 9.10, 12.32) in patients treated with nivolumab in combination with ipilimumab. For allother studied CNS paediatric tumour types, the median PFS ranged from 1.23 to 2.35 months inpatients treated with nivolumab monotherapy and from 1.45 to 3.09 months in patients treated withnivolumab in combination with ipilimumab. There were no objective responses observed in the studywith the exception of one ependymoma patient treated with nivolumab monotherapy who had a partialresponse. Results for OS, PFS, and ORR observed in study CA209908 do not suggest clinicallymeaningful benefit over what may be expected in these patient populations.

The European Medicines Agency has deferred the obligation to submit the results of studies withnivolumab in all subsets of the paediatric population in the treatment of malignant neoplasms oflymphoid tissue (see section 4.2 for information on paediatric use).

Safety and efficacy in elderly patients

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and youngerpatients (< 65 years). Data from SCCHN, adjuvant melanoma, and adjuvant OC or GEJC patients75 years of age or older are too limited to draw conclusions on this population. Data from cHLpatients 65 years of age or older are too limited to draw conclusions on this population. Data from

MPM patients showed a higher rate of serious adverse reactions and discontinuation rate due toadverse reactions in patients 75 years of age or older (68% and 35%, respectively) relative to allpatients who received nivolumab in combination with ipilimumab (54% and 28%, respectively).

Nivolumab monotherapy

The pharmacokinetics (PK) of nivolumab is linear in the dose range of 0.1 to 10 mg/kg. The geometricmean clearance (CL), terminal half-life, and average exposure at steady state at 3 mg/kg every 2 weeksof nivolumab were 7.9 mL/h, 25.0 days, and 86.6 μg/mL, respectively, based on a population PKanalysis.

Nivolumab CL in cHL patients was approximately 32% lower relative to NSCLC. Nivolumab baseline

CL in adjuvant melanoma patients was approximately 40% lower and steady state CL approximately20% lower relative to advanced melanoma. With available safety data, these decreases in CL were notclinically meaningful.

The metabolic pathway of nivolumab has not been characterised. Nivolumab is expected to bedegraded into small peptides and amino acids via catabolic pathways in the same manner asendogenous IgG.

Nivolumab in combination with ipilimumab

When nivolumab 1 mg/kg was administered in combination with ipilimumab 3 mg/kg, the CL ofnivolumab was increased by 29% and the CL of ipilimumab was increased by 9%, which was notconsidered clinically relevant. When nivolumab 3 mg/kg was administered in combination withipilimumab 1 mg/kg, the CL of nivolumab was increased by 1% and the CL of ipilimumab wasdecreased by 1.5%, which were not considered clinically relevant.

When administered in combination with ipilimumab, the CL of nivolumab increased by 20% in thepresence of anti-nivolumab antibodies and the CL of ipilimumab increased by 5.7% in the presence ofanti-ipilimumab antibodies. These changes were not considered clinically relevant.

Nivolumab in combination with ipilimumab and chemotherapy

When nivolumab 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kgevery 6 weeks and with 2 cycles of chemotherapy, the CL of nivolumab decreased approximately 10%and the CL of ipilimumab increased approximately 22%, which were not considered clinicallyrelevant.

A population PK analysis suggested no difference in CL of nivolumab based on age, gender, race,solid tumour type, tumour size, and hepatic impairment. Although ECOG status, baseline glomerularfiltration rate (GFR), albumin, body weight, and mild hepatic impairment had an effect on nivolumab

CL, the effect was not clinically meaningful.

For nivolumab monotherapy, the exposures of nivolumab in adolescents 12 years of age and older whoweigh at least 50 kg are expected to be comparable to those in adult patients at the recommended dose.

Body weight-based dosing is recommended for adolescents 12 years of age and older who weigh lessthan 50 kg.

For nivolumab in combination with ipilimumab, the exposures of nivolumab and ipilimumab inadolescents 12 years of age and older are expected to be comparable to those in adult patients at therecommended dose.

The effect of renal impairment on the CL of nivolumab was evaluated in patients with mild(GFR < 90 and ≥ 60 mL/min/1.73 m2; n = 379), moderate (GFR < 60 and ≥ 30 mL/min/1.73 m2;n = 179), or severe (GFR < 30 and ≥ 15 mL/min/1.73 m2; n = 2) renal impairment compared topatients with normal renal function (GFR ≥ 90 mL/min/1.73 m2; n = 342) in population PK analyses.

