OPDIVO 600mg injectible solution medication leaflet

OPDIVO 600 mg solution for injection.

Each mL of solution for injection contains 120 mg of nivolumab.

One vial of 5 mL contains 600 mg of nivolumab.

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

For the full list of excipients, see section 6.1.

Solution for injection.

Clear to opalescent, colourless to yellow liquid, essentially free of visible particulates. The solutionhas a pH of 5.5-6.5 and an osmolality of 296-444 mOsm/kg.

OPDIVO as monotherapy or in combination with ipilimumab is indicated for the treatment ofadvanced (unresectable or metastatic) melanoma in adults (see section 4.2).

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 with Stage IIB or IICmelanoma, or melanoma with involvement of lymph nodes or metastatic disease who have undergonecomplete resection (see section 5.1).

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

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 sections 4.2 and 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).

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 (see sections 4.2 and 5.1).

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 (see sections 4.2 and 5.1);

- treatment of metastatic colorectal cancer after prior fluoropyrimidine-based combinationchemotherapy (see sections 4.2 and 5.1).

Oesophageal squamous cell carcinoma (OSCC)

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.

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

Patients currently receiving intravenous nivolumab monotherapy, or in combination withchemotherapy or cabozantinib, may transition to OPDIVO solution for injection.

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,and 5.1).

OPDIVO as monotherapy

The recommended dose of OPDIVO solution for injection is either nivolumab 600 mg every 2 weeksor 1200 mg every 4 weeks (see section 5.1).

If patients need to be switched from the 600 mg every 2 weeks schedule to the 1200 mg every 4 weeksschedule, the first 1200 mg dose should be administered two weeks after the last 600 mg dose.

Conversely, if patients need to be switched from the 1200 mg every 4 weeks schedule to the 600 mgevery 2 weeks schedule, the first 600 mg dose should be administered four weeks after the last1200 mg dose.

OPDIVO in combination with ipilimumab

* Intravenous administration - OPDIVO combination phase

The recommended dose of OPDIVO solution for infusion is 1 mg/kg nivolumab in combination with3 mg/kg ipilimumab administered intravenously over 30 minutes every 3 weeks for the first 4 doses.

* Subcutaneous administration - OPDIVO monotherapy phase

The recommended dose of OPDIVO solution for injection is either 600 mg every 2 weeks or 1200 mgevery 4 weeks (see section 5.1). For the monotherapy phase, the first dose of nivolumab should beadministered; 3 weeks after the last dose of the intravenous combination of nivolumab and ipilimumab ifusing 600 mg every 2 weeks; or 6 weeks after the last dose of the intravenous combination of nivolumab and ipilimumab ifusing 1200 mg every 4 weeks.

* Intravenous administration - OPDIVO combination phase

The recommended dose of OPDIVO solution for infusion is 3 mg/kg nivolumab in combination with1 mg/kg ipilimumab administered intravenously over 30 minutes every 3 weeks for the first 4 doses.

* Subcutaneous administration - OPDIVO monotherapy phase

The recommended dose of OPDIVO solution for injection is either 600 mg every 2 weeks or 1200 mgevery 4 weeks. For the monotherapy phase, the first dose of nivolumab should be administered; 3 weeks after the last dose of the intravenous combination of nivolumab and ipilimumab ifusing 600 mg every 2 weeks; or 6 weeks after the last dose of the intravenous combination of nivolumab and ipilimumab ifusing 1200 mg every 4 weeks.

dMMR or MSI-H colorectal cancer

First-line treatment of dMMR or MSI-H CRC

* Intravenous administration - OPDIVO combination phase

The recommended dose is 240 mg of nivolumab in combination with 1 mg/kg ipilimumabadministered intravenously every 3 weeks for a maximum of 4 doses.

* Subcutaneous administration - OPDIVO monotherapy phase

The recommended dose of OPDIVO solution for injection is 600 mg every 2 weeks or 1200 mg every4 weeks. For the monotherapy phase, the first dose of nivolumab should be administered 3 weeks afterthe last dose of the intravenous combination of nivolumab and ipilimumab. Treatment with nivolumabis recommended until disease progression, unacceptable toxicity, or up to 24 months in patientswithout disease progression.

Treatment of dMMR or MSI-H CRC after prior first-line fluoropyrimidine-based combinationchemotherapy

* Intravenous administration - OPDIVO combination phase

The recommended dose is 3 mg/kg nivolumab in combination with 1 mg/kg ipilimumab administeredintravenously every 3 weeks for the first 4 doses.

* Subcutaneous administration - OPDIVO monotherapy phase

The recommended dose of OPDIVO solution for injection is either 600 mg every 2 weeks or 1200 mgevery 4 weeks. For the monotherapy phase, the first dose of nivolumab should be administered3 weeks after the last dose of the intravenous combination of nivolumab and ipilimumab.

OPDIVO in combination with cabozantinib

The recommended dose of OPDIVO solution for injection is either 600 mg every 2 weeks or 1200 mgevery 4 weeks in combination with 40 mg cabozantinib administered orally every day.

OPDIVO in combination with chemotherapy

Oesophageal squamous cell carcinoma

The recommended dose of OPDIVO solution for injection is either 600 mg every 2 weeks or 1200 mgevery 4 weeks administered in combination with fluoropyrimidine- and platinum-based chemotherapy(see section 5.1). Treatment with nivolumab is recommended until disease progression, unacceptabletoxicity, or up to 24 months in patients without disease progression.

Gastric, gastro-oesophageal junction or oesophageal adenocarcinoma

The recommended dose of OPDIVO solution for injection is 600 mg 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

* Intravenous administration - OPDIVO combination phase

The recommended dose of OPDIVO solution for infusion is 360 mg administered intravenously over30 minutes in combination with cisplatin and gemcitabine every 3 weeks for up to 6 cycles.

* Subcutaneous administration - OPDIVO monotherapy phase

The recommended dose of OPDIVO solution for injection is 600 mg every 2 weeks or 1200 mg every4 weeks (see section 5.1). Treatment with nivolumab is recommended until disease progression,unacceptable toxicity, or up to 24 months from first dose, whichever comes first.

Treatment with OPDIVO, either as a monotherapy or in combination with other therapeutic agents,should be continued as long as clinical benefit is observed or until treatment is no longer tolerated bythe 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 1. 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 1: Recommended treatment modifications for OPDIVO or OPDIVO in combination

Immune-related Severity Treatment modificationadverse reaction

Grade 2 pneumonitis Withhold dose(s) until symptomsresolve, radiographic abnormalities

Immune-related improve, and management withpneumonitis corticosteroids is complete

Grade 3 or 4 pneumonitis Permanently discontinue treatment

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

Grade 3 diarrhoea or colitis

- OPDIVO monotherapy Withhold dose(s) until symptoms

Immune-related colitis resolve and management withcorticosteroids is complete

- OPDIVO+ipilimumaba Permanently discontinue treatment

Grade 4 diarrhoea or colitis Permanently discontinue treatment

Immune-related Grade 2 elevation in aspartate Withhold dose(s) until laboratoryhepatitis aminotransferase (AST), alanine values return to baseline andaminotransferase (ALT), or total management with corticosteroids, if

NOTE: for RCC bilirubin needed, is completepatients treatedwith OPDIVO in Grade 3 or 4 elevation in AST, ALT, or Permanently discontinue treatmentcombination with total bilirubincabozantinib with liverenzyme elevations, seedosing guidelinesfollowing this table.

Immune-related Severity Treatment modificationadverse reaction

Grade 2 or 3 creatinine elevation Withhold dose(s) until creatinine

Immune-related returns to baseline and managementnephritis and renal with corticosteroids is completedysfunction

Grade 4 creatinine elevation Permanently discontinue treatment

Symptomatic Grade 2 or 3 Withhold dose(s) until symptomshypothyroidism, hyperthyroidism, resolve and management withhypophysitis, corticosteroids (if needed for symptoms

Grade 2 adrenal insufficiency of acute inflammation) is complete.

Grade 3 diabetes Treatment should be continued in thepresence of hormone replacement

Immune-related therapyb as long as no symptoms areendocrinopathies present

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis Permanently discontinue treatment

Grade 3 or 4 adrenal insufficiency

Grade 4 diabetes

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

Immune-related skinadverse reactions Grade 4 rash Permanently discontinue treatment

Stevens-Johnson syndrome (SJS) or Permanently discontinue treatment (seetoxic epidermal necrolysis (TEN) 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 discontinue treatment

Grade 3 (first occurrence) Withhold dose(s)

Other immune-related Grade 4 or recurrent Grade 3; persistentadverse reactions Grade 2 or 3 despite treatmentmodification; inability to reduce Permanently discontinue treatmentcorticosteroid dose to 10 mg prednisoneor 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 intravenously in combination with ipilimumab, if either agent iswithheld, the other agent should also be withheld. If dosing is resumed after a delay, either theintravenous combination treatment or OPDIVO monotherapy administered intravenously orsubcutaneously 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 1 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 solution for injection in children below 18 years of age have notbeen established.

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

Based on the population pharmacokinetic (PK) results for intravenous nivolumab, no dose adjustmentis required in patients with mild or moderate renal impairment (see section 5.2). Data from patientswith severe renal impairment are too limited to draw conclusions on this population.

Based on the population PK results for intravenous nivolumab, no dose adjustment is required inpatients with mild hepatic impairment (see section 5.2). Data from patients with moderate or severehepatic impairment are too limited to draw conclusions on these populations. OPDIVO must beadministered with caution in patients with moderate (total bilirubin > 1.5 × to 3 × the upper limit ofnormal [ULN] and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.

OPDIVO solution for injection is for subcutaneous use

It is important to check the vial labels to ensure that the appropriate formulation (intravenous orsubcutaneous formulation) and dose is being administered to the patient as prescribed.

OPDIVO solution for injection is not intended for intravenous administration and must be given bysubcutaneous injection only using the doses specified. More than one vial of OPDIVO solution forinjection may be needed to give the total dose for the patient. For instructions on use and handling ofthe OPDIVO solution for injection before administration, see section 6.6.

Administer the full contents of the syringe of OPDIVO solution for injection into the subcutaneoustissue of the abdomen or thigh over a period of 3 to 5 minutes. The dose should not be split betweentwo syringes or between two sites of administration. Alternate injection sites for successive injections.

Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars ormoles. If the administration of OPDIVO solution for injection is interrupted, it can be resumed at thesame site, or at an alternate site.

During the treatment course with OPDIVO solution for injection, other medicinal products forsubcutaneous administration should preferably be injected at different sites.

OPDIVO solution for infusion (intravenous formulation)

The Summary of Product Characteristics (SmPC) of OPDIVO concentrate for solution for infusionshould be referred to for information on dosing instructions and method of administration.

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.

Cases of acute graft-versus-host disease (GVHD) and transplant related mortality (TRM) have beenobserved from the follow-up of patients with classical Hodgkin lymphoma undergoing allogeneichaematopoietic stem cell transplant (HSCT) after previous exposure to intravenous nivolumab. Carefulconsideration to the potential benefits of HSCT and the possible increased risk of transplant relatedcomplications should be made case-by-case. In patients treated with intravenous nivolumab afterallogeneic HSCT, rapid-onset and severe GVHD, some with fatal outcome, have been reported in thepost-marketing setting. Treatment with nivolumab may increase the risk of severe GVHD and death inpatients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. Thebenefit of treatment with nivolumab versus the possible risk should be considered in these patients.

Infusion reactions (intravenous formulation)

Severe infusion reactions have been reported in clinical trials of intravenous nivolumab or intravenousnivolumab in combination with ipilimumab (see section 4.8). In case of a severe or life-threateninginfusion reaction, the intravenous nivolumab or intravenous nivolumab in combination withipilimumab infusion must be discontinued and appropriate medical therapy administered. Patients withmild or moderate infusion reaction may receive intravenous nivolumab or intravenous nivolumab incombination with ipilimumab with close monitoring and use of premedication according to localtreatment 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.

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).

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).

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 chemotherapy should be used with caution in these populations aftercareful consideration of the potential benefit/risk on an individual basis.

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).

OPDIVO contains polysorbate 80 (E433)

This medicinal product contains 2.5 mg of polysorbate 80 in each 5 mL vial which is equivalent to 5mg/10 mL. Polysorbates may cause allergic reactions.

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 administered intravenously across tumour types(n = 4646) with minimum follow-up ranging from 2.3 to 28 months, the most frequent adversereactions (≥ 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%), abdominal pain (15%), upper respiratory tract infection (15%), pyrexia(13%), headache (13%), anaemia (13%) and vomiting (12%). The majority of adverse reactions weremild to moderate (Grade 1 or 2). The incidence of Grade 3-5 adverse reactions was 44%, with 0.3%fatal adverse reactions attributed to study drug. With a minimum of 63 months follow-up in NSCLC,no new safety signals were identified.

The safety of nivolumab administered subcutaneously was similar to the known safety profile of theintravenous formulation of nivolumab, with an additional adverse reaction of injection site reaction(7% in the subcutaneous nivolumab arm (n = 247) vs 0% in the intravenous nivolumab arm (n = 245)).

Adverse reactions reported in the pooled dataset for patients treated with nivolumab monotherapy(n = 4646) are presented in Table 2. 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 2: 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

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 ventriculararrhythmia)

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

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, injection site reactionm

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 2 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 programme-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.

m Reported in a study outside of the pooled dataset (subcutaneous injection related). The frequency is based onexposure to OPDIVO solution for injection in CA20967T and includes injection site erythema, application site pain,injection site oedema, injection site pain, application site erythema, application site rash, injection site discolouration,injection site inflammation, and injection site pruritus.

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 = 2294) with minimum follow-up ranging from 6 to 47 months,the most frequent adverse reactions (≥ 10%) were fatigue (49%), diarrhoea (37%), rash (37%), nausea(30%), pruritus (29%), musculoskeletal pain (27%), pyrexia (24%), decreased appetite (23%), cough(22%), vomiting (19%), constipation (19%), arthralgia (19%), abdominal pain (19%), dyspnoea(18%), hypothyroidism (16%), headache (15%), upper respiratory tract infection (15%), oedema(13%), and dizziness (10%). The incidence of Grade 3-5 adverse reactions was 67% for nivolumab incombination with ipilimumab (with or without chemotherapy), with 0.7% fatal adverse reactionsattributed to study drug. Among patients treated with nivolumab 1 mg/kg in combination withipilimumab 3 mg/kg, fatigue (62%), rash (57%), diarrhoea (52%), nausea (42%), pruritus (40%),pyrexia (36%), and headache (26%) were reported at an incidence rate ≥ 10% higher than the ratesreported in the pooled dataset of nivolumab in combination with ipilimumab (with or withoutchemotherapy) incidence rate. Among patients treated with nivolumab 360 mg in combination withipilimumab 1 mg/kg and chemotherapy, anaemia (32%) and neutropaenia (15%) were reported at anincidence rate ≥ 10% higher than the rates reported in the pooled dataset of nivolumab in combinationwith 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 = 1572), with a minimum follow-up ranging from 7.4 to20 months for gastric, GEJ or oesophageal adenocarcinoma, OSCC, or urothelial carcinoma, orfollowing 3 cycles of treatment for resectable NSCLC, the most frequent adverse reactions (≥ 10%)were nausea (51%), fatigue (41%), peripheral neuropathy (34%), decreased appetite (32%),constipation (31%), diarrhoea (30%), vomiting (26%), stomatitis (19%), abdominal pain (19%), rash(19%), musculoskeletal pain (18%), pyrexia (17%), oedema (including peripheral oedema) (13%),cough (12%), and hypoalbuminaemia (10%). Incidences of Grade 3-5 adverse reactions were 72% fornivolumab in combination with chemotherapy, with 1.3% fatal adverse reactions attributed tonivolumab in combination with chemotherapy. Median duration of therapy was 6.44 months(95% CI: 5.95, 6.80) for nivolumab in combination with chemotherapy, pct. 4.34 months(95% CI: 4.04, 4.70) for chemotherapy for gastric, GEJ or oesophageal adenocarcinoma, or OSCC,and 7.39 months (95% CI: 7.06, 8.38) for urothelial carcinoma. For resectable NSCLC, ninety-three percent (93%) of patients received 3 cycles of nivolumab in combination with chemotherapy.

Nivolumab in combination with cabozantinib

In the dataset of nivolumab intravenous formulation 240 mg every 2 weeks in combination withcabozantinib 40 mg once daily in RCC (n =320), with a minimum follow-up of 16.0 months, the mostfrequent adverse reactions (≥ 10%) were diarrhoea (64.7%), fatigue (51.3%), palmar-plantarerythrodysaesthesia syndrome (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 reactionsattributed to study drug.

Adverse reactions reported in the pooled dataset for patients treated with nivolumab in combinationwith ipilimumab (with or without chemotherapy) (n = 2294), nivolumab in combination withchemotherapy (n = 1572), and nivolumab in combination with cabozantinib (n = 320) are presented in

Table 3. 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 3: 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

Very common anaemiab,i, neutropaeniab, anaemiab,i, 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 related reaction anaphylactic reaction)release syndrome), (including cytokinehypersensitivity release syndrome)

Uncommon infusion relatedhypersensitivity reaction

Rare sarcoidosis

Not known solid organ transplantrejectionf

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

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, hypoalbuminaemia, hypoglycaemiab,hypoglycaemiab hyperglycaemiab, hyperglycaemiab, weighthypoglycaemiab decreased

Common dehydration, hypophosphataemia dehydrationhypoalbuminaemia,hypophosphataemia,weight decreased

Uncommon metabolic acidosis

Rare tumour lysis syndrome

Not known tumour lysis syndromeg

Very common headache, dizziness peripheral neuropathy dysgeusia, dizziness, headache

Common peripheral neuropathy paraesthesia, dizziness, peripheral neuropathyheadache

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

Rare Guillain-Barré syndrome, Guillain-Barréneuritis, myelitis (including syndrome, encephalitistransverse 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

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

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

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

Not known pericardial disordersh

Very common hypertension

Common hypertension thrombosisa, j, thrombosisjhypertension, vasculitis

Very common cough, dyspnoea cough dysphonia, dyspnoea, cough

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

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

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

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 disorders

Rare toxic epidermalnecrolysisa,d, lichensclerosus

Not known lichen sclerosus, other lichendisorders

Very common musculoskeletal paine, musculoskeletal paine musculoskeletal paine,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

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 noninfectiveg

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

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

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 3 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 Reported also in studies outside the pooled dataset. The frequency is based on the programme-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 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 4 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 4 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 4: 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 2.4 1.8 2.5

Colitis 1.2 6 1.8 2.5

Hepatitis 1.1 5 0.8 4.1

Nephritis and renal 0.3 1.2 3.3 0.6dysfunction

Endocrinopathies 0.5 2.3 0.6 1.3

Skin 0.8 1.0 1.0 2.2

Hypersensitivity/Infusion 0.1 0.3 1.8 0reaction

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

Pneumonitis 65 59 58 56

Colitis 14 31 8 8

Hepatitis 21 36 8 23

Nephritis and renal 22 27 7 9dysfunction

Endocrinopathies 5 19 5 4.2

Skin 3.3 8 6 8

Hypersensitivity/Infusion 18 16 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 6.5% (150/2294). Grade 2,

Grade 3, and Grade 4 cases were reported in 3.2% (74/2294), 1.1% (26/2294), and 0.3% (8/2294) 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 124 patients (82.7%) 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 4.3% (67/1572). Grade 2, Grade 3, and Grade 4 cases werereported in 2.1% (33/1572), 0.9% (14/1572), and 0.2% (3/1572), of patients, respectively. Twopatients (0.1%) had a fatal outcome. Median time to onset was 25 weeks (range: 1.6-96.9). Resolutionoccurred in 48 patients (71.6%) with a median time to resolution of 10.4 weeks (range: 0.3+-121.3+).

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 27.3% (626/2294). Grade 2, Grade 3, and Grade 4 cases werereported in 8.5% (194/2294), 6.5% (150/2294), and 0.2% (4/2294), of patients, respectively. Onepatient (<0.1%) had a fatal outcome. Median time to onset was 1.4 months (range: 0.0-48.9).

Resolution occurred in 567 patients (91%) with a median time to resolution of 2.7 weeks(range: 0.1-159.4+). Among patients treated with nivolumab 1 mg/kg in combination withipilimumab 3 mg/kg, 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 24.0% (377/1572). Grade 2, Grade 3, and Grade 4 cases were reported in 7.3% (115/1572),3.2% (51/1572), and 0.4% (6/1572) 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 329 patients(87.7%) 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 19.3% (442/2294). Grade 2, Grade 3, and

Grade 4 cases were reported in 4.5% (104/2294), 7.5% (171/2294), and 1.1% (25/2294) of patients,respectively. Median time to onset was 2 months (range: 0.0-36.6). Resolution occurred in388 patients (88.2%) with a median time to resolution of 5.4 weeks (range: 0.1-175.9+). Amongpatients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, the incidence ofliver function test abnormalities was 30.1% including Grade 2 (6.9%), Grade 3 (15.8%), and Grade 4(1.8%).

In patients treated with nivolumab in combination with chemotherapy, the incidence of liver functiontest abnormalities was 18.6% (293/1572). Grade 2, Grade 3 and Grade 4 cases were reported in 5.6%(88/1572), 2.9% (45/1572) and < 0.1% (1/1572) of patients, respectively. Median time to onset was7.7 weeks (range: 0.1-99.0). Resolution occurred in 231 patients (79.9%) 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 5.9% (135/2294). Grade 2, Grade 3, and Grade 4cases were reported in 2.2% (50/2294), 0.9% (20/2294), and 0.5% (11/2294) 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 104 patients (75.8%) with a median time to resolution of 6.1 weeks(range: 0.1-172.1+).

In patients treated with nivolumab in combination with chemotherapy, the incidence of nephritis orrenal dysfunction was 10.8% (170/1572). Grade 2, Grade 3, and Grade 4 cases were reported in4.1% (64/1572), 1.5% (24/1572), and 0.1% (2/1572) of patients, respectively. Two patients (0.1%) hada fatal outcome. Median time to onset was 6.9 weeks (range: 0.1-60.7). Resolution occurred in111 patients (65.3%) with a median time to resolution of 11.6 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 22.9% (526/2294). Grade 2 and Grade 3 thyroid disorders werereported in 12.2% (281/2294) and 1.0% (24/2294) of patients, respectively.

Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 2.0% (45/2294)and 1.6% (37/2294) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.7%(16/2294) and 0.5% (11/2294) 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%(62/2294), 1.7% (39/2294) and 0.2% (4/2294) 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% (1/2294), 0.3% (8/2294), 0.2% (5/2294), and 0.3% (6/2294) of patients, respectively. Mediantime to onset of these endocrinopathies was 2.1 months (range: 0.0-28.1). Resolution occurred in254 patients (39.1%). 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 12.7% (199/1572). Grade 2 thyroid disorder was reported in 6.2% (97/1572) patients.

Grade 3 hypophysitis occurred in 0.1% (2/1572) of patients. Grade 2 and Grade 3 hypopituitarismoccurred in 0.2% (3/1572) and 0.3% (4/1572) of patients, respectively. Grade 2, Grade 3 and

Grade 4 adrenal insufficiency occurred in 0.6% (9/1572), 0.2% (3/1572) and <0.1% (1/1572) ofpatients, respectively. Diabetes mellitus including Type 1 diabetes mellitus, fulminant Type 1 diabetesmellitus, and diabetic ketoacidosis (3 Grade 2, 2 Grade 3, and 1 Grade 4) were reported. Median timeto onset of these endocrinopathies was 14.7 weeks (range: 1.1-124.3). Resolution occurred in81 patients (37.2%). Time to resolution ranged from 0.4 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 45.2% (1038/2294). Grade 2, Grade 3, and Grade 4 cases were reported in13.6% (312/2294), pct. 4.4% (102/2294), and < 0.1% (2/2294) of patients, respectively. Median time toonset was 0.8 months (range: 0.0-33.8). Resolution occurred in 724 patients (70%) with a median timeto resolution of 11.3 weeks (range: 0.1-268.7+). Among patients treated with nivolumab 1 mg/kg incombination with ipilimumab 3 mg/kg, 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 was25.6% (402/1572). Grade 2 and Grade 3 cases were reported in 6.2% (97/1572) and 2.5% (39/1572) ofpatients, respectively. Median time to onset was 7.0 weeks (range: 0.1-97.4). Resolution occurred in273 patients (68.1%) with a median time to resolution of 12.3 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 (seesections 4.2 and 4.4).

Infusion reactions (intravenous formulation)

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 4.8% (110/2294). Grade 1, Grade 2, Grade 3,and Grade 4 cases were reported in 2.0% (47/2294), 2.5% (57/2294), 0.2% (5/2294), and < 0.1%(1/2294) 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 8.5% (134/1572). Grade 2, Grade 3, and Grade 4 cases werereported in 4.8% (76/1572), 1.1% (18/1572), and 0.2% (3/1572) 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.

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, 1.4% for thrombocytopaenia, 2.1% for leucopoenia,7.0% for lymphopaenia, 3.2% for neutropaenia, 2.8% for increased alkaline phosphatase, 7.0% forincreased AST, 8.1% for increased ALT, 1.3% for increased total bilirubin, 1.7% for increasedcreatinine, 5.8% for hyperglycaemia, 0.7% for hypoglycaemia, 8.2% for increased amylase, 16.3% forincreased lipase, 0.7% for hypocalcaemia, 0.2% for hypernatraemia, 0.9% for hypercalcaemia, 1.9%for hyperkalaemia, 0.5% for hypermagnesaemia, 0.4% for hypomagnesaemia, 3.2% for hypokalaemia,and 9.2% for hyponatraemia.

Among patients treated with nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg, a higherproportion of patients experienced a worsening from baseline to Grade 3 or 4 increased 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:15.8% for anaemia, 6.9% for thrombocytopaenia, 12.2% leukopaenia, 14.6% for lymphopaenia, 27.6%neutropaenia, 2.4% for increased alkaline phosphatase, 3.4% for increased AST, 2.6% for increased

ALT, 2.0% for increased bilirubin, 1.4% for increased creatinine, 4.5% for increased amylase, pct. 5.2%for increased lipase, 0.5% for hypernatraemia, 8.8% for hyponatraemia, 1.9% for hyperkalaemia, 5.6%for hypokalaemia, 0.8% for hypercalcaemia, 1.9% for hypocalcaemia, 1.5% for hypermagnesaemia,2.9% for hypomagnesaemia, 3.5% for hyperglycaemia, and 0.7% 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.

Subcutaneous formulation

Of the 202 patients who were treated with nivolumab solution for injection and evaluable for thepresence of anti-nivolumab antibodies, approximately 23% (46/202) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 1% (2/202) hadneutralizing antibodies against nivolumab. The incidence of treatment-emergent anti-recombinanthuman hyaluronidase PH20 (anti-rHuPH20) antibodies in patients treated with nivolumab solution forinjection was 8.8% (19/215).

Intravenous formulation

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 patients whowere treated with nivolumab 240 mg every 2 weeks or 360 mg every 3 weeks in combination withchemotherapy and evaluable for the presence of anti-product-antibodies, 7.5% 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.

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).

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.

OPDIVO solution for injection contains the active substance nivolumab, which provides thetherapeutic effect of this medicinal product, and recombinant human hyaluronidase (rHuPH20), anenzyme used to increase the dispersion and absorption of co-formulated substances when administeredsubcutaneously.

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.

Subcutaneous formulation

Results from a simulation-based pharmacokinetic bridging analyses showed that across all solidtumour types evaluated, subcutaneous nivolumab dosing regimens (600 mg every 2 weeks and1200 mg every 4 weeks) produced exposures that were noninferior (geometric mean ratio >1) to thosefor the approved intravenous nivolumab dosing regimens (240 mg every 2 weeks and 480 mg every4 weeks). Geometric mean exposures were also below those for intravenous nivolumab 10 mg/kg

Q2W, a regimen shown to be safe in clinical studies.

The subcutaneous nivolumab clinical safety profile was comparable to intravenous nivolumab.

Treatment of advanced melanoma

Intravenous formulation

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 1 000 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 5.

Table 5: 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.

Intravenous formulation

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 6.

Table 6: 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.

Intravenous formulation

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, 1mg/kg, 3 mg/kg, or 10 mg/kg for a maximum of 2 years. In this patient population, objective responsewas 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).

Intravenous formulation

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 1 008 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 7below.

Table 7: 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.

Intravenous formulation

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), Figures 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 8.

Table 8: 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 8) after90 months of follow-up, with a best overall response of complete response correlating to an improvedsurvival 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.

Intravenous formulation

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).

Intravenous formulation

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 9 and Figure 8.

Table 9: 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.

Intravenous formulation

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 10and Figures 9 and 10 (all randomised population).

Table 10: 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).

Treatment of NSCLC after prior chemotherapy

Squamous NSCLC

Intravenous formulation

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).

Probability of overall survival

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 11.

Figure 11: 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)

Probability of survival

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 11.

Table 11: 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)nivolumab docetaxel(n = 135) (n = 137)

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+)

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.

Intravenous formulation

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% CI 1.77,3.15). The PFS was measured by RECIST, version 1.1. The estimated 1-year survivalrate was 41%.

Intravenous formulation

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 12 below.

Table 12: 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

Intravenous formulation

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 12.

Figure 12: 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 13.

Table 13: 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 14 summarises results of ORR and OS by tumour PD-L1 expression.

Table 14: 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.

Subcutaneous formulation

Randomised, open-label phase 3 study vs. intravenous nivolumab (CA20967T)

The safety and efficacy of nivolumab subcutaneous formulation was evaluated in a multicentre,randomised, open-label study in patients with advanced or metastatic clear cell RCC (CA20967T).

Patients 18 years of age or older with histologically confirmed advanced or metastatic RCC with aclear cell component, including those with sarcomatoid features, and who received no more than 2prior systemic treatment regimens were randomised to receive nivolumab 1200 mg every 4 weekssubcutaneously or nivolumab 3 mg/kg every 2 weeks intravenously. Patients with untreated,symptomatic CNS metastases; leptomeningeal metastases; concurrent malignancies requiringtreatment or history of prior malignancy within the prior 2 years; active, known, or suspectedautoimmune disease; or who received prior treatment with a checkpoint inhibitor were excluded fromthe study. Patients with asymptomatic, stable CNS metastases that did not require immediate treatmentwere eligible if there was no evidence of progression within 28 days prior to the first dose of studydrug administration.

Stratification factors for randomisation were weight (<80 kg vs ≥80 kg) and International Metastatic

Renal Cell Carcinoma Database Consortium (IMDC) risk classification (favourable vs intermediate vspoor risk).

The primary objective of the study was to demonstrate noninferiority of the serum nivolumab Cavgd28and Cminss for the subcutaneous administration of nivolumab to the intravenous administration ofnivolumab (see section 5.2). The key secondary objective of the study was to demonstratenoninferiority of the ORR for the subcutaneous administration of nivolumab to the intravenousadministration of nivolumab, as assessed by blinded independent central review (BICR). Additionalsecondary objectives included assessing duration of response (DOR), progression-free survival (PFS),and overall survival (OS).

A total of 495 patients were randomised to receive either subcutaneous nivolumab (n = 248) orintravenous nivolumab (n = 247). The median age was 65 years (range: 20 to 93), with 51% ≥65 yearsof age and 14% ≥75 years of age, 85% White, 0.8% Asian, and 0.4% Black, and 68% male. Fifty-seven percent of patients weighed <80 kg and 43% weighed ≥80 kg. Baseline Karnofsky performancestatus was 70 (7%), 80 (20%), 90 (34%), or 100 (39%). Patient distribution by IMDC risk categorieswas 21% favourable, 62% intermediate, and 17% poor.

The study demonstrated noninferiority of nivolumab 1200 mg administered subcutaneously tonivolumab 3 mg/kg administered intravenously (see section 5.2). At the primary analysis (minimumfollow-up of 8 months) ORR was 24.2% (95% CI: 19.0, 30.0) for subcutaneous nivolumab and 18.2%(95% CI: 13.6, 23.6) for intravenous nivolumab. The estimate of objective response risk ratio was 1.33(95% CI: 0.94, 1.88). To declare noninferiority, the lower bound of the two-sided 95% CI of theobjective response risk ratio had to be ≥0.60. Updated efficacy results with a minimum follow-up of14.9 months (data cut-off 21-Feb-2024) are shown in Table 15.

T able 15: Efficacy results - CA20967T

Subcutaneous nivolumab Intravenous nivolumab

ORRa per BICR % (n/N) 26.6% (66/248) 20.6% (51/247)95% CIb(21.2, 32.6) (15.8, 26.2)

Estimate of objective response 1.28 (0.93, 1.77)risk ratio (95% CI)c, d,

DORa per BICR

Median, months (95% CI)e 13.57 (8.57, NE) NR (15.7, NE)

NR = not reached, NE = non-estimablea Descriptive analysis.b Confidence interval based on the Clopper and Pearson method.c Stratified by weight (<80 kg vs ≥ 80 kg) and IMDC risk group (favourable vs intermediate vs poor).d Strata adjusted risk ratio (subcutaneous nivolumab over intravenous nivolumab) using Mantel-Haenszelmethod.e Median computed using Kaplan-Meier method.

Intravenous formulation

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 a 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 13.

Figure 13: 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)

Probability of survival

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 16 and Figure 13). OSbenefit was observed regardless of tumour PD-L1 expression level.

Efficacy results are shown in Table 16.

Table 16: 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.

Intravenous formulation

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.

Intravenous formulation

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 17 (primary analysis with aminimum follow-up of 17.5 months and with a minimum follow-up of 60 months) and in Figure 14(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 17: 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)nivolumab + ipilimumab sunitinib(n = 425) (n = 422)

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)

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 14: 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.

Intravenous formulation

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 18.

Table 18: 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)

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 18). 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. sunitinibregardless 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 15 and 16). 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 15: 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 16: 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)

Intravenous formulation

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),

Probability of survival400 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 17. Efficacy results are shown in Table 19.

Figure 17: 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 19: 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 20).

Table 20: 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 21). Due to thesmall numbers of patients in the subgroups, and exploratory nature of the analysis, no definitiveconclusions can be drawn from these data.

Table 21: 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.

Treatment of advanced urothelial carcinoma

Intravenous formulation

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 22 and Figures 18 and 19.

Table 22: 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 18: 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 19: 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 22). Results for PFS with and without censoring for new anti-cancer treatmentbefore disease progression were consistent.

Intravenous formulation

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.

Probability of Progression-free Survival

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 wascontinued 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 23: 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.

Intravenous formulation

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

Intravenous formulation

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 24 and Figure 20.

Table 24: 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 20: 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

Intravenous formulation

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 the first-line treatment of unresectable or metastatic CRC with known tumour MSI-H or dMMR status were

Probability of Disease-Free Survivalevaluated in a randomised, multi-arm, phase 3, open-label study (CA2098HW). Study treatment armsincluded nivolumab monotherapy, nivolumab in combination with ipilimumab, or investigator’schoice 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 randomised 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 every 4weeks. Patients in the chemotherapy arm received: mFOLFOX6 (oxaliplatin, leucovorin, andfluorouracil) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400mg/m2, and fluorouracil 400 mg/m2 bolus followed by fluorouracil 2400 mg/m2 over 46 hours every2 weeks. Bevacizumab 5 mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6 every 2weeks; or FOLFIRI (irinotecan, leucovorin, and fluorouracil) with or without either bevacizumab orcetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus andfluorouracil 2400 mg/m2 over 46 hours every 2 weeks. Bevacizumab 5 mg/kg on or cetuximab 500mg/m2 administered prior to FOLFIRI every 2 weeks. Treatment continued until disease progression,unacceptable toxicity, or for nivolumab in combination with ipilimumab up to 24 months. Patientswho discontinued combination therapy because of an adverse reaction attributed to ipilimumab werepermitted to continue nivolumab as a single agent. Tumour assessments per RECIST v1.1 wereconducted every 6 weeks for the first 24 weeks, then every 8 weeks thereafter until week 96, thenevery 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; and 39patients 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 25 and Figure 21. At the time of this interimanalysis, the other endpoints, including the data from nivolumab monotherapy arm, were not tested,due to testing hierarchy.

Table 25: Efficacy results in first-line MSI-H/dMMR centrally confirmed CRC(CA2098HW)a,nivolumab + ipilimumab chemotherapy(n = 171) (n = 84)

Progression-free survival

Events 48 (28%) 52 (62%)

Hazard ratio 0.2195% CI (0.14, 0.32)p-value b < 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 21: 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 setting

Probability of progression-free survivalshould 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.

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 26.

Table 26: 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

Intravenous formulation

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 27 and Figure 22.

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 27: 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)nivolumab investigator’s choice(n = 210) (n = 209)

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 22: Kaplan-Meier curves of OS (ONO-4538-24/CA209473)

Overall Survival (Months)

Number of subjects at risk

Nivolumab210 182 167 147 126 11 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-L1

Probability of Overall Survival (%)negative 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.

Intravenous formulation

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

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 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 28.

Table 28: 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)

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 23 and 24.

Figure 23: 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 24: 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

Intravenous formulation

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 any

Probability of progression-free survivalcause, 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.

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 29 and Figure 25.

Table 29: 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 25: 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

Intravenous formulation

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 the

Probability of Disease-Free Survivalstudy. 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).

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 30, and Figures 26 and 27.

Table 30: 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 26: 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 27: 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

Subcutaneous formulation

No dedicated studies of OPDIVO solution for injection have been conducted in paediatric patients.

The European Medicines Agency has waived the obligation to submit the results of studies with

OPDIVO solution for injection for subcutaneous use in all subsets of the paediatric population in thetreatment of malignant neoplasms (except central nervous system neoplasms, haematopoietic andlymphoid tissue neoplasms other than Hodgkin lymphoma) (see section 4.2 for information onpaediatric 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.

Probability of progression-free survival

Nivolumab solution for injection pharmacokinetics (PK) were assessed using a population PKapproach. The PK was studied at a dose of 1200 mg administered as multiple doses every 4 weeks.

Nivolumab time-averaged serum concentration over 28 days (Cavgd28) showed non-inferiority ofsubcutaneous nivolumab (77.4 mcg/mL) to intravenous nivolumab (36.9 mcg/mL), with a geometricmean ratio of 2.098 (90% CI: 2.001, 2.200). Nivolumab minimum serum concentration at steady state(Cminss) showed non-inferiority of subcutaneous nivolumab (122.2 mcg/mL) to intravenous nivolumab(68.9 mcg/mL), with a geometric mean ratio of 1.774 (90% CI: 1.633, 1.927).

The mean absorption rate constant (Ka) and bioavailability (F) of nivolumab solution for injection are0.0123 hr-1 (or 0.295 Day-1) and 78.8%, respectively. Peak concentrations occurred by around 6 days.

The geometric mean (CV%) volume of distribution at steady state (Vss) is 6.32 L (21.3%).

Nivolumab solution for injection human clearance (CL) decreases over time, with a mean maximalreduction from baseline values (CV%) of 24.6% (15.8%) resulting in a geometric mean (CV%)steady-state clearance (CLss) of 7.18 mL/h (52.3%) in patients with RCC; the decrease in CLss is notconsidered clinically relevant.

The geometric mean (CV%) elimination half-life (t1/2) is 26.5 days (32.1%).

The following factors had no clinically important effect on the bioavailability of nivolumab solutionfor injection: sex and performance status. The following factors had no clinically important effect onthe clearance of nivolumab solution for injection: body weight (35 to 153 kg), sex, eGFR (24 to124 mL/min/1.73 m2), or performance status.

In population PK analyses for intravenous nivolumab, the effect of renal impairment on the CL ofnivolumab 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 < 30and ≥ 15 mL/min/1.73 m2; n = 2) renal impairment compared to patients with normal renal function(GFR ≥ 90 mL/min/1.73 m2; n = 342). No clinically important differences in the CL of nivolumabwere found between patients with mild or moderate renal impairment and patients with normal renalfunction. Data from patients with severe renal impairment are too limited to draw conclusions on thispopulation (see section 4.2).

In population PK analyses for intravenous nivolumab, the effect of hepatic impairment on the CL ofnivolumab was evaluated in patients with mild hepatic impairment (total bilirubin 1.0 × to 1.5 × ULNor AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n = 92)compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN; n = 804). Noclinically important differences in the CL of nivolumab were found between patients with mild hepaticimpairment and normal hepatic function. Nivolumab has not been studied in patients with moderate(total bilirubin > 1.5 × to 3 × ULN and any AST) or severe hepatic impairment (totalbilirubin > 3 × ULN and any AST) (see section 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.

Subcutaneous formulation

Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant humanhyaluronidase reveal no special hazard for humans based on conventional studies of repeated dosetoxicity including safety pharmacology endpoints. Reproductive toxicology studies with rHuPH20revealed embryofoetal toxicity in mice at high systemic exposure but did not show teratogenicpotential.

Recombinant human hyaluronidase (rHuPH20)

Histidine

Histidine hydrochloride monohydrate

Sucrose

Pentetic acid

Polysorbate 80 (E433)

Methionine

Water for injection

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial3 years

Storage in syringe

From a microbiological point of view, once transferred from the vial to the syringe, the medicinalproduct should be used immediately since the medicinal product does not contain any antimicrobialpreservative or bacteriostatic agents. If not used immediately, OPDIVO solution for injectiontransferred to the syringe can be stored in the refrigerator at 2°C to 8°C, protected from light for up to7 days and/or at room temperature 20°C to 25°C and room light for up to 8 hours. Discard if storagetime exceeds these limits. Aseptic handling should be ensured during the preparation of the syringe forinjection.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after preparation of the syringe, see section 6.3.

Type I glass vial with a butyl rubber stopper and an aluminium seal with a plastic orange flip-off capcontaining 5 mL of solution for injection.

Pack of one vial.

Preparation should be performed by trained personnel in accordance with good practices rules,especially with respect to asepsis.

Preparation of the syringe

OPDIVO solution for injection is for single use only and is ready to use.

OPDIVO solution for injection should NOT be diluted or mixed with other medicinal products.

OPDIVO solution for injection is compatible with polypropylene, polycarbonate, polyethylene,polyurethane, polyvinyl chloride, fluorinated ethylene propylene, and stainless steel.

OPDIVO solution for injection should be a clear to opalescent, colourless to yellow solution. Prior touse, visually inspect and discard if discoloured or contains extraneous particulate matter other than afew translucent-to-white particles.

Do not shake the vial.

A syringe and a transfer needle are needed to withdraw the medicinal product from the vial. OPDIVOsolution for injection may be administered subcutaneously using a 23G-25G hypodermic injectionneedle or subcutaneous administration set (e.g., winged/butterfly).

If a dose of 600 mg is to be administered, allow 1 vial to reach room temperature, then withdraw 5 mLof OPDIVO solution for injection into the syringe.

If a dose of 1200 mg is to be administered, allow 2 vials to reach room temperature, then withdraw10 mL of OPDIVO solution for injection into the syringe.

The hypodermic injection needle must be attached to the syringe immediately prior to administrationto avoid clogging.

It is recommended to use the prepared dose immediately.

If storage is required (see section 6.3), apply a syringe tip cap prior to storage.

If stored in the refrigerator, allow the solution to reach ambient temperature before administration.

Discard any unused solution remaining in the vial.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/15/1014/005

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.