No clinically important differences in the CL of nivolumab were found between patients with mild ormoderate renal impairment and patients with normal renal function. Data from patients with severerenal impairment are too limited to draw conclusions on this population (see section 4.2).

The effect of hepatic impairment on the CL of nivolumab was evaluated in patients with differenttumour types (NSCLC, SCLC, melanoma, RCC, SCCHN, UC, GC, and cHL) with mild hepaticimpairment (total bilirubin 1.0 × to 1.5 × ULN or AST > ULN as defined using the National Cancer

Institute criteria of hepatic dysfunction; n = 351) and in patients with moderate hepatic impairment(total bilirubin > 1.5 × to 3 × ULN and any AST; n = 10) compared to patients with normal hepaticfunction (total bilirubin and AST ≤ ULN; n = 3096) in a population PK analysis. No clinicallyimportant differences in the CL of nivolumab were found between patients with mild or moderatehepatic impairment and normal hepatic function. Similar results were observed in patients with HCC(mild hepatic impairment: n = 152; moderate hepatic impairment: n = 13). Nivolumab has not beenstudied in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST) (seesection 4.2).

Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt toleranceto the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnataldevelopment were evaluated in monkeys that received nivolumab twice weekly from the onset oforganogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higherthan those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was adose-dependent increase in foetal losses and increased neonatal mortality beginning in the thirdtrimester.

The remaining offspring of nivolumab-treated females survived to scheduled termination, with notreatment-related clinical signs, alterations to normal development, organ-weight effects, or gross andmicroscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral,immunological, and clinical pathology parameters throughout the 6-month postnatal period werecomparable to the control group. However, based on its mechanism of action, foetal exposure tonivolumab may increase the risk of developing immune-related disorders or altering the normalimmune response and immune-related disorders have been reported in PD-1 knockout mice.

Fertility studies have not been performed with nivolumab.

Sodium citrate dihydrate

Sodium chloride

Mannitol (E421)

Pentetic acid (diethylenetriaminepentaacetic acid)

Polysorbate 80 (E433)

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts. OPDIVO should not be infused concomitantly in the same intravenous line with othermedicinal products.

Unopened vial3 years

Chemical and physical in-use stability from the time of preparation has been demonstrated as follows(times are inclusive of the administration period):

Chemical and physical in-use stability

Infusion preparation Storage at 2ºC to 8ºC Storage at room temperatureprotected from light (≤ 25°C) and room light

Undiluted or diluted with sodiumchloride 9 mg/mL (0.9%) solution 30 days 24 hoursfor injection (of total 30 days storage)

Diluted with 50 mg/mL (5%) 8 hoursglucose solution for injection 7 days (of total 7 days storage)

From a microbiological point of view the prepared solution for infusion, regardless of the diluent,should be used immediately. If not used immediately, in-use storage times and conditions prior to useare the responsibility of the user and would normally not be longer than 7 days at 2°C to 8°C or8 hours (of the total 7 days of storage) at room temperature (≤ 25°C). Aseptic handling should beensured during the preparation of infusion (see section 6.6).

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to48 hours.

For storage conditions after preparation of the infusion, see section 6.3.

4 mL of concentrate in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and a darkblue flip-off seal (aluminium). Pack size of 1 vial.10 mL of concentrate in a 10 mL vial (Type I glass) with a stopper (coated butyl rubber) and a greyflip-off seal (aluminium). Pack size of 1 vial.12 mL of concentrate in a 25 mL vial (Type I glass) with a stopper (coated butyl rubber) and a blueflip-off seal (aluminium). Pack size of 1 vial.24 mL of concentrate in a 25 mL vial (Type I glass) with a stopper (coated butyl rubber) and a redmatte flip-off seal (aluminium). Pack size of 1 vial.

Not all pack sizes may be marketed.

Preparation should be performed by trained personnel in accordance with good practices rules,especially with respect to asepsis.

Preparation and administration

Calculating the dose

More than one vial of OPDIVO concentrate may be needed to give the total dose for the patient.

Nivolumab monotherapy

The prescribed dose for the adult patient is 240 mg or 480 mg given regardless of body weightdepending on indication (see section 4.2).

Melanoma (advanced or adjuvant treatment) in adolescents. The prescribed dose foradolescents 12 years of age and older weighing at least 50 kg is 240 mg or 480 mg. Foradolescents 12 years of age and older and weighing less than 50 kg, the prescribed dose is given inmg/kg. Based on this prescribed dose, calculate the total dose to be given. The total nivolumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg. The volume of OPDIVO concentrate to prepare the dose (mL) = the total nivolumab dose in mg,divided by 10 (the OPDIVO concentrate strength is 10 mg/mL).

Nivolumab in combination with ipilimumab

The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the totaldose to be given (please see above).

Nivolumab in combination with ipilimumab in MPM

The prescribed dose for the patient is 360 mg given regardless of body weight.

Nivolumab in combination with ipilimumab in advanced colorectal cancer

The prescribed dose for the patient can be based on body weight (3 mg/kg) or can be 240 mg givenregardless of body weight.

Nivolumab in combination with ipilimumab in OSCC

The prescribed dose for the patient can be based on body weight (3 mg/kg) or 360 mg given regardlessof body weight.

Nivolumab in combination with chemotherapy in resectable NSCLC

The prescribed dose for the patient is 360 mg given regardless of body weight.

Nivolumab in combination with chemotherapy in OSCC

The prescribed dose for the patient is 240 mg or 480 mg given regardless of body weight.

Nivolumab in combination with chemotherapy in gastric, GEJ or oesophageal adenocarcinoma

The prescribed dose for the patient is 360 mg or 240 mg given regardless of body weight.

Nivolumab in combination with ipilimumab and chemotherapy

The prescribed dose for the patient is 360 mg given regardless of body weight.

Nivolumab in combination with cabozantinib

The prescribed dose for the patient is nivolumab 240 mg or 480 mg given regardless of body weight.

Preparing the infusion

Take care to ensure aseptic handling when you prepare the infusion.

OPDIVO can be used for intravenous administration either: without dilution, after transfer to an infusion container using an appropriate sterile syringe; or after diluting according to the following instructions:

 the final infusion concentration should range between 1 and 10 mg/mL the total volume of infusion must not exceed 160 mL. For patients weighing less than40 kg, the total volume of infusion must not exceed 4 mL per kilogram of patient weight.

OPDIVO concentrate may be diluted with either:

 sodium chloride 9 mg/mL (0.9%) solution for injection; or 50 mg/mL (5%) glucose solution for injection.

STEP 1 Inspect the OPDIVO concentrate for particulate matter or discoloration. Do not shake the vial.

OPDIVO concentrate is a clear to opalescent, colourless to pale yellow liquid. Discard the vialif the solution is cloudy, is discoloured, or contains particulate matter other than a fewtranslucent-to-white particles.

 Withdraw the required volume of OPDIVO concentrate using an appropriate sterile syringe.

STEP 2 Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC orpolyolefin). If applicable, dilute with the required volume of sodium chloride 9 mg/mL (0.9%) solution forinjection or 50 mg/mL (5%) glucose solution for injection. For ease of preparation, theconcentrate can also be transferred directly into a pre-filled bag containing the appropriatevolume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucosesolution for injection.

 Gently mix the infusion by manual rotation. Do not shake.

OPDIVO infusion must not be administered as an intravenous push or bolus injection.

Administer the OPDIVO infusion intravenously over a period of 30 or 60 minutes depending on thedose.

OPDIVO infusion should not be infused at the same time in the same intravenous line with otheragents. Use a separate infusion line for the infusion.

Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore sizeof 0.2 μm to 1.2 μm).

OPDIVO infusion is compatible with PVC and polyolefin containers, glass bottles, PVC infusion setsand in-line filters with polyethersulfone membranes with pore sizes of 0.2 μm to 1.2 μm.

After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%)solution for injection or 50 mg/mL (5%) glucose solution for injection.

Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product orwaste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/15/1014/001

EU/1/15/1014/002

EU/1/15/1014/003

EU/1/15/1014/004

Date of first authorisation: 19 June 2015

Date of latest renewal: 23 April 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu