KEYTRUDA 50mg powder for concentrate infusion solution medication leaflet

KEYTRUDA 25 mg/mL concentrate for solution for infusion.

One vial of 4 mL of concentrate contains 100 mg of pembrolizumab.

Each mL of concentrate contains 25 mg of pembrolizumab.

Pembrolizumab is a humanised monoclonal anti-programmed cell death-1 (PD-1) antibody(IgG4/kappa isotype with a stabilising sequence alteration in the Fc region) produced in Chinesehamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless to slightly yellow solution, pH 5.2 - 5.8.

KEYTRUDA as monotherapy is indicated for the treatment of adults and adolescents aged 12 yearsand older with advanced (unresectable or metastatic) melanoma.

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults and adolescents aged12 years and older with Stage IIB, IIC or III melanoma and who have undergone complete resection(see section 5.1).

KEYTRUDA, in combination with platinum-containing chemotherapy as neoadjuvant treatment, andthen continued as monotherapy as adjuvant treatment, is indicated for the treatment of resectablenon-small cell lung carcinoma at high risk of recurrence in adults (for selection criteria, seesection 5.1).

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with non-small celllung carcinoma who are at high risk of recurrence following complete resection and platinum-basedchemotherapy (for selection criteria, see section 5.1).

KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lungcarcinoma in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) withno EGFR or ALK positive tumour mutations.

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous non-small cell lung carcinoma in adults whose tumourshave no EGFR or ALK positive mutations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated forthe first-line treatment of metastatic squamous non-small cell lung carcinoma in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastaticnon-small cell lung carcinoma in adults whose tumours express PD-L1 with a ≥ 1% TPS and whohave received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumourmutations should also have received targeted therapy before receiving KEYTRUDA.

Malignant pleural mesothelioma (MPM)

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for thefirst-line treatment of adults with unresectable non-epithelioid malignant pleural mesothelioma.

KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologousstem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatmentoption.

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the first-line treatment ofunresectable or metastatic urothelial carcinoma in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastaticurothelial carcinoma in adults who have received prior platinum-containing chemotherapy (seesection 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastaticurothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whosetumours express PD-L1 with a combined positive score (CPS) ≥ 10 (see section 5.1).

KEYTRUDA, as monotherapy or in combination with platinum and 5-fluorouracil (5-FU)chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head andneck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (seesection 5.1).

KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic head and necksquamous cell carcinoma in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressingon or after platinum-containing chemotherapy (see section 5.1).

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renalcell carcinoma in adults (see section 5.1).

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of advancedrenal cell carcinoma in adults (see section 5.1).

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cellcarcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy andresection of metastatic lesions (for selection criteria, see section 5.1).

Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers

KEYTRUDA as monotherapy is indicated for adults with MSI-H or dMMR colorectal cancer in thefollowing settings:

- first-line treatment of metastatic colorectal cancer;

- treatment of unresectable or metastatic colorectal cancer after previousfluoropyrimidine-based combination therapy.

Non-colorectal cancers

KEYTRUDA as monotherapy is indicated for the treatment of the following MSI-H or dMMRtumours in adults with:

- advanced or recurrent endometrial carcinoma, who have disease progression on or followingprior treatment with a platinum-containing therapy in any setting and who are not candidatesfor curative surgery or radiation;

- unresectable or metastatic gastric, small intestine, or biliary cancer, who have diseaseprogression on or following at least one prior therapy.

KEYTRUDA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicatedfor the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagusin adults whose tumours express PD-L1 with a CPS ≥ 10 (see section 5.1).

KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued asmonotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locallyadvanced, or early-stage triple-negative breast cancer at high risk of recurrence (see section 5.1).

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrentunresectable or metastatic triple-negative breast cancer in adults whose tumours express PD-L1 with a

CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease (see section 5.1).

KEYTRUDA, in combination with carboplatin and paclitaxel, is indicated for the first-line treatmentof primary advanced or recurrent endometrial carcinoma in adults who are candidates for systemictherapy.

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrentendometrial carcinoma in adults who have disease progression on or following prior treatment with aplatinum-containing therapy in any setting and who are not candidates for curative surgery orradiation.

Cervical cancer

KEYTRUDA, in combination with chemoradiotherapy (external beam radiation therapy followed bybrachytherapy), is indicated for the treatment of FIGO 2014 Stage III - IVA locally advanced cervicalcancer in adults who have not received prior definitive therapy.

KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for thetreatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD-L1with a CPS ≥ 1.

Gastric or gastro-oesophageal junction (GEJ) adenocarcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine and platinum-containingchemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic

HER2-positive gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumoursexpress PD-L1 with a CPS ≥ 1.

KEYTRUDA, in combination with fluoropyrimidine and platinum-containing chemotherapy, isindicated for the first-line treatment of locally advanced unresectable or metastatic HER2-negativegastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a

CPS ≥ 1 (see section 5.1).

Biliary tract carcinoma (BTC)

KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the first-line treatmentof locally advanced unresectable or metastatic biliary tract carcinoma in adults.

Therapy must be initiated and supervised by specialist physicians experienced in the treatment ofcancer.

If specified in the indication, patient selection for treatment with KEYTRUDA based on the tumourexpression of PD-L1 should be confirmed by a validated test (see sections 4.1, pct. 4.4, pct. 4.8 and 5.1).

MSI/MMR testing

If specified in the indication, patient selection for treatment with KEYTRUDA based on

MSI-H/dMMR tumour status should be confirmed by a validated test (see sections 4.1 and 5.1).

The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every6 weeks administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and olderwith cHL or patients aged 12 years and older with melanoma is 2 mg/kg bodyweight (bw) (up to amaximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes.

For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitanttherapies.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity (andup to maximum duration of therapy if specified for an indication). Atypical responses (i.e. an initialtransient increase in tumour size or small new lesions within the first few months followed by tumourshrinkage) have been observed. It is recommended to continue treatment for clinically stable patientswith initial evidence of disease progression until disease progression is confirmed.

For the adjuvant treatment of melanoma, NSCLC, or RCC, KEYTRUDA should be administered untildisease recurrence, unacceptable toxicity, or for a duration of up to one year.

For the neoadjuvant and adjuvant treatment of resectable NSCLC, patients should be treated withneoadjuvant KEYTRUDA in combination with chemotherapy for 4 doses of 200 mg every 3 weeks or2 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery orunacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 13 dosesof 200 mg every 3 weeks or 7 doses of 400 mg every 6 weeks or until disease recurrence orunacceptable toxicity. Patients who experience disease progression that precludes definitive surgery orunacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination withchemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.

For the neoadjuvant and adjuvant treatment of TNBC, patients should be treated with neoadjuvant

KEYTRUDA in combination with chemotherapy for 8 doses of 200 mg every 3 weeks or 4 doses of400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptabletoxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 9 doses of 200 mgevery 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptabletoxicity. Patients who experience disease progression that precludes definitive surgery or unacceptabletoxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy shouldnot receive KEYTRUDA monotherapy as adjuvant treatment.

For locally advanced cervical cancer, patients should be treated with KEYTRUDA concurrent withchemoradiotherapy, followed by KEYTRUDA as monotherapy. KEYTRUDA can be administered aseither 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicityor up to 24 months.

No dose reductions of KEYTRUDA are recommended. KEYTRUDA should be withheld ordiscontinued to manage adverse reactions as described in Table 1.

Table 1: Recommended treatment modifications for KEYTRUDA

Immune-mediated Severity Treatment modificationadverse reactions

Pneumonitis Grade 2 Withhold until adverse reactionsrecover to Grades 0-1*

Grades 3 or 4, or recurrent Grade 2 Permanently discontinue

Colitis Grades 2 or 3 Withhold until adverse reactionsrecover to Grades 0-1*

Grade 4 or recurrent Grade 3 Permanently discontinue

Nephritis Grade 2 with creatinine > 1.5 to Withhold until adverse reactions≤ 3 times upper limit of normal recover to Grades 0-1*(ULN)

Grade ≥ 3 with creatinine > 3 times Permanently discontinue

ULN

Endocrinopathies Grade 2 adrenal insufficiency and Withhold treatment untilhypophysitis controlled by hormonereplacement

Grades 3 or 4 adrenal insufficiency Withhold until adverse reactionsor symptomatic hypophysitis recover to Grades 0-1*

Type 1 diabetes associated with For patients with Grade 3 or

Grade ≥ 3 hyperglycaemia (glucose Grade 4 endocrinopathies that> 250 mg/dL or > 13.9 mmol/L) or improved to Grade 2 or lowerassociated with ketoacidosis and are controlled with hormonereplacement, if indicated,

Hyperthyroidism Grade ≥ 3 continuation of pembrolizumabmay be considered aftercorticosteroid taper, if needed.

Otherwise treatment should bediscontinued.

Immune-mediated Severity Treatment modificationadverse reactions

Hypothyroidism Hypothyroidism may bemanaged with replacementtherapy without treatmentinterruption.

Hepatitis Grade 2 with aspartate Withhold until adverse reactionsaminotransferase (AST) or alanine recover to Grades 0-1*

NOTE: for RCC patients aminotransferase (ALT) > 3 totreated with 5 times ULN or total bilirubin > 1.5pembrolizumab in to 3 times ULNcombination with Grade ≥ 3 with AST or ALT Permanently discontinueaxitinib with liver enzyme > 5 times ULN or total bilirubinelevations, see dosing > 3 times ULNguidelines following this In case of liver metastasis with Permanently discontinuetable. baseline Grade 2 elevation of ASTor ALT, hepatitis with AST or ALTincreases ≥ 50% and lasts ≥ 1 week

Skin reactions Grade 3 or suspected Withhold until adverse reactions

Stevens-Johnson syndrome (SJS) or recover to Grades 0-1*toxic epidermal necrolysis (TEN)

Grade 4 or confirmed SJS or TEN Permanently discontinue

Other immune-mediated Based on severity and type of Withhold until adverse reactionsadverse reactions reaction (Grade 2 or Grade 3) recover to Grades 0-1*

Grades 3 or 4 myocarditis Permanently discontinue

Grades 3 or 4 encephalitis

Grades 3 or 4 Guillain-Barrésyndrome

Grade 4 or recurrent Grade 3 Permanently discontinue

Infusion-related Grades 3 or 4 Permanently discontinuereactions

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

Version 4.0 (NCI-CTCAE v.4).

* If treatment-related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of KEYTRUDA, or ifcorticosteroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks,

KEYTRUDA should be permanently discontinued.

The safety of re-initiating pembrolizumab therapy in patients previously experiencingimmune-mediated myocarditis is not known.

KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for

Grade 4 or recurrent Grade 3 immune-mediated adverse reactions, unless otherwise specified in

Table 1.

For Grade 4 haematological toxicity, only in patients with cHL, KEYTRUDA should be withheld untiladverse reactions recover to Grades 0-1.

For RCC patients treated with KEYTRUDA in combination with axitinib, see the SmPC regardingdosing of axitinib. When used in combination with pembrolizumab, dose escalation of axitinib abovethe initial 5 mg dose may be considered at intervals of six weeks or longer (see section 5.1).

For liver enzyme elevations, in patients with RCC being treated with KEYTRUDA in combination withaxitinib:

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

ULN, both KEYTRUDA and axitinib should be withheld until these adverse reactions recover to

Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine orsequential rechallenge with both medicines after recovery may be considered. If rechallengingwith axitinib, dose reduction as per the axitinib SmPC may be considered.

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

ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroidtherapy may be considered.

When used in combination with lenvatinib, one or both medicines should be interrupted asappropriate. Lenvatinib should be withheld, dose reduced, or discontinued in accordance with theinstructions in the lenvatinib SmPC for combination with pembrolizumab. No dose reductions arerecommended for KEYTRUDA.

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

KEYTRUDA (see also package leaflet).

No dose adjustment is necessary in patients ≥ 65 years (see sections 4.4 and 5.1).

No dose adjustment is needed for patients with mild or moderate renal impairment. KEYTRUDA hasnot been studied in patients with severe renal impairment (see sections 4.4 and 5.2).

No dose adjustment is needed for patients with mild or moderate hepatic impairment. KEYTRUDAhas not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).

The safety and efficacy of KEYTRUDA in children below 18 years of age have not been establishedexcept in paediatric patients with melanoma or cHL. Currently available data are described insections 4.8, 5.1 and 5.2.

KEYTRUDA is for intravenous use. It must be administered by infusion over 30 minutes.

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

When administering KEYTRUDA as part of a combination with intravenous chemotherapy,

KEYTRUDA should be administered first.

When administering KEYTRUDA as part of a combination with enfortumab vedotin, KEYTRUDAshould be administered after enfortumab vedotin when given on the same day.

For instructions on dilution of the medicinal product before administration, see section 6.6.

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

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

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robustmethodology is chosen to minimise false negative or false positive determinations.

Immune-mediated adverse reactions

Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patientsreceiving pembrolizumab. Most immune-mediated adverse reactions occurring during treatment withpembrolizumab were reversible and managed with interruptions of pembrolizumab, administration ofcorticosteroids and/or supportive care. Immune-mediated adverse reactions have also occurred afterthe last dose of pembrolizumab. Immune-mediated adverse reactions affecting more than one bodysystem can occur simultaneously.

For suspected immune-mediated adverse reactions, adequate evaluation to confirm aetiology orexclude other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumabshould be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroidtaper should be initiated and continued over at least 1 month. Based on limited data from clinicalstudies in patients whose immune-mediated adverse reactions could not be controlled withcorticosteroid use, administration of other systemic immunosuppressants can be considered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adversereaction recovers to Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone orequivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune-mediated adverse reactionthat recurs and for any Grade 4 immune-mediated adverse reaction toxicity, except forendocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).

Immune-mediated pneumonitis

Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients shouldbe monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmedwith radiographic imaging and other causes excluded. Corticosteroids should be administered for

Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper);pembrolizumab should be withheld for Grade 2 pneumonitis, and permanently discontinued for

Grade 3, Grade 4 or recurrent Grade 2 pneumonitis (see section 4.2).

Immune-mediated colitis

Colitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should bemonitored for signs and symptoms of colitis, and other causes excluded. Corticosteroids should beadministered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed bya taper); pembrolizumab should be withheld for Grade 2 or Grade 3 colitis, and permanentlydiscontinued for Grade 4 or recurrent Grade 3 colitis (see section 4.2). The potential risk ofgastrointestinal perforation should be taken into consideration.

Immune-mediated hepatitis

Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should bemonitored for changes in liver function (at the start of treatment, periodically during treatment and asindicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded.

Corticosteroids should be administered (initial dose of 0.5-1 mg/kg/day (for Grade 2 events) and1-2 mg/kg/day (for Grade ≥ 3 events) prednisone or equivalent followed by a taper) and, based onseverity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (seesection 4.2).

Immune-mediated nephritis

Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should bemonitored for changes in renal function, and other causes of renal dysfunction excluded.

Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1-2 mg/kg/day prednisoneor equivalent followed by a taper) and, based on severity of creatinine elevations, pembrolizumabshould be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (seesection 4.2).

Immune-mediated endocrinopathies

Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus,diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumabtreatment.

Long-term hormone replacement therapy may be necessary in cases of immune-mediatedendocrinopathies.

Adrenal insufficiency (primary and secondary) has been reported in patients receiving pembrolizumab.

Hypophysitis has also been reported in patients receiving pembrolizumab (see section 4.8). Patientsshould be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (includinghypopituitarism) and other causes excluded. Corticosteroids to treat adrenal insufficiency and otherhormone replacement should be administered as clinically indicated. Pembrolizumab should bewithheld for Grade 2 adrenal insufficiency or hypophysitis until the event is controlled with hormonereplacement. Pembrolizumab should be withheld or discontinued for Grades 3 or 4 adrenalinsufficiency or symptomatic hypophysitis. Continuation of pembrolizumab may be considered, aftercorticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should bemonitored to ensure appropriate hormone replacement.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receivingpembrolizumab (see section 4.8). Patients should be monitored for hyperglycaemia or other signs andsymptoms of diabetes. Insulin should be administered for type 1 diabetes, and pembrolizumab shouldbe withheld in cases of type 1 diabetes associated with Grade ≥ 3 hyperglycaemia or ketoacidosis untilmetabolic control is achieved (see section 4.2).

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported inpatients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism ismore frequently reported in patients with HNSCC with prior radiation therapy. Patients should bemonitored for changes in thyroid function (at the start of treatment, periodically during treatment andas indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders.

Hypothyroidism may be managed with replacement therapy without treatment interruption andwithout corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab shouldbe withheld for Grade ≥ 3 until recovery to Grade ≤ 1 hyperthyroidism. Thyroid function and hormonelevels should be monitored to ensure appropriate hormone replacement.

For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and arecontrolled with hormone replacement, if indicated, continuation of pembrolizumab may be consideredafter corticosteroid taper, if needed. Otherwise treatment should be discontinued (see sections 4.2 and4.8).

Immune-mediated skin adverse reactions

Immune-mediated severe skin reactions have been reported in patients receiving pembrolizumab (seesection 4.8). Patients should be monitored for suspected severe skin reactions and other causes shouldbe excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld for

Grade 3 skin reactions until recovery to Grade ≤ 1 or permanently discontinued for Grade 4 skinreactions, and corticosteroids should be administered (see section 4.2).

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reportedin patients receiving pembrolizumab (see section 4.8). For suspected SJS or TEN, pembrolizumabshould be withheld and the patient should be referred to a specialised unit for assessment andtreatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued (seesection 4.2).

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

Other immune-mediated adverse reactions

The following additional clinically significant, immune-mediated adverse reactions have been reportedin clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis,pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis,encephalitis, myelitis, vasculitis, cholangitis sclerosing, gastritis, cystitis noninfective,hypoparathyroidism and pericarditis (see sections 4.2 and 4.8).

Based on the severity and type of the adverse reaction, pembrolizumab should be withheld for Grade 2or Grade 3 events and corticosteroids administered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adversereaction recovers to Grade ≤ 1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone orequivalent per day.

Pembrolizumab must be permanently discontinued for any Grade 3 immune-mediated adverse reactionthat recurs and for any Grade 4 immune-mediated adverse reaction.

For Grades 3 or 4 myocarditis, encephalitis or Guillain-Barré syndrome, pembrolizumab should bepermanently discontinued (see sections 4.2 and 4.8).

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

PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organtransplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organrejection should be considered in these patients.

Allogeneic HSCT after treatment with pembrolizumab

Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have beenobserved in patients with cHL undergoing allogeneic HSCT after previous exposure topembrolizumab. Until further data become available, careful consideration to the potential benefits of

HSCT and the possible increased risk of transplant-related complications should be made case by case(see section 4.8).

Allogeneic HSCT prior to treatment with pembrolizumab

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reportedafter treatment with pembrolizumab. Patients who experienced GVHD after their transplant proceduremay be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit oftreatment with pembrolizumab versus the risk of possible GVHD in patients with a history ofallogeneic HSCT.

Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported inpatients receiving pembrolizumab (see section 4.8). For Grades 3 or 4 infusion reactions, infusionshould be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with

Grades 1 or 2 infusion reaction may continue to receive pembrolizumab with close monitoring;premedication with antipyretic and antihistamine may be considered.

Pembrolizumab in combination with chemotherapy should be used with caution in patients ≥ 75 yearsafter careful consideration of the potential benefit/risk on an individual basis (see section 5.1).

Use of pembrolizumab in urothelial carcinoma patients who have received prior platinum-containingchemotherapy

Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment inpatients with poorer prognostic features and/or aggressive disease. In urothelial carcinoma, a highernumber of deaths within 2 months was observed in pembrolizumab compared to chemotherapy (seesection 5.1). Factors associated with early deaths were fast progressive disease on prior platinumtherapy and liver metastases.

Use of pembrolizumab in urothelial carcinoma for patients who are considered ineligible forcisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS ≥ 10

The baseline and prognostic disease characteristics of the study population of KEYNOTE-052included a proportion of patients eligible for a carboplatin-based combination, for whom the benefithas been assessed in a comparative study (KEYNOTE-361). In KEYNOTE-361, a higher number ofdeaths within 6 months of treatment initiation followed by a long-term survival benefit was observedwith pembrolizumab monotherapy compared to chemotherapy (see section 5.1). No specific factor(s)associated with early deaths could be identified. Physicians should consider the delayed onset ofpembrolizumab effect before initiating treatment in patients with urothelial carcinoma who areconsidered eligible for carboplatin-based combination chemotherapy. KEYNOTE-052 also includedpatients eligible for mono-chemotherapy, for whom no randomised data are available. In addition, nosafety and efficacy data are available in frailer patients (e.g. ECOG performance status 3) considerednot eligible for chemotherapy. In the absence of these data, pembrolizumab should be used withcaution in this population after careful consideration of the potential risk-benefit on an individualbasis.

In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed tobe higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions ofeach of these components (see sections 4.2 and 4.8). A direct comparison of pembrolizumab whenused in combination with chemotherapy to pembrolizumab monotherapy is not available.

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumabmonotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment inpreviously untreated patients with NSCLC whose tumours express PD-L1.

In KEYNOTE-042, a higher number of deaths within 4 months of treatment initiation followed by along-term survival benefit was observed with pembrolizumab monotherapy compared tochemotherapy (see section 5.1).

In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed tobe higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions ofeach of these components (see section 4.8).

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumabmonotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment inpatients with HNSCC whose tumours express PD-L1 (see section 5.1).

Use of pembrolizumab for treatment of patients with advanced or recurrent MSI-H or dMMRendometrial carcinoma

A direct comparison of pembrolizumab when used in combination with lenvatinib to pembrolizumabmonotherapy is not available. Physicians should consider the benefit/risk balance of the availabletreatment options (pembrolizumab monotherapy or pembrolizumab in combination with lenvatinib)before initiating treatment in patients with advanced or recurrent MSI-H or dMMR endometrialcarcinoma.

A trend toward increased frequency of severe and serious adverse reactions in patients ≥ 75 years wasobserved. Safety data of pembrolizumab in the adjuvant melanoma setting in patients ≥ 75 years arelimited.

When pembrolizumab is given with axitinib, higher than expected frequencies of Grades 3 and 4 ALTand AST elevations have been reported in patients with advanced RCC (see section 4.8). Liverenzymes should be monitored before initiation of and periodically throughout treatment. Morefrequent monitoring of liver enzymes as compared to when the medicines are used in monotherapymay be considered. Medical management guidelines for both medicines should be followed (seesection 4.2 and refer to the SmPC for axitinib).

In KEYNOTE-177, the hazard rates for overall survival events were greater for pembrolizumabcompared with chemotherapy for the first 4 months of treatment, followed by a long-term survivalbenefit for pembrolizumab (see section 5.1).

Use of pembrolizumab for first-line treatment of patients with BTC

Cholangitis and biliary tract infections are not uncommon in patients with BTC. Cholangitis eventswere reported in KEYNOTE-966 in both treatment groups (11.2% [n=59] of participants in thepembrolizumab plus chemotherapy arm and 10.3% [n=55] of participants in the placebo pluschemotherapy arm). Patients with biliary stents and drains (n=74) were at increased risk of cholangitisand biliary tract infections in KEYNOTE-966 (39.4% [n=13] of participants in the pembrolizumabplus chemotherapy arm vs. 29.3% [n=12] of participants in the placebo plus chemotherapy arm).

Patients with BTC (especially those with biliary stents) should be closely monitored for developmentof cholangitis or biliary tract infections before initiation of treatment and, regularly, thereafter.

Patients with the following conditions were excluded from clinical studies: active CNS metastases;

ECOG PS ≥ 2 (except for urothelial carcinoma and RCC); HIV infection, hepatitis B or hepatitis Cinfection (except for BTC); active systemic autoimmune disease; interstitial lung disease; priorpneumonitis requiring systemic corticosteroid therapy; a history of severe hypersensitivity to anothermonoclonal antibody; receiving immunosuppressive therapy and a history of severe immune-mediatedadverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicityrequiring corticosteroid treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks.

Patients with active infections were excluded from clinical studies and were required to have theirinfection treated prior to receiving pembrolizumab. Patients with active infections occurring duringtreatment with pembrolizumab were managed with appropriate medical therapy. Patients withclinically significant renal (creatinine > 1.5 x ULN) or hepatic (bilirubin > 1.5 x ULN, ALT, AST> 2.5 x ULN in the absence of liver metastases) abnormalities at baseline were excluded from clinicalstudies, therefore information is limited in patients with severe renal and moderate to severe hepaticimpairment.

There are limited data on the safety and efficacy of KEYTRUDA in patients with ocular melanoma(see section 5.1).

After careful consideration of the potential increased risk, pembrolizumab may be used withappropriate medical management in these patients.

All prescribers of KEYTRUDA must be familiar with the Physician Information and Management

Guidelines. The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patientwill be provided with the patient card with each prescription.

No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Sincepembrolizumab is cleared from the circulation through catabolism, no metabolic drug-druginteractions are expected.

The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should beavoided because of their potential interference with the pharmacodynamic activity and efficacy ofpembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used afterstarting pembrolizumab to treat immune-mediated adverse reactions (see section 4.4). Corticosteroidscan also be used as premedication, when pembrolizumab is used in combination with chemotherapy,as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

Women of childbearing potential should use effective contraception during treatment withpembrolizumab and for at least 4 months after the last dose of pembrolizumab.

There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies havenot been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss(see section 5.3). These results indicate a potential risk, based on its mechanism of action, thatadministration of pembrolizumab during pregnancy could cause foetal harm, including increased ratesof abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier;therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to thedeveloping foetus. Pembrolizumab should not be used during pregnancy unless the clinical conditionof the woman requires treatment with pembrolizumab.

It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies canbe secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should bemade whether to discontinue breast-feeding or to discontinue pembrolizumab, taking into account thebenefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.

No clinical data are available on the possible effects of pembrolizumab on fertility. There were nonotable effects in the male and female reproductive organs in monkeys based on 1-month and 6-monthrepeat-dose toxicity studies (see section 5.3).

Pembrolizumab has a minor influence on the ability to drive and use machines. In some patients,dizziness and fatigue have been reported following administration of pembrolizumab (see section 4.8).

Pembrolizumab is most commonly associated with immune-mediated adverse reactions. Most ofthese, including severe reactions, resolved following initiation of appropriate medical therapy orwithdrawal of pembrolizumab (see “Description of selected adverse reactions” below). Thefrequencies included below and in Table 2 are based on all reported adverse drug reactions, regardlessof the investigator assessment of causality.

The safety of pembrolizumab as monotherapy has been evaluated in 7 631 patients across tumourtypes and across four doses (2 mg/kg bw every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bw every2 or 3 weeks) in clinical studies. In this patient population, the median observation time was8.5 months (range: 1 day to 39 months) and the most frequent adverse reactions with pembrolizumabwere fatigue (31%), diarrhoea (22%), and nausea (20%). The majority of adverse reactions reportedfor monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions wereimmune-mediated adverse reactions and severe infusion-related reactions (see section 4.4). Theincidences of immune-mediated adverse reactions were 37% all Grades and 9% for Grades 3-5 forpembrolizumab monotherapy in the adjuvant setting and 25% all Grades and 6% for Grades 3-5 in themetastatic setting. No new immune-mediated adverse reactions were identified in the adjuvant setting.

Pembrolizumab in combination with chemotherapy or chemoradiotherapy (CRT) (see section 4.2)

When pembrolizumab is administered in combination, refer to the SmPC for the respectivecombination therapy components prior to initiation of treatment.

The safety of pembrolizumab in combination with chemotherapy or CRT has been evaluated in6 334 patients across tumour types receiving 200 mg, 2 mg/kg bw or 10 mg/kg bw pembrolizumabevery 3 weeks, in clinical studies. In this patient population, the most frequent adverse reactions werenausea (52%), anaemia (51%), fatigue (36%), diarrhoea (35%), constipation (32%), vomiting (28%),neutrophil count decreased (27%), and decreased appetite (27%). Incidences of Grades 3-5 adversereactions in patients with NSCLC were 69% for pembrolizumab combination therapy and 61% forchemotherapy alone, in patients with HNSCC were 85% for pembrolizumab combination therapy and84% for chemotherapy plus cetuximab, in patients with oesophageal carcinoma were 86% forpembrolizumab combination therapy and 83% for chemotherapy alone, in patients with TNBC were80% for pembrolizumab combination therapy and 77% for chemotherapy alone, in patients withcervical cancer were 77% for pembrolizumab combination therapy (chemotherapy with or withoutbevacizumab or in combination with CRT) and 71% for chemotherapy with or without bevacizumabor CRT alone, in patients with gastric cancer were 74% for pembrolizumab combination therapy(chemotherapy with or without trastuzumab) and 68% for chemotherapy with or without trastuzumab,in patients with biliary tract carcinoma were 85% for pembrolizumab combination therapy and 84%for chemotherapy alone, in patients with EC were 59% for pembrolizumab combination therapy and46% for chemotherapy alone and in patients with malignant pleural mesothelioma were 44% forpembrolizumab combination therapy and 30% for chemotherapy alone.

When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPCfor axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety informationrelated to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima.

For additional axitinib safety information for elevated liver enzymes see also section 4.4.

The safety of pembrolizumab in combination with axitinib or lenvatinib in advanced RCC, and incombination with lenvatinib in advanced EC has been evaluated in a total of 1 456 patients withadvanced RCC or advanced EC receiving 200 mg pembrolizumab every 3 weeks with either axitinib5 mg twice daily or lenvatinib 20 mg once daily in clinical studies, as appropriate. In these patientpopulations, the most frequent adverse reactions were diarrhoea (58%), hypertension (54%),hypothyroidism (46%), fatigue (41%), decreased appetite (40%), nausea (40%), arthralgia (30%),vomiting (28%), weight decreased (28%), dysphonia (28%), abdominal pain (28%), proteinuria (27%),palmar-plantar erythrodysaesthesia syndrome (26%), rash (26%), stomatitis (25%),constipation (25%), musculoskeletal pain (23%), headache (23%) and cough (21%). Grades 3-5adverse reactions in patients with RCC were 80% for pembrolizumab in combination with eitheraxitinib or lenvatinib and 71% for sunitinib alone. In patients with EC, Grades 3-5 adverse reactionswere 89% for pembrolizumab in combination with lenvatinib and 73% for chemotherapy alone.

Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combinationwith chemotherapy or CRT or other anti-tumour medicines or reported from post-marketing use ofpembrolizumab are listed 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); and notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in the order of decreasing seriousness. Adverse reactions known to occur withpembrolizumab or combination therapy components given alone may occur during treatment withthese medicinal products in combination, even if these reactions were not reported in clinical studieswith combination therapy.

For additional safety information when pembrolizumab is administered in combination, refer to the

SmPC for the respective combination therapy components.

Table 2: Adverse reactions in patients treated with pembrolizumab†

MedDRA SOC Monotherapy In combination with In combination withand frequency chemotherapy or axitinib or lenvatinibcategory chemoradiotherapy

Very common urinary tract infection

Common pneumonia pneumonia pneumonia

Very common anaemia anaemia, neutropenia, anaemiathrombocytopenia

Common thrombocytopenia, febrile neutropenia, neutropenia,neutropenia, leukopenia, lymphopenia thrombocytopenia,lymphopenia lymphopenia,leukopenia

Uncommon leukopenia, immune haemolytic anaemia⁎, eosinophiliathrombocytopenia, eosinophiliaeosinophilia

Rare haemolytic immuneanaemia⁎, thrombocytopeniahaemophagocyticlymphohistiocytosis,pure red cell aplasia

Common infusion-related infusion-related reaction⁎ infusion-relatedreaction⁎ reaction⁎

Uncommon sarcoidosis⁎

Rare sarcoidosis

Not known solid organtransplant rejection

Very common hypothyroidism⁎ hypothyroidism⁎ hypothyroidism

Common hyperthyroidism adrenal insufficiency⁎, adrenal insufficiency⁎,hyperthyroidism⁎, hyperthyroidism,thyroiditis⁎ thyroiditis⁎

Uncommon adrenal hypophysitis⁎ hypophysitis⁎insufficiency⁎,hypophysitis⁎,thyroiditis⁎

Rare hypoparathyroidism hypoparathyroidism hypoparathyroidism

MedDRA SOC Monotherapy In combination with In combination withand frequency chemotherapy or axitinib or lenvatinibcategory chemoradiotherapy

Very common decreased appetite hypokalaemia, decreased decreased appetiteappetite

Common hyponatraemia, hyponatraemia, hyponatraemia,hypokalaemia, hypocalcaemia hypokalaemia,hypocalcaemia hypocalcaemia

Uncommon type 1 diabetes type 1 diabetes mellitus⁎ type 1 diabetesmellitus⁎ mellitus⁎

Very common insomnia

Common insomnia insomnia

Very common headache neuropathy peripheral, headache, dysgeusiaheadache, dizziness

Common dizziness, dysgeusia dizziness, neuropathyneuropathy peripheral, lethargyperipheral, lethargy,dysgeusia

Uncommon myasthenic encephalitis⁎, epilepsy, myasthenicsyndrome⁎, epilepsy lethargy syndrome⁎,encephalitis⁎

Rare Guillain-Barré myasthenic syndrome⁎, optic neuritissyndrome⁎, Guillain-Barréencephalitis⁎, syndrome⁎, myelitis,myelitis⁎, optic optic neuritis, meningitisneuritis, meningitis (aseptic)(aseptic)⁎

Common dry eye dry eye dry eye

Uncommon uveitis⁎ uveitis⁎ uveitis⁎

Rare Vogt-Koyanagi-Har Vogt-Koyanagi-Haradada syndrome a syndrome

Common cardiac arrhythmia‡ cardiac arrhythmia‡ cardiac arrhythmia‡(including atrial (including atrial (including atrialfibrillation) fibrillation) fibrillation)

Uncommon myocarditis, myocarditis⁎, myocarditis,pericarditis⁎, pericarditis⁎, pericardial pericardial effusionpericardial effusion effusion

Very common hypertension

Common hypertension hypertension

Uncommon vasculitis⁎ vasculitis⁎

Rare vasculitis⁎

Very common dyspnoea, cough dyspnoea, cough dyspnoea, cough

Common pneumonitis⁎ pneumonitis⁎ pneumonitis⁎

Very common diarrhoea, diarrhoea, nausea, diarrhoea, abdominalabdominal pain⁎, vomiting, abdominal pain⁎, nausea,nausea, vomiting, pain⁎, constipation vomiting, constipationconstipation

MedDRA SOC Monotherapy In combination with In combination withand frequency chemotherapy or axitinib or lenvatinibcategory chemoradiotherapy

Common colitis⁎, dry mouth colitis⁎, gastritis⁎, dry colitis⁎, pancreatitis⁎,mouth gastritis⁎, dry mouth

Uncommon pancreatitis⁎, pancreatitis⁎, gastrointestinalgastritis⁎, gastrointestinal ulceration⁎gastrointestinal ulceration⁎ulceration⁎

Rare pancreatic exocrine pancreatic exocrine small intestinalinsufficiency, small insufficiency, small perforationintestinal intestinal perforation,perforation, coeliac coeliac diseasedisease

Not known pancreatic exocrineinsufficiency, coeliacdisease

Common hepatitis⁎ hepatitis⁎ hepatitis⁎

Rare cholangitis cholangitis sclerosing⁎sclerosing

Very common pruritus⁎, rash⁎ rash⁎, alopecia, pruritus⁎, rash⁎, pruritus⁎

Common severe skin severe skin reactions⁎, severe skin reactions⁎,reactions⁎, erythema, dermatitis, erythema, dry dermatitis, dry skin,dermatitis, dry skin, skin, dermatitis erythema, dermatitisvitiligo⁎, eczema, acneiform, eczema acneiform, alopeciaalopecia, dermatitisacneiform

Uncommon psoriasis, lichenoid psoriasis, lichenoid eczema, lichenoidkeratosis⁎, papule, keratosis⁎, vitiligo⁎, keratosis⁎, psoriasis,hair colour changes papule vitiligo⁎, papule, haircolour changes

Rare Stevens-Johnson Stevens-Johnson toxic epidermalsyndrome, erythema syndrome, erythema necrolysis,nodosum, toxic nodosum, hair colour Stevens-Johnsonepidermal necrolysis changes syndrome

Very common musculoskeletal musculoskeletal pain⁎, arthralgia,pain⁎, arthralgia arthralgia musculoskeletal pain⁎,myositis⁎, pain inextremity

Common myositis⁎, pain in myositis⁎, pain in arthritis⁎extremity, arthritis⁎ extremity, arthritis⁎

Uncommon tenosynovitis⁎ tenosynovitis⁎ tenosynovitis⁎

Rare Sjogren’s syndrome Sjogren’s syndrome Sjogren’s syndrome

Common acute kidney injury nephritis⁎

Uncommon nephritis⁎ nephritis⁎, cystitisnoninfective

Rare cystitis noninfective cystitis noninfective

Very common fatigue, asthenia, fatigue, asthenia, pyrexia, fatigue, asthenia,oedema⁎, pyrexia oedema⁎ oedema⁎, pyrexia

MedDRA SOC Monotherapy In combination with In combination withand frequency chemotherapy or axitinib or lenvatinibcategory chemoradiotherapy

Common influenza-like influenza-like illness, influenza-like illness,illness, chills chills chills

Very common alanine aminotransferase lipase increased,increased, aspartate alanineaminotransferase aminotransferaseincreased increased, aspartateaminotransferaseincreased, bloodcreatinine increased

Common alanine blood bilirubin increased, amylase increased,aminotransferase blood alkaline blood bilirubinincreased, aspartate phosphatase increased, increased, bloodaminotransferase blood creatinine alkaline phosphataseincreased, blood increased, increased,alkaline phosphatase hypercalcaemia hypercalcaemiaincreased,hypercalcaemia,blood bilirubinincreased, bloodcreatinine increased

Uncommon amylase increased amylase increased†Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may containcontributions from the underlying disease or from other medicinal products used in a combination.‡Based upon a standard query including bradyarrhythmias and tachyarrhythmias.⁎The following terms represent a group of related events that describe a medical condition rather than a single event:

* haemolytic anaemia (autoimmune haemolytic anaemia and Coombs negative haemolytic anaemia)

* infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity,infusion-related hypersensitivity reaction, cytokine release syndrome and serum sickness)

* sarcoidosis (cutaneous sarcoidosis and pulmonary sarcoidosis)

* hypothyroidism (myxoedema, immune-mediated hypothyroidism and autoimmune hypothyroidism)

* adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute and secondary adrenocorticalinsufficiency)

* thyroiditis (autoimmune thyroiditis, silent thyroiditis, thyroid disorder, thyroiditis acute and immune-mediatedthyroiditis)

* hyperthyroidism (Graves' disease)

* hypophysitis (hypopituitarism and lymphocytic hypophysitis)

* type 1 diabetes mellitus (diabetic ketoacidosis)

* myasthenic syndrome (myasthenia gravis, including exacerbation)

* encephalitis (autoimmune encephalitis and noninfective encephalitis)

* Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)

* myelitis (including transverse myelitis)

* meningitis aseptic (meningitis and meningitis noninfective)

* uveitis (chorioretinitis, iritis and iridocyclitis)

* myocarditis (autoimmune myocarditis)

* pericarditis (autoimmune pericarditis, pleuropericarditis and myopericarditis)

* vasculitis (central nervous system vasculitis, aortitis and giant cell arteritis)

* pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis, immune-mediated lungdisease and autoimmune lung disease)

* abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)

* colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis and immune-mediatedenterocolitis)

* gastritis (gastritis erosive, gastritis haemorrhagic and immune-mediated gastritis)

* pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis)

* gastrointestinal ulceration (gastric ulcer and duodenal ulcer)

* hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis)

* cholangitis sclerosing (immune-mediated cholangitis)

* pruritus (urticaria, urticaria papular and pruritus genital)

* rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicularand genital rash)

* severe skin reactions (exfoliative rash, pemphigus, and Grade ≥ 3 of the following: cutaneous vasculitis, dermatitisbullous, dermatitis exfoliative, dermatitis exfoliative generalised, erythema multiforme, lichen planus, oral lichenplanus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rashpustular, skin necrosis and toxic skin eruption)

* vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)

* lichenoid keratosis (lichen planus and lichen sclerosus)

* musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain andtorticollis)

* myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis)

* arthritis (joint swelling, polyarthritis, joint effusion, autoimmune arthritis and immune-mediated arthritis)

* tenosynovitis (tendonitis, synovitis and tendon pain)

* nephritis (autoimmune nephritis, immune-mediated nephritis, tubulointerstitial nephritis and renal failure, renal failureacute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis, glomerulonephritismembranous and glomerulonephritis acute)

* oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, faceoedema, localised oedema and periorbital oedema)

Pembrolizumab in combination with enfortumab vedotin (see section 4.2)

When pembrolizumab is administered in combination with enfortumab vedotin, refer to the SmPC forenfortumab vedotin prior to initiation of treatment.

The safety of pembrolizumab in combination with enfortumab vedotin has been evaluated among564 patients with unresectable or metastatic urothelial carcinoma receiving 200 mg pembrolizumab on

Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle.

Overall, the incidence of adverse reactions for pembrolizumab in combination with enfortumabvedotin was observed to be higher than for pembrolizumab monotherapy reflecting the contribution ofenfortumab vedotin and the longer duration of treatment of the combination therapy.

Adverse reactions were generally similar to those observed in patients receiving pembrolizumab orenfortumab vedotin as monotherapy. The incidence of rash maculo-papular was 36% all Grades (10%

Grades 3-4), which is higher than observed in pembrolizumab monotherapy.

Generally, adverse event frequencies were higher in patients ≥ 65 years of age compared to < 65 yearsof age, particularly for serious adverse events (56.3% and 35.3%, respectively) and ≥ Grade 3 events(80.3% and 64.2%, respectively), similar to observations with the chemotherapy comparator.

Data for the following immune-mediated adverse reactions are based on patients who receivedpembrolizumab across four doses (2 mg/kg bw every 3 weeks, 10 mg/kg bw every 2 or 3 weeks, or200 mg every 3 weeks) in clinical studies (see section 5.1). The management guidelines for theseadverse reactions are described in section 4.4.

Immune-mediated adverse reactions (see section 4.4)

Immune-mediated pneumonitis

Pneumonitis occurred in 324 (4.2%) patients, including Grade 2, 3, 4 or 5 cases in 143 (1.9%),81 (1.1%), 19 (0.2%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median timeto onset of pneumonitis was 3.9 months (range: 2 days to 27.2 months). The median duration was2.0 months (range: 1 day to 51.0+ months). Pneumonitis occurred more frequently in patients with ahistory of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation(3.9%). Pneumonitis led to discontinuation of pembrolizumab in 131 (1.7%) patients. Pneumonitisresolved in 196 patients, 6 with sequelae.

In patients with NSCLC, pneumonitis occurred in 230 (6.1%), including Grade 2, 3, 4 or 5 cases in103 (2.7%), 63 (1.7%), 17 (0.4%) and 10 (0.3%), respectively. In patients with locally advanced ormetastatic NSCLC, pneumonitis occurred in 8.9% with a history of prior thoracic radiation. In patientswith cHL, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in

KEYNOTE-087 (n=210) and KEYNOTE-204 (n=148), respectively.

Immune-mediated colitis

Colitis occurred in 158 (2.1%) patients, including Grade 2, 3 or 4 cases in 49 (0.6%), 82 (1.1%) and6 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was4.3 months (range: 2 days to 24.3 months). The median duration was 1.1 month (range: 1 day to45.2 months). Colitis led to discontinuation of pembrolizumab in 48 (0.6%) patients. Colitis resolvedin 132 patients, 2 with sequelae. In patients with CRC treated with pembrolizumab as monotherapy(n=153), the incidence of colitis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4.

Immune-mediated hepatitis

Hepatitis occurred in 80 (1.0%) patients, including Grade 2, 3 or 4 cases in 12 (0.2%), 55 (0.7%) and8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was3.5 months (range: 8 days to 26.3 months). The median duration was 1.3 months (range: 1 day to29.0+ months). Hepatitis led to discontinuation of pembrolizumab in 37 (0.5%) patients. Hepatitisresolved in 60 patients.

Immune-mediated nephritis

Nephritis occurred in 37 (0.5%) patients, including Grade 2, 3 or 4 cases in 11 (0.1%), 19 (0.2%) and2 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onsetof nephritis was 4.2 months (range: 12 days to 21.4 months). The median duration was 3.3 months(range: 6 days to 28.2+ months). Nephritis led to discontinuation of pembrolizumab in 17 (0.2%)patients. Nephritis resolved in 25 patients, 5 with sequelae. In patients with non-squamous NSCLCtreated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), theincidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.

Immune-mediated endocrinopathies

Adrenal insufficiency occurred in 74 (1.0%) patients, including Grade 2, 3 or 4 cases in 34 (0.4%),31 (0.4%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset ofadrenal insufficiency was 5.4 months (range: 1 day to 23.7 months). The median duration was notreached (range: 3 days to 40.1+ months). Adrenal insufficiency led to discontinuation ofpembrolizumab in 13 (0.2%) patients. Adrenal insufficiency resolved in 28 patients, 11 with sequelae.

Hypophysitis occurred in 52 (0.7%) patients, including Grade 2, 3 or 4 cases in 23 (0.3%), 24 (0.3%)and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset ofhypophysitis was 5.9 months (range: 1 day to 17.7 months). The median duration was 3.6 months(range: 3 days to 48.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 14 (0.2%)patients. Hypophysitis resolved in 23 patients, 8 with sequelae.

Hyperthyroidism occurred in 394 (5.2%) patients, including Grade 2 or 3 cases in 108 (1.4%) and9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset ofhyperthyroidism was 1.4 months (range: 1 day to 23.2 months). The median duration was 1.6 months(range: 4 days to 43.1+ months). Hyperthyroidism led to discontinuation of pembrolizumab in4 (0.1%) patients. Hyperthyroidism resolved in 326 (82.7%) patients, 11 with sequelae. In patientswith melanoma, NSCLC and RCC treated with pembrolizumab monotherapy in the adjuvant setting(n=2 060), the incidence of hyperthyroidism was 11.0%, the majority of which were Grade 1 or 2.

Hypothyroidism occurred in 939 (12.3%) patients, including Grade 2 or 3 cases in 687 (9.0%) and8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset ofhypothyroidism was 3.4 months (range: 1 day to 25.9 months). The median duration was not reached(range: 2 days to 63.0+ months). Hypothyroidism led to discontinuation of pembrolizumab in 6 (0.1%)patients. Hypothyroidism resolved in 216 (23.0%) patients, 16 with sequelae. In patients with cHL(n=389) the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. In patients with

HNSCC treated with pembrolizumab as monotherapy (n=909), the incidence of hypothyroidism was16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab incombination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidismwas 15.2%, all of which were Grade 1 or 2. In patients treated with pembrolizumab in combinationwith axitinib or lenvatinib (n=1 456), the incidence of hypothyroidism was 46.2% (all Grades) with0.8% Grade 3 or 4. In patients with melanoma, NSCLC and RCC treated with pembrolizumabmonotherapy in the adjuvant setting (n=2 060), the incidence of hypothyroidism was 18.5%, themajority of which were Grade 1 or 2.

Immune-mediated skin adverse reactions

Immune-mediated severe skin reactions occurred in 130 (1.7%) patients, including Grade 2, 3, 4 or 5cases in 11 (0.1%), 103 (1.3%), 1 (< 0.1%) and 1 (< 0.1%) patients, respectively, receivingpembrolizumab. The median time to onset of severe skin reactions was 2.8 months (range: 2 days to25.5 months). The median duration was 1.9 months (range: 1 day to 47.1+ months). Severe skinreactions led to discontinuation of pembrolizumab in 18 (0.2%) patients. Severe skin reactionsresolved in 95 patients, 2 with sequelae.

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

Of 14 patients in KEYNOTE-013 who proceeded to allogeneic HSCT after treatment withpembrolizumab, 6 patients reported acute GVHD and 1 patient reported chronic GVHD, none ofwhich were fatal. Two patients experienced hepatic VOD, one of which was fatal. One patientexperienced engraftment syndrome post-transplant.

Of 32 patients in KEYNOTE-087 who proceeded to allogeneic HSCT after treatment withpembrolizumab, 16 patients reported acute GVHD and 7 patients reported chronic GVHD, two ofwhich were fatal. No patients experienced hepatic VOD. No patients experienced engraftmentsyndrome post-transplant.

Of 14 patients in KEYNOTE-204 who proceeded to allogeneic HSCT after treatment withpembrolizumab, 8 patients reported acute GVHD and 3 patients reported chronic GVHD, none ofwhich were fatal. No patients experienced hepatic VOD. One patient experienced engraftmentsyndrome post-transplant.

In a clinical study of previously untreated patients with RCC receiving pembrolizumab in combinationwith axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and ASTincreased (13%) were observed. The median time to onset of ALT increased was 2.3 months (range:7 days to 19.8 months). In patients with ALT ≥ 3 times ULN (Grades 2-4, n=116), ALT resolved to

Grades 0-1 in 94%. Fifty-nine percent of the patients with increased ALT received systemiccorticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with eitherpembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% hadno recurrence of ALT > 3 times ULN, and of those patients with recurrence of ALT > 3 times ULN,all recovered. There were no Grade 5 hepatic events.

In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced ashift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.9% for lymphocytesdecreased, 7.3% for sodium decreased, 5.7% for haemoglobin decreased, pct. 4.6% for glucose increased,4.5% for phosphate decreased, 3.1% for ALT increased, 2.9% for AST increased, 2.6% for alkalinephosphatase increased, 2.2% for potassium decreased, 2.1% for neutrophils decreased, 1.7% forbilirubin increased, 1.7% for platelets decreased, 1.7% for potassium increased, 1.6% for calciumincreased, 1.4% for albumin decreased, 1.3% for calcium decreased, 1.2% for creatinine increased,0.8% for leukocytes decreased, 0.8% for magnesium increased, 0.6% for glucose decreased, 0.2% formagnesium decreased, and 0.2% for sodium increased.

In patients treated with pembrolizumab in combination with chemotherapy or CRT, the proportion ofpatients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was asfollows: 37.6% for neutrophils decreased, 30.9% for lymphocytes decreased, 24.4% for leukocytesdecreased, 20.7% for haemoglobin decreased, 12.4% for platelets decreased, 9.3% for sodiumdecreased, 7.9% for potassium decreased, 7.3% for phosphate decreased, 5.5% for glucose increased,5.1% for ALT increased, pct. 4.6% for AST increased, 3.5% for calcium decreased, 3.1% for bilirubinincreased, 3.0% for potassium increased, 3.0% for creatinine increased, 2.4% for alkaline phosphataseincreased, 2.3% for albumin decreased, 1.6% for calcium increased, 0.9% for glucose decreased and0.4% for sodium increased.

In patients treated with pembrolizumab in combination with axitinib or lenvatinib, the proportion ofpatients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was asfollows: 23.0% for lipase increased (not measured in patients treated with pembrolizumab andaxitinib), 12.3% for lymphocyte decreased, 11.4% for sodium decreased, 11.2% for amylaseincreased, 11.2% for triglycerides increased, 10.4% for ALT increased, 8.9% for AST increased, 7.8%for glucose increased, 6.8% for phosphate decreased, 6.1% for potassium decreased, 5.1% forpotassium increased, 4.5% for cholesterol increased, pct. 4.4% for creatinine increased, 4.2% forhaemoglobin decreased, 4.0% for neutrophils decreased, 3.1% for alkaline phosphatase increased,3.0% for platelets decreased, 2.8% for bilirubin increased, 2.2% for calcium decreased, 2.2% formagnesium increased, 1.7% for leukocytes decreased, 1.5% for magnesium decreased, 1.5% forprothrombin INR increased, 1.4% for glucose decreased, 1.2% for albumin decreased, 1.0% forcalcium increased, 0.4% for sodium increased, and 0.1% for haemoglobin increased.

In clinical studies in patients treated with pembrolizumab 2 mg/kg bw every three weeks, 200 mgevery three weeks, or 10 mg/kg bw every two or three weeks as monotherapy, 36 (1.8%) of2 034 evaluable patients tested positive for treatment-emergent antibodies to pembrolizumab, of which9 (0.4%) patients had neutralising antibodies against pembrolizumab. There was no evidence of analtered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibodydevelopment.

The safety of pembrolizumab as monotherapy has been evaluated in 161 paediatric patients aged9 months to 17 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, orrefractory solid tumours at 2 mg/kg bw every 3 weeks in the Phase I/II study KEYNOTE-051. ThecHL population (n=22) included patients 11 to 17 years of age. The safety profile in paediatric patientswas generally similar to that seen in adults treated with pembrolizumab. The most common adversereactions (reported in at least 20% of paediatric patients) were pyrexia (33%), vomiting (30%),headache (26%), abdominal pain (22%), anaemia (21%), cough (21%) and constipation (20%). Themajority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity.

Seventy-six (47.2%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (3.1%) patientshad 1 or more adverse reactions that resulted in death. The frequencies are based on all reportedadverse drug reactions, regardless of the investigator assessment of causality. Long-term safety data ofpembrolizumab in adolescents with Stage IIB, IIC and III melanoma treated in the adjuvant setting arecurrently unavailable.

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.

There is no information on overdose with pembrolizumab.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions,and appropriate symptomatic treatment instituted.

Pharmacotherapeutic group: Antineoplastic agents, PD-1/PDL-1 (Programmed cell death protein1/death ligand 1) inhibitors. ATC code: L01FF02

KEYTRUDA is a humanised monoclonal antibody which binds to the programmed cell death-1(PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is anegative regulator of T-cell activity that has been shown to be involved in the control of T-cellimmune responses. KEYTRUDA potentiates T-cell responses, including anti-tumour responses,through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presentingcells and may be expressed by tumours or other cells in the tumour microenvironment.

The anti-angiogenic effect of lenvatinib (multi-TKI) in combination with the immune-stimulatoryeffect of pembrolizumab (anti-PD-1) results in a tumour microenvironment with greater T-cellactivation to help overcome primary and acquired resistance to immunotherapy and may improvetumour responses compared to either treatment alone. In preclinical murine models, PD-1 plus TKIinhibitors have demonstrated enhanced anti-tumour activity compared to either agent alone.

Pembrolizumab doses of 2 mg/kg bw every 3 weeks, 10 mg/kg bw every 3 weeks, and 10 mg/kg bwevery 2 weeks were evaluated in melanoma or previously treated NSCLC clinical studies. Based onthe modelling and simulation of dose/exposure relationships for efficacy and safety forpembrolizumab, there are no clinically significant differences in efficacy or safety among the doses of200 mg every 3 weeks, 2 mg/kg bw every 3 weeks, and 400 mg every 6 weeks (see section 4.2).

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre,open-label, controlled, Phase III study for the treatment of advanced melanoma in patients who werenaïve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg bw every2 (n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg bw every 3 weeks (n=278). Patients with BRAF

V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity.

Clinically stable patients with initial evidence of disease progression were permitted to remain ontreatment until disease progression was confirmed. Assessment of tumour status was performed at12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter.

Of the 834 patients, 60% were male, 44% were ≥ 65 years (median age was 62 years [range: 18-89])and 98% were white. Sixty-five percent of patients had M1c stage, 9% had a history of brainmetastases, 66% had no and 34% had one prior therapy. Thirty-one percent had an ECOG

Performance Status of 1, 69% had ECOG Performance Status of 0 and 32% had elevated LDH. BRAFmutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours,139 (46%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measures were progression-free survival (PFS; as assessed by

Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in

Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcomemeasures were objective response rate (ORR) and response duration. Table 3 summarises key efficacymeasures in patients naïve to treatment with ipilimumab at the final analysis performed after aminimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysisare shown in Figures 1 and 2.

Table 3: Efficacy results in KEYNOTE-006

Endpoint Pembrolizumab Pembrolizumab Ipilimumab10 mg/kg bw every 10 mg/kg bw 3 mg/kg bw3 weeks every 2 weeks every 3 weeksn=277 n=279 n=278

OS

Number (%) of 119 (43%) 122 (44%) 142 (51%)patients with event

Hazard ratio* 0.68 (0.53, 0.86) 0.68 (0.53, 0.87) ---(95% CI)p-Value† < 0.001 < 0.001 ---

Median in months Not reached Not reached 16(95% CI) (24, NA) (22, NA) (14, 22)

PFS

Number (%) of 183 (66%) 181 (65%) 202 (73%)patients with event

Hazard ratio* 0.61 (0.50, 0.75) 0.61 (0.50, 0.75) ---(95% CI)p-Value† < 0.001 < 0.001 ---

Median in months 4.1 5.6 2.8(95% CI) (2.9, 7.2) (3.4, 8.2) (2.8, 2.9)

Best objectiveresponse

ORR % (95% CI) 36% 37% 13%(30, 42) (31, 43) (10, 18)

Complete 13% 12% 5%response

Partial response 23% 25% 8%

Response duration‡

Median in months Not reached Not reached Not reached(range) (2.0, 22.8+) (1.8, 22.8+) (1.1+, 23.8+)% ongoing at 68%§ 71%§ 70%§18 months

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportionalhazard model† Based on stratified log-rank test‡ Based on patients with a best objective response as confirmed complete or partial response§ Based on Kaplan-Meier estimation

NA = not available

Figure 1: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-006 (intent to treat population)

Treatment arm OS rate at 24 months HR (95% CI) p-value

Pembrolizumab 10 mg/kg every 2 weeks 55.1% 0.68 (0.53, 0.87) 0.0008510 Pembrolizumab 10 mg/kg every 3 weeks 55.3% 0.68 (0.53, 0.86) 0.00083ipilimumab 43.0%0 4 8 12 16 20 24 28

Time in Months

Number at Risk

Pembrolizumab 10 mg/kg every 2 weeks: 279 249 221 202 176 156 44 0

Pembrolizumab 10 mg/kg every 3 weeks: 277 251 215 184 174 156 43 0ipilimumab: 278 213 170 145 122 110 28 0

Figure 2: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-006 (intent to treat population)

Treatment arm PFS rate at 18 months HR (95% CI) p-value

Pembrolizumab 10 mg/kg every 2 weeks 32.4% 0.61 (0.50, 0.75) 0.0000090 Pembrolizumab 10 mg/kg every 3 weeks 32.9% 0.61 (0.50, 0.75) 0.00000ipilimumab 15.2%0 4 8 12 16 20 24 28

Time in Months

Number at Risk

Pembrolizumab 10 mg/kg every 2 weeks: 279 148 116 98 82 52 16 0

Pembrolizumab 10 mg/kg every 3 weeks: 277 136 111 91 84 60 13 0ipilimumab: 278 88 48 34 29 16 5 0

Progression-Free Survival (%) Overall Survival (%)

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-002, a multicentre,double-blind, controlled study for the treatment of advanced melanoma in patients previously treatedwith ipilimumab and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor. Patients wererandomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=180) or 10 mg/kg bw (n=181) every3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, orcarboplatin+paclitaxel). The study excluded patients with autoimmune disease or those receivingimmunosuppression; further exclusion criteria were a history of severe or life-threateningimmune-mediated adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicityor Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent dose) forgreater than 12 weeks; ongoing adverse reactions ≥ Grade 2 from previous treatment with ipilimumab;previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitiallung disease; HIV, hepatitis B or hepatitis C infection and ECOG Performance Status ≥ 2.

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity.

Clinically stable patients with initial evidence of disease progression were permitted to remain ontreatment until disease progression was confirmed. Assessment of tumour status was performed at12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. Patients onchemotherapy who experienced independently-verified progression of disease after the first scheduleddisease assessment were able to crossover and receive 2 mg/kg bw or 10 mg/kg bw of pembrolizumabevery 3 weeks in a double-blind fashion.

Of the 540 patients, 61% were male, 43% were ≥ 65 years (median age was 62 years [range: 15-89])and 98% were white. Eighty-two percent had M1c stage, 73% had at least two and 32% of patients hadthree or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG

Performance Status of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour.

The primary efficacy outcome measures were PFS as assessed by IRO using RECIST version 1.1 and

OS. Secondary efficacy outcome measures were ORR and response duration. Table 4 summarises keyefficacy measures at the final analysis in patients previously treated with ipilimumab, and the

Kaplan-Meier curve for PFS is shown in Figure 3. Both pembrolizumab arms were superior tochemotherapy for PFS, and there was no difference between pembrolizumab doses. There was nostatistically significant difference between pembrolizumab and chemotherapy in the final OS analysisthat was not adjusted for the potentially confounding effects of crossover. Of the patients randomisedto the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

Table 4: Efficacy results in KEYNOTE-002

Endpoint Pembrolizumab Pembrolizumab Chemotherapy2 mg/kg bw every 10 mg/kg bw every3 weeks 3 weeksn=180 n=181 n=179

PFS

Number (%) of patients 150 (83%) 144 (80%) 172 (96%)with event

Hazard ratio* (95% CI) 0.58 (0.46, 0.73) 0.47 (0.37, 0.60) ---p-Value† < 0.001 < 0.001 ---

Median in months (95% CI) 2.9 (2.8, 3.8) 3.0 (2.8, pct. 5.2) 2.8 (2.6, 2.8)

OS

Number (%) of patients 123 (68%) 117 (65%) 128 (72%)with event

Hazard ratio* (95% CI) 0.86 (0.67, 1.10) 0.74 (0.57, 0.96) ---p-Value† 0.1173 0.0106‡ ---

Median in months (95% CI) 13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8)

Best objective response

ORR % (95% CI) 22% (16, 29) 28% (21, 35) 5% (2, 9)

Complete response 3% 7% 0%

Partial response 19% 20% 5%

Response duration§

Median in months (range) 22.8 Not reached 6.8(1.4+, 25.3+) (1.1+, 28.3+) (2.8, 11.3)% ongoing at 12 months 73% ¶ 79% ¶ 0% ¶

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model† Based on stratified log-rank test‡ Not statistically significant after adjustment for multiplicity§ Based on patients with a best objective response as confirmed complete or partial response from the final analysis¶ Based on Kaplan-Meier estimation

Figure 3: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-002 (intent to treat population)

Treatment arm PFS rate at 18 months HR (95% CI) p-value

Pembrolizumab 2 mg/kg every 3 weeks 19.6% 0.58 (0.46, 0.73) <0.000190 Pembrolizumab 10 mg/kg every 3 weeks 25.0% 0.47 (0.37, 0.60) <0.0001

Chemotherapy 1.3%0 3 6 9 12 15 18 21 24 27 30 33 36

Time in Months

Number at Risk

Pembrolizumab 2 mg/kg every 3 weeks: 180 59 36 29 19 1 0

Pembrolizumab 10 mg/kg every 3 weeks: 181 69 48 42 30 5 0

Chemotherapy: 179 31 9 2 1 0 0

The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated inan uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from twodefined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve totreatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of2 mg/kg bw every 3 weeks or 10 mg/kg bw every 3 weeks. Patients were treated with pembrolizumabuntil disease progression or unacceptable toxicity. Clinically stable patients with initial evidence ofdisease progression were permitted to remain on treatment until disease progression was confirmed.

Exclusion criteria were similar to those of KEYNOTE-002.

Of the 89 patients receiving 2 mg/kg bw of pembrolizumab who were previously treated withipilimumab, 53% were male, 33% were ≥ 65 years of age and the median age was 59 years (range:18-88). All but two patients were white. Eighty-four percent had M1c stage and 8% of patients had ahistory of brain metastases. Seventy percent had at least two and 35% of patients had three or moreprior systemic therapies for advanced melanoma. BRAF mutations were reported in 13% of the studypopulation. All patients with BRAF mutant tumours were previously treated with a BRAF inhibitor.

Of the 51 patients receiving 2 mg/kg bw of pembrolizumab who were naïve to treatment withipilimumab, 63% were male, 35% were ≥ 65 years of age and the median age was 60 years (range:35-80). All but one patient was white. Sixty-three percent had M1c stage and 2% of patients had ahistory of brain metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAFmutations were reported in 20 (39%) patients. Among patients with BRAF mutant tumours, 10 (50%)were previously treated with a BRAF inhibitor.

The primary efficacy outcome measure was ORR as assessed by independent review using

RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; includingcomplete response, partial response and stable disease), response duration, PFS and OS. Tumour

Progression-Free Survival (%)response was assessed at 12 week intervals. Table 5 summarises key efficacy measures in patientspreviously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at a dose of2 mg/kg bw based on a minimum follow-up time of 30 months for all patients.

Table 5: Efficacy results in KEYNOTE-001

Endpoint Pembrolizumab 2 mg/kg bw Pembrolizumab 2 mg/kg bwevery 3 weeks in patients every 3 weeks in patientspreviously treated with naïve to treatment withipilimumab ipilimumabn=89 n=51

Best objective response* by

IRO†

ORR % (95% CI) 26% (17, 36) 35% (22, 50)

Complete response 7% 12%

Partial response 19% 24%

Disease control rate %‡ 48% 49%

Response duration§

Median in months (range) 30.5 (2.8+, 30.6+) 27.4 (1.6+, 31.8+)% ongoing at 24 months¶ 75% 71%

PFS

Median in months (95% CI) 4.9 (2.8, 8.3) 4.7 (2.8, 13.8)

PFS rate at 12 months 34% 38%

OS

Median in months (95% CI) 18.9 (11, not available) 28.0 (14, not available)

OS rate at 24 months 44% 56%

* Includes patients without measurable disease at baseline by independent radiology† IRO = Integrated radiology and oncologist assessment using RECIST 1.1‡ Based on best response of stable disease or better§ Based on patients with a confirmed response by independent review, starting from the date the response was firstrecorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab¶ Based on Kaplan-Meier estimation

Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab(n=52) who received 10 mg/kg bw of pembrolizumab every 3 weeks were similar to those seen inpatients who received 2 mg/kg bw of pembrolizumab every 3 weeks.

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients whowere BRAF wild type (n=414; 77%) or BRAF mutant with prior BRAF treatment (n=126; 23%) assummarised in Table 6.

Table 6: Efficacy results by BRAF mutation status in KEYNOTE-002

BRAF wild type BRAF mutant with prior BRAF treatment

Pembrolizumab Chemotherapy Pembrolizumab Chemotherapy2 mg/kg bw every (n=137) 2 mg/kg bw every (n=42)

Endpoint 3 weeks (n=136) 3 weeks (n=44)

PFS 0.50 (0.39, 0.66) --- 0.79 (0.50, 1.25) ---

Hazardratio*(95% CI)

OS 0.78 (0.58, 1.04) --- 1.07 (0.64, 1.78) ---

Hazardratio*(95% CI)

ORR % 26% 6% 9% 0%

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients whowere BRAF wild type (n=525; 63%), BRAF mutant without prior BRAF treatment (n=163; 20%) and

BRAF mutant with prior BRAF treatment (n=139; 17%) as summarised in Table 7.

Table 7: Efficacy results by BRAF mutation status in KEYNOTE-006

BRAF wild type BRAF mutant without prior BRAF mutant with prior BRAF

BRAF treatment treatment

Pembrolizumab Ipilimumab Pembrolizumab Ipilimumab Pembrolizumab Ipilimumab10 mg/kg bw (n=170) 10 mg/kg bw every (n=55) 10 mg/kg bw (n=52)every 2 or 2 or 3 weeks every 2 or 3 weeks3 weeks (pooled) (pooled)

Endpoint (pooled)

PFS 0.61 (0.49, 0.76) --- 0.52 (0.35, 0.78) --- 0.76 (0.51, 1.14) ---

Hazardratio*(95% CI)

OS 0.68 (0.52, 0.88) --- 0.70 (0.40, 1.22) --- 0.66 (0.41, 1.04) ---

Hazardratio*(95% CI)

ORR % 38% 14% 41% 15% 24% 10%

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients whowere PD-L1 positive (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cellsrelative to all viable tumour cells - MEL score) vs. PD-L1 negative. PD-L1 expression was testedretrospectively by immunohistochemistry (IHC) assay with the 22C3 anti-PD-L1 antibody. Amongpatients who were evaluable for PD-L1 expression (79%), 69% (n=294) were PD-L1 positive and 31%(n=134) were PD-L1 negative. Table 8 summarises efficacy results by PD-L1 expression.

Table 8: Efficacy results by PD-L1 expression in KEYNOTE-002

Endpoint Pembrolizumab Chemotherapy Pembrolizumab Chemotherapy2 mg/kg bw 2 mg/kg bwevery 3 weeks every 3 weeks

PD-L1 positive PD-L1 negative

PFS Hazard 0.55 (0.40, 0.76) --- 0.81 (0.50, 1.31) ---ratio*(95% CI)

OS Hazard 0.90 (0.63, 1.28) --- 1.18 (0.70, 1.99) ---ratio*(95% CI)

ORR % 25% 4% 10% 8%

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportionalhazard model

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients whowere PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who wereevaluable for PD-L1 expression (98%), 82% were PD-L1 positive and 18% were PD-L1 negative.

Table 9 summarises efficacy results by PD-L1 expression.

Table 9: Efficacy results by PD-L1 expression in KEYNOTE-006

Endpoint Pembrolizumab Ipilimumab Pembrolizumab Ipilimumab10 mg/kg bw every 2 10 mg/kg bw every 2or 3 weeks (pooled) or 3 weeks (pooled)

PD-L1 positive PD-L1 negative

PFS Hazard ratio* (95% CI) 0.53 (0.44, 0.65) --- 0.87 (0.58, 1.30) ---

OS Hazard ratio* (95% CI) 0.63 (0.50, 0.80) --- 0.76 (0.48, 1.19) ---

ORR % 40% 14% 24% 13%

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model

In 20 subjects with ocular melanoma included in KEYNOTE-001, no objective responses werereported; stable disease was reported in 6 patients.

KEYNOTE-716: Placebo-controlled study for the adjuvant treatment of patients with resected Stage

IIB or IIC melanoma

The efficacy of pembrolizumab was evaluated in KEYNOTE-716, a multicentre, randomised,double-blind, placebo-controlled study in patients with resected Stage IIB or IIC melanoma. A total of976 patients were randomised (1:1) to receive pembrolizumab 200 mg every three weeks (or thepaediatric [12 to 17 years old] dose of 2 mg/kg intravenously [up to a maximum of 200 mg] everythree weeks) (n=487) or placebo (n=489), for up to one year or until disease recurrence orunacceptable toxicity. Randomisation was stratified by American Joint Committee on Cancer (AJCC)8th edition T stage. Patients with active autoimmune disease or a medical condition that requiredimmunosuppression or mucosal or ocular melanoma were ineligible. Patients who received priortherapy for melanoma other than surgery were ineligible. Patients underwent imaging every sixmonths from randomisation through the 4th year, and then once in year 5 from randomisation or untilrecurrence, whichever came first.

Among the 976 patients, the baseline characteristics were: median age of 61 years (range: 16-87; 39%age 65 or older; 2 adolescent patients [one per treatment arm]); 60% male; and ECOG PS of 0 (93%)and 1 (7%). Sixty-four percent had Stage IIB and 35% had Stage IIC.

The primary efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) inthe whole population, where RFS was defined as the time between the date of randomisation and thedate of first recurrence (local, regional, or distant metastasis) or death, whichever occurred first. Thesecondary outcome measures were distant metastasis-free survival (DMFS) and OS in the wholepopulation. OS was not formally assessed at the time of this analysis. The study initially demonstrateda statistically significant improvement in RFS (HR 0.65; 95% CI 0.46, 0.92; p-Value = 0.00658) forpatients randomised to the pembrolizumab arm compared with placebo at its pre-specified interimanalysis. Results reported from the pre-specified final analysis for RFS at a median follow-up of20.5 months are summarised in Table 10. Updated RFS results at a median follow-up of 38.5 monthswere consistent with the final analysis for RFS for patients randomised to the pembrolizumab armcompared with placebo (HR 0.62; 95% CI 0.49, 0.79) (see Figure 4). The study demonstrated astatistically significant improvement in DMFS (HR 0.64; 95% CI 0.47, 0.88; p-Value = 0.00292) forpatients randomised to the pembrolizumab arm compared with placebo at its pre-specified interimanalysis at a median follow-up of 26.9 months. Results reported from the pre-specified final analysisfor DMFS at a median follow-up time of 38.5 months are summarised in Table 10 and Figure 5.

Table 10: Efficacy results in KEYNOTE-716

Endpoint Pembrolizumab Placebo200 mg every3 weeksn=487 n=489

RFS

Number (%) of patients with event 72 (15%) 115 (24%)

Median in months (95% CI) NR (NR, NR) NR (29.9, NR)

Hazard ratio* (95% CI) 0.61 (0.45, 0.82)p-Value (stratified log-rank)† 0.00046

DMFS

Number (%) of patients with event 74 (15.2%) 119 (24.3%)

Median in months (95% CI) NR (NR, NR) NR (NR, NR)

Hazard ratio* (95% CI) 0.59 (0.44, 0.79)

* Based on the stratified Cox proportional hazard model† Nominal p-Value based on log-rank test stratified by American Joint Committee on

Cancer (AJCC) 8th edition T stage

NR = not reached

Figure 4: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-716(intent to treat population)

Treatment arm RFS rate at 36 months HR (95% CI)

Pembrolizumab 76% 0.62 (0.49, 0.79)

Placebo 63%

Time in Months

Number at Risk

Pembrolizumab

Placebo

Recurrence-Free Survival (%)

Figure 5: Kaplan-Meier curve for distant metastasis-free survival by treatment arm in

KEYNOTE-716 (intent to treat population)

Treatment arm DMFS rate at 36 months HR (95% CI)

Pembrolizumab 84% 0.59 (0.44, 0.79)

Placebo 75%

Time in Months

Number at Risk

Pembrolizumab

Placebo

KEYNOTE-054: Placebo-controlled study for the adjuvant treatment of patients with completelyresected Stage III melanoma

The efficacy of pembrolizumab was evaluated in KEYNOTE-054, a multicentre, randomised,double-blind, placebo-controlled study in patients with completely resected stage IIIA (> 1 mm lymphnode metastasis), IIIB or IIIC melanoma. A total of 1 019 adult patients were randomised (1:1) toreceive pembrolizumab 200 mg every three weeks (n=514) or placebo (n=505), for up to one yearuntil disease recurrence or unacceptable toxicity. Randomisation was stratified by AJCC 7th editionstage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥ 4 positive lymph nodes) andgeographic region (North America, European countries, Australia and other countries as designated).

Patients must have undergone lymph node dissection, and if indicated, radiotherapy within 13 weeksprior to starting treatment. Patients with active autoimmune disease or a medical condition thatrequired immunosuppression or mucosal or ocular melanoma were ineligible. Patients who receivedprior therapy for melanoma other than surgery or interferon for thick primary melanomas withoutevidence of lymph node involvement were ineligible. Patients underwent imaging every 12 weeksafter the first dose of pembrolizumab for the first two years, then every 6 months from year 3 to 5, andthen annually.

Among the 1 019 patients, the baseline characteristics were: median age of 54 years (25% age 65 orolder); 62% male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% hadstage IIIB; 18% had stage IIIC (1-3 positive lymph nodes) and 20% had stage IIIC (≥ 4 positive lymphnodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type. PD-L1 expression

Distant Metastases-Free Survival (%)was tested retrospectively by IHC assay with the 22C3 anti-PD-L1 antibody; 84% of patients had

PD-L1-positive melanoma (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cellsrelative to all viable tumour cells). The same scoring system was used for metastatic melanoma (MELscore).

The primary efficacy outcome measures were investigator-assessed RFS in the whole population andin the population with PD-L1 positive tumours, where RFS was defined as the time between the dateof randomisation and the date of first recurrence (local, regional, or distant metastasis) or death,whichever occurred first. The secondary outcome measures were DMFS and OS in the wholepopulation and in the population with PD-L1 positive tumours. OS was not formally assessed at thetime of these analyses. The study initially demonstrated a statistically significant improvement in RFS(HR 0.57; 98.4% CI 0.43, 0.74; p-Value < 0.0001) for patients randomised to the pembrolizumab armcompared with placebo at its pre-specified interim analysis. Updated efficacy results with a medianfollow-up time of 45.5 months are summarised in Table 11 and Figures 6 and 7.

Table 11: Efficacy results in KEYNOTE-054

Endpoint Pembrolizumab Placebo200 mg every3 weeksn=514 n=505

RFS

Number (%) of patients with 203 (40%) 288 (57%)event

Median in months (95% CI) NR 21.4 (16.3,27.0)

Hazard ratio* (95% CI) 0.59 (0.49, 0.70)

DMFS

Number (%) of patients with 173 (34%) 245 (49%)event

Median in months (95% CI) NR 40.0 (27.7, NR)

Hazard ratio* (95% CI) 0.60 (0.49, 0.73)p-Value (stratified log-rank) < 0.0001

* Based on the stratified Cox proportional hazard model

NR = not reached

Figure 6: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-054(intent to treat population)

Treatment arm RFS rate at 36 months HR (95% CI)

Pembrolizumab 64% 0.59 (0.49, 0.70)

Placebo 44%

Time in Months

Number at Risk

Pembrolizumab

Placebo:

Figure 7: Kaplan-Meier curve for distant metastasis-free survival by treatment arm in

KEYNOTE-054 (intent to treat population)

Treatment arm DMFS rate at 36 months HR (95% CI) p-value

Pembrolizumab 68% 0.60 (0.49, 0.73) <0.0001

Placebo 52%

Time in Months

Number at Risk

Pembrolizumab:

Placebo:

Distant Metastasis-Free Survival (%) Recurrence-Free Survival (%)

RFS and DMFS benefit was consistently demonstrated across subgroups, including tumour PD-L1expression, BRAF mutation status, and stage of disease (using AJCC 7th edition). These results wereconsistent when reclassified in a post-hoc analysis according to the current AJCC 8th edition stagingsystem.

Non-small cell lung carcinoma

KEYNOTE-671: Controlled study for the neoadjuvant and adjuvant treatment of patients withresectable non-small cell lung carcinoma (NSCLC)

The efficacy of pembrolizumab in combination with platinum-containing chemotherapy, given asneoadjuvant treatment and continued as monotherapy as adjuvant treatment was investigated in

KEYNOTE-671, a multicentre, randomised, double-blind, placebo-controlled study. Key eligibilitycriteria were previously untreated and resectable patients with NSCLC who are at high risk (Stage II,

IIIA, or IIIB (N2) by AJCC 8th edition) of recurrence, regardless of tumour PD-L1 expression basedon the PD-L1 IHC 22C3 pharmDxTM Kit. Testing for genomic tumour aberrations or oncogenicdrivers was not mandatory for enrolment.

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of the patient population with Stage II - IIIB (N2) accordingto the 8th edition staging system: tumour size > 4 cm; or tumours of any size that are eitheraccompanied by N1 or N2 status; or tumours that invade thoracic structures (directly invade theparietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium,mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body,carina); or tumours that involve a mainstem bronchus with tumour > 4 cm; or tumours > 4 cm thatcause obstructive atelectasis that extends to the hilum; or tumours with separate nodule(s) in the samelobe or different ipsilateral lobe as the primary lung cancer.

If indicated, patients received adjuvant radiation therapy prior to adjuvant pembrolizumab or placebo.

Patients with active autoimmune disease that required systemic therapy within 2 years of treatment ora medical condition that required immunosuppression were ineligible. Randomisation was stratified bystage (II vs. III), tumour PD-L1 expression (TPS ≥ 50% or < 50%), histology (squamous vs.non- squamous), and geographic region (East Asia vs. non-East Asia).

Patients were randomised (1:1) to one of the following treatment arms:

* Treatment Arm A: neoadjuvant pembrolizumab 200 mg on Day 1 in combination withcisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine1 000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Followingsurgery, pembrolizumab 200 mg was administered every 3 weeks for up to 13 cycles.

* Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1 000 mg/m2 on

Days 1 and 8 of each 21-day cycle for up to 4 cycles. Following surgery, placebo wasadministered every 3 weeks for up to 13 cycles.

All study medications were administered via intravenous infusion. Treatment with pembrolizumab orplacebo continued until completion of the treatment (17 cycles), disease progression that precludeddefinitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did notundergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity.

Assessment of tumour status was performed at baseline, Week 7, and Week 13 in the neoadjuvantphase, and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvantphase, assessment of tumour status was performed every 16 weeks through the end of Year 3, and thenevery 6 months thereafter.

The primary efficacy outcome measures were OS and investigator-assessed event-free survival (EFS).

Secondary efficacy outcome measures were pathological complete response (pCR) rate and majorpathological response (mPR) rate as assessed by blinded independent pathology review (BIPR).

A total of 797 patients in KEYNOTE-671 were randomised: 397 patients to the pembrolizumab armand 400 to the placebo arm. Baseline characteristics were: median age of 64 years (range: 26 to 83),45% age 65 or older; 71% male; 61% White, 31% Asian, and 2% Black. Sixty-three percent and 37%had ECOG performance of 0 or 1, respectively; 30% had Stage II and 70% had Stage III disease; 33%had TPS ≥ 50% and 67% had TPS < 50%; 43% had tumours with squamous histology and 57% hadtumours with non-squamous histology; 31% were from the East Asian region. Four percent of patientshad EGFR mutations and in 66% EGFR mutation status was unknown. Three percent of patients had

ALK translocations and in 68% ALK translocation status was unknown.

Eighty-one percent of patients in the pembrolizumab in combination with platinum-containingchemotherapy arm had definitive surgery compared to 76% of patients in the platinum-containingchemotherapy arm.

The study demonstrated statistically significant improvements in OS, EFS, pCR and mPR for patientsrandomised to pembrolizumab in combination with platinum-containing chemotherapy followed bypembrolizumab monotherapy compared with patients randomised to placebo in combination withplatinum-containing chemotherapy followed by placebo alone. At a pre-specified interim analysis(median follow-up time of 21.4 months (range: 0.4 to 50.6 months)) the EFS HR was 0.58 (95% CI:0.46, 0.72; p < 0.0001) for patients randomised to pembrolizumab in combination withplatinum-containing chemotherapy followed by pembrolizumab monotherapy compared with patientsrandomised to placebo in combination with platinum-containing chemotherapy followed by placeboalone. At the time of this analysis, OS results were not mature.

Table 12 summarises key efficacy measures at a pre-specified interim analysis at a median follow-uptime of 29.8 months (range: 0.4 to 62.0 months). The Kaplan-Meier curves for OS and EFS are shownin Figures 8 and 9.

Table 12: Efficacy results in KEYNOTE-671

Endpoint Pembrolizumab with Placebo withchemotherapy/ chemotherapy/

Pembrolizumab Placebon=397 n=400

OS

Number (%) of patients with event 110 (28%) 144 (36%)

Median in months* (95% CI) NR (NR, NR) 52.4 (45.7, NR)

Hazard ratio† (95% CI) 0.72 (0.56, 0.93)p-Value‡ 0.00517

EFS

Number (%) of patients with event 174 (44%) 248 (62%)

Median in months* (95% CI) 47.2 (32.9, NR) 18.3 (14.8, 22.1)

Hazard ratio† (95% CI) 0.59 (0.48, 0.72)

* Based on Kaplan-Meier estimates† Based on Cox regression model with treatment as a covariate stratified by stage, tumour PD-L1 expression,histology, and geographic region‡ Based on stratified log-rank test

NR = not reached

Figure 8: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-671 (intent to treat population)

Treatment arm OS Rate at 30 months HR (95% CI) p-value

Pembrolizumab 74% 0.72 (0.56, 0.93) 0.00517

Control 68%

Time in Months

Number at Risk

Pembrolizumab

Control

Overall Survival (%)

Figure 9: Kaplan-Meier curve for event-free survival by treatment arm in

KEYNOTE-671 (intent to treat population)

Treatment arm EFS Rate at 30 months HR (95% CI)

Pembrolizumab 57% 0.59 (0.48, 0.72)

Control 38%

Time in Months

Number at Risk

Pembrolizumab

Control

A post-hoc exploratory subgroup analysis was performed in KEYNOTE-671 in patients who had

PD-L1 TPS ≥ 50% (pembrolizumab arm [n=132; 33%] vs. placebo arm [n=134; 34%]);

TPS = 1 - 49% (pembrolizumab arm [n=127; 32%] vs. placebo arm [n=115; 29%]) and TPS < 1%(pembrolizumab arm [n=138; 35%] vs. placebo arm [n=151; 38%]). The EFS HR was, 0.48 (95% CI:0.33, 0.71) in patients with a TPS ≥ 50%, 0.52 (95% CI: 0.36, 0.73) in patients with a TPS = 1 - 49%and 0.75 (95% CI: 0.56, 1.01) in patients with a TPS < 1%. The OS HR was 0.55 (95% CI: 0.33, 0.92)in patients with a TPS ≥ 50%, 0.69 (95% CI: 0.44, 1.07) in patients with a TPS = 1 - 49% and0.91 (95% CI: 0.63, 1.32) in patients with a TPS < 1%.

KEYNOTE-091: Placebo-controlled study for the adjuvant treatment of patients with resected NSCLC

The efficacy of pembrolizumab was investigated in KEYNOTE-091, a multicentre, randomised,triple-blind, placebo-controlled study in patients with NSCLC who are at high risk (stage IB[T2a ≥ 4 cm], II or IIIA by AJCC 7th edition) of recurrence following complete resection, regardless oftumour PD-L1 expression status, no prior neoadjuvant radiotherapy and/or neoadjuvant chemotherapy,and no prior or planned adjuvant radiotherapy for the current malignancy. Testing for genomic tumouraberrations/oncogenic drivers was not mandatory for enrolment.

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of the patient population with stage IB [T2a ≥ 4 cm], II or IIIAaccording to the 7th edition staging system: Tumour size ≥ 4 cm; or tumours of any size that are eitheraccompanied by N1 or N2 status; or tumours that are invasive of thoracic structures (directly invade

Event-Free Survival (%)the parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium,mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body,carina); or tumours that involve the main bronchus < 2 cm distal to the carina but without involvementof the carina; or tumours that are associated with atelectasis or obstructive pneumonitis of the entirelung; or tumours with separate nodule(s) in the same lobe or different ipsilateral lobe as the primary.

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

Patients may or may not have received adjuvant chemotherapy as recommended by their physician.

Patients with autoimmune disease that required systemic therapy within 2 years of treatment; amedical condition that required immunosuppression; or who had received more than 4 cycles ofadjuvant chemotherapy were ineligible. Randomisation was stratified by stage (IB vs. II vs. IIIA),adjuvant chemotherapy (no adjuvant chemotherapy vs. adjuvant chemotherapy), PD-L1 status(TPS < 1% [negative] vs. TPS 1-49% vs. TPS ≥ 50%), and geographic region (Western Europe vs.

Eastern Europe vs. Asia vs. Rest of World). Patients were randomised (1:1) to receive pembrolizumab200 mg (n=590) or placebo (n=587) intravenously every 3 weeks.

Treatment continued until RECIST 1.1-defined disease recurrence as determined by the investigator,unacceptable toxicity, or approximately 1 year (18 doses). Patients underwent imaging every 12 weeksafter the first dose of pembrolizumab for the first year, then every 6 months for years 2 to 3, and thenannually up to the end of year 5. After year 5, imaging is performed as per local standard of care.

Of 1 177 patients randomised, 1 010 (86%) received adjuvant platinum-based chemotherapy followingcomplete resection. Among these 1 010 patients in KEYNOTE-091, baseline characteristics were:median age of 64 years (range: 35 to 84), 49% age 65 or older; 68% male; and 77% White,18% Asian, 86% current or former smokers. Sixty-one percent and 39% had ECOG performance of 0or 1, respectively. Twelve percent had stage IB (T2a ≥ 4 cm), 57% had stage II, and 31% had stage

IIIA disease. Thirty-nine percent had tumour PD-L1 expression TPS < 1% [negative], 33% had TPS1-49%, 28% had TPS ≥ 50%. Seven percent had known EGFR mutations, thirty-eight percent without

EGFR mutations and in fifty-six percent EGFR mutation status was unknown. Fifty-two percent werefrom Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World.

The primary efficacy outcome measures were investigator-assessed disease-free survival (DFS) in theoverall population and in the population with tumour PD-L1 expression TPS ≥ 50% where DFS wasdefined as the time between the date of randomisation and the date of first recurrence (local/regionalrecurrence, distant metastasis), a second malignancy, or death, whichever occurred first. Secondaryefficacy outcome measures were investigator-assessed DFS in the population with tumour PD-L1expression TPS ≥ 1%, and OS in the overall population and in the populations with tumour PD-L1expression TPS ≥ 50% and TPS ≥ 1%.

The study demonstrated a statistically significant improvement in DFS in the overall population(HR = 0.76 [95% CI: 0.63, 0.91; p = 0.0014]) at a pre-specified interim analysis with a medianfollow-up time of 32.4 months (range: 0.6 to 68 months) for patients randomised to thepembrolizumab arm compared to patients randomised to the placebo arm. Table 13 and Figure 10summarise efficacy results in patients who received adjuvant chemotherapy at the final analysis for

DFS performed at a median follow-up time of 46.7 months (range: 0.6 to 84.2). At the time of thisanalysis, OS results were not mature with only 58% of pre-specified OS events in the overallpopulation. An exploratory analysis of OS suggested a trend in favour of pembrolizumab compared toplacebo with a HR of 0.79 (95% CI: 0.62, 1.01) in patients who received adjuvant chemotherapy.

Table 13: Efficacy results in KEYNOTE-091 for patients who received adjuvant chemotherapy

Endpoint Pembrolizumab Placebo200 mg every3 weeksn=506 n=504

DFS

Number (%) of patients with 225 (44%) 262 (52%)event

Hazard ratio* (95% CI) 0.76 (0.64, 0.91)

Median in months (95% CI) 53.8 (46.2, 70.4) 40.5 (32.9, 47.4)

* Based on the multivariate Cox regression model

Figure 10: Kaplan-Meier curve for disease-free survival by treatment arm in KEYNOTE-091(for patients who received adjuvant chemotherapy)

Treatment arm DFS Rate at 24 months HR (95% CI)

Pembrolizumab 67% 0.76 (0.64, 0.91)

Placebo 59%

Time in Months

Number at Risk

Pembrolizumab

Placebo

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre,open-label, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had

PD-L1 expression with a  50% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients wererandomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=154) orinvestigator’s choice platinum-containing chemotherapy (n=151; including pemetrexed+carboplatin,

Disease-Free Survival (%)(%)pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin.

Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Patients were treatedwith pembrolizumab until unacceptable toxicity or disease progression. Treatment could continuebeyond disease progression if the patient was clinically stable and was considered to be derivingclinical benefit by the investigator. Patients without disease progression could be treated for up to24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmunedisease that required systemic therapy within 2 years of treatment; a medical condition that requiredimmunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy whoexperienced independently-verified progression of disease were able to crossover and receivepembrolizumab.

Among the 305 patients in KEYNOTE-024, baseline characteristics were: median age 65 years (54%age 65 or older); 61% male; 82% White, 15% Asian; and ECOG performance status 0 and 1 in 35%and 65%, respectively. Disease characteristics were squamous (18%) and non-squamous (82%); M1(99%); and brain metastases (9%).

The primary efficacy outcome measure was PFS as assessed by blinded independent central review(BICR) using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by

BICR using RECIST 1.1). Table 14 summarises key efficacy measures for the entire intent to treat(ITT) population. PFS and ORR results are reported from an interim analysis at a median follow-up of11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

Table 14: Efficacy results in KEYNOTE-024

Endpoint Pembrolizumab Chemotherapy200 mg every3 weeksn=154 n=151

PFS

Number (%) of patients with 73 (47%) 116 (77%)event

Hazard ratio* (95% CI) 0.50 (0.37, 0.68)p-Value† < 0.001

Median in months (95% CI) 10.3 (6.7, NA) 6.0 (4.2, 6.2)

OS

Number (%) of patients with 73 (47%) 96 (64%)event

Hazard ratio* (95% CI) 0.63 (0.47, 0.86)p-Value† 0.002

Median in months (95% CI) 30.0 14.2(18.3, NA) (9.8, 19.0)

Objective response rate

ORR % (95% CI) 45% (37, 53) 28% (21, 36)

Complete response 4% 1%

Partial response 41 % 27 %

Response duration‡

Median in months (range) Not reached 6.3(1.9+, 14.5+) (2.1+, 12.6+)% with duration ≥ 6 months 88%§ 59% ¶

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Coxproportional hazard model† Based on stratified log-rank test‡ Based on patients with a best objective response as confirmed complete or partialresponse§ Based on Kaplan-Meier estimates; includes 43 patients with responses of 6 months orlonger¶ Based on Kaplan-Meier estimates; includes 16 patients with responses of 6 months orlonger

NA = not available

Figure 11: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-024 (intent to treat population)

Treatment arm PFS rate at 6 months PFS rate at 12 months HR (95% CI) p-value

Pembrolizumab 62% 48% 0.50 (0.37, 0.68) <0.001

Chemotherapy 50% 15%0 3 6 9 12 15 18

Time in Months

Number at Risk

Pembrolizumab: 154 104 89 44 22 3 1

Chemotherapy: 151 99 70 18 9 1 0

Figure 12: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-024 (intent to treat population)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab 70% 52% 0.63 (0.47, 0.86) 0.00210 Chemotherapy 55% 35%0 3 6 9 12 15 18 21 24 27 30 33

Time in Months

Number at Risk

Pembrolizumab: 154 136 121 112 106 96 89 83 52 22 5 0

Chemotherapy: 151 123 107 88 80 70 61 55 31 16 5 0

In a subgroup analysis, a reduced survival benefit of pembrolizumab compared to chemotherapy wasobserved in the small number of patients who were never-smokers; however, due to the small numberof patients, no definitive conclusions can be drawn from these data.

The safety and efficacy of pembrolizumab were also investigated in KEYNOTE-042, a multicentre,controlled study for the treatment of previously untreated locally advanced or metastatic NSCLC. The

Progression-Free Survival (%)

Overall Survival (%)study design was similar to that of KEYNOTE-024, except that patients had PD-L1 expression with a 1% TPS based on the PD-L1 IHC 22C3 pharmDxTM Kit. Patients were randomised (1:1) to receivepembrolizumab at a dose of 200 mg every 3 weeks (n=637) or investigator’s choice platinum-containing chemotherapy (n=637; including pemetrexed+carboplatin or paclitaxel+carboplatin.

Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Assessment of tumourstatus was performed every 9 weeks for the first 45 weeks, and every 12 weeks thereafter.

Among the 1 274 patients in KEYNOTE-042, 599 (47%) had tumours that expressed PD-L1 with TPS≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these599 patients included: median age 63 years (45% age 65 or older); 69% male; 63% White and32% Asian; 17% Hispanic or Latino; and ECOG performance status 0 and 1 in 31% and 69%,respectively. Disease characteristics were squamous (37%) and non-squamous (63%); stage IIIA(0.8%); stage IIIB (9%); stage IV (90%); and treated brain metastases (6%).

The primary efficacy outcome measure was OS. Secondary efficacy outcome measures were PFS and

ORR (as assessed by BICR using RECIST 1.1). The study demonstrated a statistically significantimprovement in OS for patients whose tumours expressed PD-L1 TPS ≥ 1% randomised topembrolizumab monotherapy compared to chemotherapy (HR 0.82; 95% CI 0.71, 0.93 at the finalanalysis) and in patients whose tumours expressed PD-L1 TPS ≥ 50% randomised to pembrolizumabmonotherapy compared to chemotherapy. Table 15 summarises key efficacy measures for the TPS 50% population at the final analysis performed at a median follow-up of 15.4 months. The Kaplan-

Meier curve for OS for the TPS ≥ 50% population based on the final analysis is shown in Figure 13.

Table 15: Efficacy results (PD-L1 TPS  50%) in KEYNOTE-042

Endpoint Pembrolizumab Chemotherapy200 mg every3 weeksn=299 n=300

OS

Number (%) of patients with 180 (60%) 220 (73%)event

Hazard ratio* (95% CI) 0.70 (0.58, 0.86)p-Value† 0.0003

Median in months (95% CI) 20.0 (15.9, 24.2) 12.2 (10.4, 14.6)

PFS

Number (%) of patients with 238 (80%) 250 (83%)event

Hazard ratio* (95% CI) 0.84 (0.70, 1.01)

Median in months (95% CI) 6.5 (5.9, 8.5) 6.4 (6.2, 7.2)

Objective response rate

ORR % (95% CI) 39% (34, 45) 32% (27, 38)

Complete response 1% 0.3%

Partial response 38% 32%

Response duration‡

Median in months (range) 22.0 10.8(2.1+, 36.5+) (1.8+, 30.4+)% with duration ≥ 18 months 57% 34%

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Coxproportional hazard model† Based on stratified log-rank test‡ Based on patients with a best objective response as confirmed complete or partialresponse

Figure 13: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-042(patients with PD-L1 expression TPS ≥ 50%, intent to treat population)

The results of a post-hoc exploratory subgroup analysis indicated a trend towards reduced survivalbenefit of pembrolizumab compared to chemotherapy, during both the first 4 months and throughoutthe entire duration of treatment, in patients who were never-smokers. However, due to the exploratorynature of this subgroup analysis, no definitive conclusions can be drawn.

KEYNOTE-189: Controlled study of combination therapy in non-squamous NSCLC patients naïve totreatment

The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy wasinvestigated in a multicentre, randomised, active-controlled, double-blind study, KEYNOTE-189. Keyeligibility criteria were metastatic non-squamous NSCLC, no prior systemic treatment for metastatic

NSCLC, and no EGFR or ALK genomic tumour aberrations. Patients with autoimmune disease thatrequired systemic therapy within 2 years of treatment; a medical condition that requiredimmunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior26 weeks were ineligible. Patients were randomised (2:1) to receive one of the following regimens:

* Pembrolizumab 200 mg with pemetrexed 500 mg/m2 and investigator’s choice ofcisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for4 cycles followed by pembrolizumab 200 mg and pemetrexed 500 mg/m2intravenously every 3 weeks (n=410)

* Placebo with pemetrexed 500 mg/m and investigator’s choice of cisplatin 75 mg/m2or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followedby placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks (n=206)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease asdetermined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration ofpembrolizumab was permitted beyond RECIST-defined disease progression by BICR or beyonddiscontinuation of pemetrexed if the patient was clinically stable and deriving clinical benefit asdetermined by the investigator. For patients who completed 24 months of therapy or had a completeresponse, treatment with pembrolizumab could be reinitiated for disease progression and administeredfor up to 1 additional year. Assessment of tumour status was performed at Week 6 and Week 12,followed by every 9 weeks thereafter. Patients receiving placebo plus chemotherapy who experiencedindependently-verified progression of disease were offered pembrolizumab as monotherapy.

Among the 616 patients in KEYNOTE-189, baseline characteristics were: median age of 64 years(49% age 65 or older); 59% male; 94% White and 3% Asian; 43% and 56% ECOG performance statusof 0 or 1 respectively; 31% PD-L1 negative (TPS < 1%); and 18% with treated or untreated brainmetastases at baseline.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1).

Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using

RECIST 1.1. Table 16 summarises key efficacy measures and Figures 14 and 15 show the

Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of18.8 months.

Table 16: Efficacy results in KEYNOTE-189

Endpoint Pembrolizumab + Placebo +

Pemetrexed + Pemetrexed +

Platinum Platinum

Chemotherapy Chemotherapyn=410 n=206

OS*

Number (%) of patients with 258 (63%) 163 (79%)event

Hazard ratio† (95% CI) 0.56 (0.46, 0.69)p-Value‡ < 0.00001

Median in months (95% CI) 22.0 10.6(19.5, 24.5) (8.7, 13.6)

PFS

Number (%) of patients with 337 (82%) 197 (96%)event

Hazard ratio† (95% CI) 0.49 (0.41, 0.59)p-Value‡ < 0.00001

Median in months (95% CI) 9.0 (8.1, 10.4) 4.9 (4.7, 5.5)

Objective response rate

ORR§ % (95% CI) 48% (43, 53) 20% (15, 26)

Complete response 1.2% 0.5%

Partial response 47% 19%p-Value¶ < 0.0001

Response duration

Median in months (range) 12.5 7.1(1.1+, 34.9+) (2.4, 27.8+)% with duration ≥ 12 months# 53% 27%

* A total of 113 patients (57%) who discontinued study treatment in the placebo pluschemotherapy arm crossed over to receive monotherapy pembrolizumab or received acheckpoint inhibitor as subsequent therapy† Based on the stratified Cox proportional hazard model‡ Based on stratified log-rank test§ Based on patients with a best objective response as confirmed complete or partialresponse¶ Based on Miettinen and Nurminen method stratified by PD-L1 status, platinumchemotherapy and smoking status# Based on Kaplan-Meier estimation

Figure 14: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-189 (intent to treat population)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab 70% 46% 0.56 (0.46, 0.69) < 0.00001

Control 48% 27%

Time in Months

Number at Risk

Pembrolizumab:

Control:

Overall Survival (%)

Figure 15: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-189 (intent to treat population)

Treatment arm PFS rate at 12 months PFS rate at 24 months HR (95% CI) p-value

Pembrolizumab 39% 22% 0.49 (0.41, 0.59) < 0.00001

Control 18% 3%

Time in Months

Number at Risk

Pembrolizumab:

Control:

An analysis was performed in KEYNOTE-189 in patients who had PD-L1 TPS < 1% [pembrolizumabcombination: n=127 (31%) vs. chemotherapy: n=63 (31%)], TPS 1-49% [pembrolizumabcombination: n=128 (31%) vs. chemotherapy: n=58 (28%)] or ≥ 50% [pembrolizumab combination:n=132 (32%) vs. chemotherapy: n=70 (34%)] (see Table 17).

Table 17: Efficacy results by PD-L1 expression in KEYNOTE-189*

Endpoint Pembrolizumab Chemotherapy Pembrolizumab Chemotherapy Pembrolizumab Chemotherapycombination combination combinationtherapy therapy therapy

TPS < 1% TPS 1 to 49% TPS ≥ 50%

OS Hazardratio† 0.51 (0.36, 0.71) 0.66 (0.46, 0.96) 0.59 (0.40, 0.86)(95% CI)

PFS Hazardratio† 0.67 (0.49, 0.93) 0.53 (0.38, 0.74) 0.35 (0.25, 0.49)(95% CI)

ORR % 33% 14% 50% 21% 62% 26%

* Based on final analysis† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on the stratified Cox proportional hazardmodel

At final analysis, a total of 57 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-189(35 in the pembrolizumab combination and 22 in the control). A HR=1.54 [95% CI 0.76, 3.14] in OSand HR=1.12 [95% CI 0.56, 2.22] in PFS for pembrolizumab combination vs. chemotherapy wasreported within this study subgroup. Data about efficacy of pembrolizumab in combination withplatinum chemotherapy are limited in this patient population.

Progression-Free Survival (%)

KEYNOTE-407: Controlled study of combination therapy in squamous NSCLC patients naïve totreatment

The efficacy of pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxelwas investigated in Study KEYNOTE-407, a randomised, double-blind, multicentre,placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC,regardless of tumour PD-L1 expression status, and no prior systemic treatment for metastatic disease.

Patients with autoimmune disease that required systemic therapy within 2 years of treatment; amedical condition that required immunosuppression; or who had received more than 30 Gy of thoracicradiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1expression (TPS < 1% [negative] vs. TPS ≥ 1%), investigator’s choice of paclitaxel or nab-paclitaxel,and geographic region (East Asia vs. non-East Asia). Patients were randomised (1:1) to one of thefollowing treatment arms via intravenous infusion:

* Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-daycycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for4 cycles or nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab wasadministered prior to chemotherapy on Day 1.

* Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles ornab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles,followed by placebo every 3 weeks.

Treatment with pembrolizumab or placebo continued until RECIST 1.1-defined progression of diseaseas determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration ofpembrolizumab was permitted beyond RECIST-defined disease progression if the patient wasclinically stable and deriving clinical benefit as determined by the investigator.

Patients in the placebo arm were offered pembrolizumab as a single agent at the time of diseaseprogression.

Assessment of tumour status was performed every 6 weeks through Week 18, every 9 weeks through

Week 45 and every 12 weeks thereafter.

A total of 559 patients were randomised. The study population characteristics were: median age of65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of0 (29%) and 1 (71%); and 8% with treated brain metastases at baseline. Thirty-five percent hadtumour PD-L1 expression TPS < 1% [negative]; 19% were East Asian; and 60% received paclitaxel.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1).

Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using

RECIST 1.1. Table 18 summarises key efficacy measures and Figures 16 and 17 show the

Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of14.3 months.

Table 18: Efficacy results in KEYNOTE-407

Endpoint Pembrolizumab Placebo

Carboplatin Carboplatin

Paclitaxel/Nab-paclitaxel Paclitaxel/Nab-paclitaxeln=278 n=281

OS*

Number (%) of patients with 168 (60%) 197 (70%)event

Median in months (95% CI) 17.1 (14.4, 19.9) 11.6 (10.1, 13.7)

Hazard ratio† (95% CI) 0.71 (0.58, 0.88)p-Value‡ 0.0006

PFS

Number (%) of patients with 217 (78%) 252 (90%)event

Median in months (95% CI) 8.0 (6.3, 8.4) 5.1 (4.3, 6.0)

Hazard ratio† (95% CI) 0.57 (0.47, 0.69)p-Value‡ < 0.0001

Objective response rate

ORR % (95% CI) 63% (57, 68) 38% (33, 44)

Complete response 2.2% 3.2%

Partial response 60% 35%p-Value§ < 0.0001

Response duration

Median in months (range) 8.8 (1.3+, 28.4+) 4.9 (1.3+, 28.3+)% with duration ≥ 12 months¶ 38% 25%

* A total of 138 patients (51%) who discontinued study treatment in the placebo plus chemotherapy armcrossed over to receive monotherapy pembrolizumab or received a checkpoint inhibitor as subsequenttherapy† Based on the stratified Cox proportional hazard model‡ Based on stratified log-rank test§ Based on method by Miettinen and Nurminen¶ Based on Kaplan-Meier estimation

Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Treatment arm OS rate at 12 months OS rate at 18 months HR (95% CI) p-value

Pembrolizumab 65% 48% 0.71 (0.58, 0.88) 0.0006

Control 50% 37%

Time in Months

Number at Risk

Pembrolizumab:

Control:

Overall Survival (%)

Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-407

Treatment arm PFS rate at 12 months PFS rate at 18 months HR (95% CI) p-value

Pembrolizumab 36% 26% 0.57 (0.47, 0.69) < 0.0001

Control 18% 11%

Number at Risk Time in Months

Pembrolizumab:

Control:

An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS < 1% [pembrolizumabplus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to49% [pembrolizumab plus chemotherapy arm: n=103 (37%) vs. placebo plus chemotherapy arm:n=104 (37%)] or TPS ≥ 50% [pembrolizumab plus chemotherapy arm: n=73 (26%) vs. placebo pluschemotherapy arm: n=73 (26%)] (see Table 19).

Table 19: Efficacy results by PD-L1 expression in KEYNOTE-407*

Endpoint Pembrolizumab Chemotherapy Pembrolizumab Chemotherapy Pembrolizumab Chemotherapycombination combination combinationtherapy therapy therapy

TPS < 1% TPS 1 to 49% TPS ≥ 50%

OS Hazardratio† 0.79 (0.56, 1.11) 0.59 (0.42, 0.84) 0.79 (0.52, 1.21)(95% CI)

PFS Hazardratio† 0.67 (0.49, 0.91) 0.52 (0.38, 0.71) 0.43 (0.29, 0.63)(95% CI)

ORR % 67% 41% 55% 42% 64% 30%

* Based on final analysis† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on the stratified Cox proportional hazardmodel

At final analysis, a total of 65 NSCLC patients aged ≥ 75 years were enrolled in study KEYNOTE-407(34 in the pembrolizumab combination and 31 in the control). An HR=0.81 [95% CI 0.43, 1.55] in OS,an HR=0.61 [95% CI 0.34, 1.09] in PFS, and an ORR of 62% and 45% for pembrolizumabcombination vs. chemotherapy was reported within this study subgroup. Data about efficacy ofpembrolizumab in combination with platinum chemotherapy are limited in this patient population.

Progression-Free Survival (%)

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-010, a multicentre,open-label, controlled study for the treatment of advanced NSCLC in patients previously treated withplatinum-containing chemotherapy. Patients had PD-L1 expression with a  1% TPS based on the

PD-L1 IHC 22C3 pharmDxTM Kit. Patients with EGFR activation mutation or ALK translocation alsohad disease progression on approved therapy for these mutations prior to receiving pembrolizumab.

Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=344) or 10 mg/kg bw(n=346) every 3 weeks or docetaxel at a dose of 75 mg/m2 every 3 weeks (n=343) until diseaseprogression or unacceptable toxicity. The study excluded patients with autoimmune disease; a medicalcondition that required immunosuppression; or who had received more than 30 Gy of thoracicradiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks.

The baseline characteristics for this population included: median age 63 years (42% age 65 or older);61% male; 72% White and 21% Asian and 34% and 66% with an ECOG performance status 0 and 1,respectively. Disease characteristics were squamous (21%) and non-squamous (70%); stage IIIA (2%);stage IIIB (7%); stage IV (91%); stable brain metastases (15%) and the incidence of mutations was

EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients receivedone (69%) or two or more (29%) treatment lines.

The primary efficacy outcome measures were OS and PFS as assessed by BICR using RECIST 1.1.

Secondary efficacy outcome measures were ORR and response duration. Table 20 summarises keyefficacy measures for the entire population (TPS  1%) and for the patients with TPS  50%, and

Figure 18 shows the Kaplan-Meier curve for OS (TPS  1%), based on a final analysis with medianfollow-up of 42.6 months.

Table 20: Response to pembrolizumab 2 or 10 mg/kg bw every 3 weeks in previously treatedpatients with NSCLC in KEYNOTE-010

Endpoint Pembrolizumab Pembrolizumab Docetaxel2 mg/kg bw 10 mg/kg bw every 75 mg/m2 everyevery 3 weeks 3 weeks 3 weeks

TPS ≥ 1%

Number of patients 344 346 343

OS

Number (%) of patients with event 284 (83%) 264 (76%) 295 (86%)

Hazard ratio* (95% CI) 0.77 (0.66, 0.91) 0.61 (0.52, 0.73) ---p-Value† 0.00128 < 0.001 ---

Median in months (95% CI) 10.4 (9.5, 11.9) 13.2 (11.2, 16.7) 8.4 (7.6, 9.5)

PFS‡

Number (%) of patients with event 305 (89%) 292 (84%) 314 (92%)

Hazard ratio* (95% CI) 0.88 (0.75, 1.04) 0.75 (0.63, 0.89) ---p-Value† 0.065 < 0.001 ---

Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.7, 4.5) 4.1 (3.8, 4.5)

Objective response rate‡

ORR % (95% CI) 20% (16, 25) 21% (17, 26) 9% (6, 13)

Complete response 2% 3% 0%

Partial response 18% 18% 9%

Response duration‡,§

Median in months (range) Not reached 37.8 7.1(2.8, 46.2+) (2.0+, 49.3+) (1.4+, 16.8)% ongoing¶ 42% 43% 6%

TPS  50%

Number of patients 139 151 152

OS

Number (%) of patients with event 97 (70%) 102 (68%) 127 (84%)

Hazard ratio* (95% CI) 0.56 (0.43, 0.74) 0.50 (0.38, 0.65) ---p-Value† < 0.001 < 0.001 ---

Median in months (95% CI) 15.8 (10.8, 22.5) 18.7 (12.1, 25.3) 8.2 (6.4, 9.8)

PFS‡

Number (%) of patients with event 107 (77%) 115 (76%) 138 (91%)

Hazard ratio* (95% CI) 0.59 (0.45, 0.77) 0.53 (0.41, 0.70) ---p-Value† < 0.001 < 0.001 ---

Median in months (95% CI) 5.3 (4.1, 7.9) 5.2 (4.1, 8.1) 4.2 (3.8, 4.7)

Objective response rate‡

ORR % (95% CI) 32% (24, 40) 32% (25, 41) 9% (5, 14)

Complete response 4% 4% 0%

Partial response 27% 28% 9%

Response duration‡,§

Median in months (range) Not reached 37.5 8.1(2.8, 44.0+) (2.0+, 49.3+) (2.6, 16.8)% ongoing¶ 55% 47% 8%

* Hazard ratio (pembrolizumab compared to docetaxel) based on the stratified Cox proportional hazard model† Based on stratified log-rank test‡ Assessed by BICR using RECIST 1.1§ Based on patients with a best objective response as confirmed complete or partial response¶ Ongoing response includes all responders who at the time of analysis were alive, progression-free, did not initiatenew anti-cancer therapies and had not been determined to be lost to follow-up

Figure 18: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-010(patients with PD-L1 expression TPS  1%, intent to treat population)

Treatment arm OS rate at 24 months OS rate at 36 months HR (95% CI) p-value

Pembrolizumab 2 mg/kg 28% 20% 0.77 (0.66, 0.91) 0.00128

Pembrolizumab 10 mg/kg 36% 26% 0.61 (0.52, 0.73) 0.00001

Docetaxel 14% 11%0 5 10 15 20 25 30 35 40 45 50 55 60

Time in Months

Number at Risk

Pembrolizumab 2 mg/kg: 344 261 177 136 111 91 72 67 36 17 2 0 0

Pembrolizumab 10 mg/kg: 346 262 197 159 137 120 99 84 50 28 3 0 0

Docetaxel: 343 226 135 90 57 44 40 35 20 13 2 0 0

Efficacy results were similar for the 2 mg/kg bw and 10 mg/kg bw pembrolizumab arms. Efficacyresults for OS were consistent regardless of the age of tumour specimen (new vs. archival) based on anintergroup comparison.

In subgroup analyses, a reduced survival benefit of pembrolizumab compared to docetaxel wasobserved for patients who were never-smokers or patients with tumours harbouring EGFR activatingmutations who received at least platinum-based chemotherapy and a tyrosine kinase inhibitor;however, due to the small numbers of patients, no definitive conclusions can be drawn from thesedata.

The efficacy and safety of pembrolizumab in patients with tumours that do not express PD-L1 havenot been established.

Malignant pleural mesothelioma

KEYNOTE-483: Controlled study of combination therapy in patients with untreated unresectableadvanced or metastatic malignant pleural mesothelioma (MPM)

The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy wasinvestigated in KEYNOTE-483, a multicentre, randomised, open-label, active-controlled study. Keyeligibility criteria were unresectable advanced or metastatic MPM with no prior systemic therapy foradvanced/metastatic disease. Patients were enrolled regardless of tumour PD-L1 expression. Patientswith autoimmune disease that required systemic therapy within 3 years of treatment or a medicalcondition that required immunosuppression were ineligible. Randomisation was stratified byhistological subtype (epithelioid vs. non-epithelioid). Patients were randomised (1:1) to one of thefollowing treatment arms; all study medications were administered via intravenous infusion:

* Pembrolizumab 200 mg with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 orcarboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles,

Overall Survival (%)followed by pembrolizumab 200 mg every 3 weeks (n=222). Pembrolizumab wasadministered prior to chemotherapy on Day 1.

* Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on

Day 1 of each 21-day cycle for up to 6 cycles (n=218).

Treatment with pembrolizumab continued until disease progression as determined by the investigatoraccording to modified RECIST 1.1 for mesothelioma (mRECIST), unacceptable toxicity, or amaximum of 24 months. Assessment of tumour status was performed every 6 weeks for 18 weeks,followed by every 12 weeks thereafter.

Among the 95 patients with non-epithelioid histology in KEYNOTE-483, baseline characteristicswere: median age of 71 years (range: 48-85 years of age) with 76% age 65 or older; 83% male;85% White, 15% not reported or unknown; 1% Hispanic or Latino and 44% and 56% ECOGperformance status of 0 or 1, respectively.

The primary efficacy outcome measure was OS. Additional efficacy outcome measures were PFS,

ORR, and DoR, as assessed by BICR using mRECIST. The study demonstrated statistically significantimprovement in the overall population in OS [0.79 (95% CI 0.64, 0.98; p-Value 0.0162)] and

PFS [0.80 (95% CI 0.65, 0.99; p-Value 0.0194)] at the final analysis and ORR [52% (95% CI 45, 59)]vs. [29% (95% CI 23, 35) p-Value < 0.00001] at the interim analysis in patients randomised topembrolizumab in combination with chemotherapy compared with patients randomised tochemotherapy alone. Table 21 summarises key efficacy measures and Figures 19 and 20 show the

Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up time of9.8 months (range: 0.9 to 60.3 months) in the patients with non-epithelioid malignant pleuralmesothelioma.

Table 21: Efficacy results in KEYNOTE-483 for patients with non-epithelioid malignant pleuralmesothelioma

Endpoint Pembrolizumab Pemetrexed +200 mg every 3 weeks + Platinum Chemotherapy

Pemetrexed + (n=49)

Platinum Chemotherapy(n=46)

OS

Number (%) of patients 37 (80%) 44 (90%)with event

Hazard ratio* (95% CI) 0.57 (0.36, 0.89)

Median in months† (95% 12.3 (8.7, 21.2) 8.2 (5.8, 9.8)

CI)

PFS

Number (%) of patients 36 (78%) 38 (78%)with event

Hazard ratio* (95% CI) 0.47 (0.29, 0.77)

Median in months† (95% 7.1 (4.5, 9.8) 4.5 (4.0, 6.4)

CI)

Objective response rate

ORR % (95% CI)‡ 41% (27, 57) 6% (1, 17)

Response duration†

Median in months (range) 11.1 (1.3+, 38.9+) 4.0 (2.4+, pct. 5.2)

* Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate† From product-limit (Kaplan-Meier) method for censored data‡ Based on the exact method for binomial data

Figure 19: Kaplan-Meier curve for overall survival in patients with non-epithelioid MPM in

KEYNOTE-483

Treatment arm

HR (95% CI)

Pembrolizumab + chemotherapy0.57 (0.36, 0.89)

Control

Time in Months

Number at Riskpembrolizumab + chemotherapy

Control

Overall Survival (%)

Figure 20: Kaplan-Meier curve for progression-free survival in patients with non-epithelioid

MPM in KEYNOTE-483

Treatment arm HR (95% CI)

Pembrolizumab + chemothera p y 0.47 (0.29, 0.77)

Control

Time in Months

Number at Riskpembrolizumab + chemotherapy

Control

KEYNOTE-204: Controlled study in patients with relapsed or refractory classical Hodgkinlymphoma (cHL)

The efficacy of pembrolizumab was investigated in KEYNOTE-204, a randomised, open-label,active-controlled study conducted in 304 patients with relapsed or refractory cHL. Patients with active,non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or > 5 years but withsymptoms of GVHD), active autoimmune disease, a medical condition that requiredimmunosuppression, or an active infection requiring systemic therapy were ineligible for the study.

Randomisation was stratified by prior ASCT (yes vs. no) and disease status after frontline therapy(primary refractory vs. relapse less than 12 months after completion vs. relapse 12 months or moreafter completion). Patients were randomised (1:1) to one of the following treatment arms:

* Pembrolizumab 200 mg intravenously every 3 weeks

* Brentuximab vedotin (BV) 1.8 mg/kg bw intravenously every 3 weeks.

Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity ordocumented disease progression, or a maximum of 35 cycles. Limited data are currently available onresponse duration following pembrolizumab discontinuation at cycle 35. Response was assessed every12 weeks, with the first planned post-baseline assessment at Week 12.

Progression-Free Survival (%)

Among the 304 patients in KEYNOTE-204, there is a subpopulation consisting of 112 patients whofailed a transplant before enrolling and 137 who failed 2 or more prior therapies and were ineligiblefor ASCT at the time of enrolment. The baseline characteristics of these 249 patients were: median age34 years (11% age 65 or older); 56% male; 80% White and 7% Asian and 58% and 41% with an

ECOG performance status 0 and 1, respectively. Approximately 30% were refractory to frontlinechemotherapy and ~ 45% had received prior ASCT. Nodular-sclerosis was the more represented cHLhistological subtype (~ 81%) and bulky disease, B symptoms and bone marrow involvement werepresent in approximately 21%, 28% and 4% of patients, respectively.

The primary efficacy outcome was PFS and the secondary efficacy outcome measure was ORR, bothassessed by BICR according to the 2007 revised International Working Group (IWG) criteria. Theadditional primary efficacy outcome measure, OS, was not formally assessed at the time of theanalysis. In the ITT population, the median follow-up time for 151 patients treated withpembrolizumab was 24.9 months (range: 1.8 to 42.0 months). The initial analysis resulted in a HR for

PFS of 0.65 (95% CI: 0.48, 0.88) with a one-sided p value of 0.0027. The ORR was 66% forpembrolizumab compared to 54% for standard treatment with a p-Value of 0.0225. Table 22summarises the efficacy results in the subpopulation. Efficacy results in this subpopulation wereconsistent with the ITT population. The Kaplan-Meier curve for PFS for this subpopulation is shownin Figure 21.

Table 22: Efficacy results in cHL patients who failed a transplant before enrolling or who failed2 or more prior therapies and were ineligible for ASCT in KEYNOTE-204

Endpoint Pembrolizumab Brentuximabvedotin200 mg every 1.8 mg/kg bw3 weeks every 3 weeksn=124 n=125

PFS

Number (%) of patients with event 68 (55%) 75 (60%)

Hazard ratio* (95% CI) 0.66 (0.47, 0.92)

Median in months (95% CI) 12.6 (8.7, 19.4) 8.2 (5.6, 8.8)

Objective response rate

ORR‡ % (95% CI) 65% (56.3, 73.6) 54% (45.3, 63.3)

Complete response 27% 22%

Partial response 39% 33%

Stable disease 12% 23%

Response duration

Median in months (range) 20.5 (0.0+, 33.2+) 11.2 (0.0+, 33.9+)

Number (%¶) of patients with duration ≥ 6 months 53 (80.8%) 28 (61.2%)

Number (%¶) of patients with duration ≥ 12 months 37 (61.7%) 17 (49.0%)

* Based on the stratified Cox proportional hazard model‡ Based on patients with a best overall response as complete or partial response¶ Based on Kaplan-Meier estimation

Figure 21: Kaplan-Meier curve for progression-free survival by treatment arm incHL patients who failed a transplant before enrolling or who failed 2 or more prior therapiesand were ineligible for ASCT in KEYNOTE-204

Treatment arm PFS rate at 12 months PFS rate at 24 months HR (95% CI)

Pembrolizumab 53% 35% 0.66 (0.47, 0.92)

Brentuximab Vedotin 35% 24%

Number at Risk Time in Months

Pembrolizumab:

Brentuximab Vedotin:

The efficacy of pembrolizumab was investigated in KEYNOTE-087 and KEYNOTE-013, twomulticentre, open-label studies for the treatment of 241 patients with cHL. These studies enrolledpatients who failed ASCT and BV, who were ineligible for ASCT because they were unable toachieve a complete or partial remission to salvage chemotherapy and failed BV, or who failed ASCTand did not receive BV. Five study subjects were ineligible to ASCT due to reasons other than failureto salvage chemotherapy. Both studies included patients regardless of PD-L1 expression. Patients withactive, non-infectious pneumonitis, an allogeneic transplant within the past 5 years (or > 5 years butwith GVHD), active autoimmune disease or a medical condition that required immunosuppressionwere ineligible for either study. Patients received pembrolizumab 200 mg every 3 weeks (n=210;

KEYNOTE-087) or 10 mg/kg bw every 2 weeks (n=31; KEYNOTE-013) until unacceptable toxicityor documented disease progression.

Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 orolder); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1,respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4(range: 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 34% whowere refractory to first-line therapy. Sixty-one percent of patients had received ASCT, 38% weretransplant ineligible; 17% had no prior brentuximab vedotin use; and 37% of patients had priorradiation therapy. Disease subtypes were 81% nodular sclerosis, 11% mixed cellularity, 4%lymphocyte-rich and 2% lymphocyte-depleted.

Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (7% age 65 orolder), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1,respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5

Progression-Free Survival (%)(range: 2 to 15). Eighty-four percent were refractory to at least one prior therapy, including 35% whowere refractory to first-line therapy. Seventy-four percent of patients had received ASCT, 26% weretransplant ineligible, and 45% of patients had prior radiation therapy. Disease subtypes were 97%nodular sclerosis and 3% mixed cellularity.

The primary efficacy outcome measures (ORR and CRR) were assessed by BICR according to the

IWG 2007 criteria. Secondary efficacy outcome measures were duration of response, PFS and OS.

Response was assessed in KEYNOTE-087 and KEYNOTE-013 every 12 and 8 weeks, respectively,with the first planned post-baseline assessment at Week 12. Main efficacy results are summarised in

Table 23.

Table 23: Efficacy results in KEYNOTE-087 and KEYNOTE-013

KEYNOTE-087* KEYNOTE-013†

Endpoint Pembrolizumab Pembrolizumab200 mg every 3 weeks 10 mg/kg bw every2 weeksn=210n=31

Objective response rate‡

ORR % (95% CI) 71% (64.8, 77.4) 58% (39.1, 75.5)

Complete remission 28% 19%

Partial remission 44% 39%

Response duration‡

Median in months (range) 16.6 (0.0+, 62.1+)§ Not reached (0.0+, 45.6+)¶% with duration ≥ 12-months 59%# 70%Þ% with duration ≥ 24-months 45%ß ---% with duration ≥ 60-months 25%à ---

Time to response

Median in months (range) 2.8 (2.1, 16.5)§ 2.8 (2.4, 8.6)¶

OS

Number (%) of patients with event 59 (28%) 6 (19%)12-month OS rate 96% 87%24-month OS rate 91% 87%60-month OS rate 71% ---

* Median follow-up time of 62.9 months† Median follow-up time of 52.8 months‡ Assessed by BICR according to the IWG 2007 criteria by PET CT scans§ Based on patients (n=150) with a response by independent review¶ Based on patients (n=18) with a response by independent review# Based on Kaplan-Meier estimation; includes 62 patients with responses of 12 months or longer

Þ Based on Kaplan-Meier estimation; includes 7 patients with responses of 12 months or longerß Based on Kaplan-Meier estimation; includes 37 patients with responses of 24 months or longerà Based on Kaplan-Meier estimation; includes 4 patients with responses of 60 months or longer

Efficacy in elderly patients

Overall, 46 cHL patients ≥ 65 years were treated with pembrolizumab in studies KEYNOTE-087,

KEYNOTE-013 and KEYNOTE-204. Data from these patients are too limited to draw any conclusionon efficacy in this population.

KEYNOTE-A39: Controlled study of combination therapy with enfortumab vedotin for the first-linetreatment of unresectable or metastatic urothelial carcinoma

The efficacy of pembrolizumab in combination with enfortumab vedotin was investigated in

KEYNOTE-A39, an open-label, multicentre, randomised, active-controlled study, that enrolled886 patients with unresectable or metastatic urothelial carcinoma. The study excluded patients withautoimmune disease or a medical condition that required immunosuppression, active CNS metastases,ongoing sensory or motor neuropathy ≥ Grade 2, or uncontrolled diabetes defined as haemoglobin

A1C (HbA1c) ≥ 8% or HbA1c ≥ 7% with associated diabetes symptoms, pneumonitis, or other formsof interstitial lung disease. Patients who received neoadjuvant chemotherapy or patients who receivedadjuvant chemotherapy following cystectomy were included in the study if recurrence was> 12 months from completion of therapy. Patients were considered cisplatin-ineligible if they had atleast one of the following criteria: glomerular filtration rate 30-59 mL/min, ECOG PS ≥ 2, Grade ≥ 2hearing loss, or NYHA Class III heart failure. Patients randomised to the gemcitabine andplatinum-based chemotherapy arm were permitted to receive maintenance immunotherapy.

Randomisation was stratified by cisplatin eligibility (eligible or ineligible), PD-L1 expression (CPS≥ 10 or CPS < 10 based on the PD-L1 IHC 22C3 pharmDxTM Kit), and liver metastases (present orabsent). Patients were randomised (1:1) to one of the following treatment arms; all study medicationswere administered via intravenous infusion;

* Pembrolizumab 200 mg over 30 minutes on Day 1 and enfortumab vedotin1.25 mg/kg on Days 1 and 8 of each 21-day cycle.

* Gemcitabine 1 000 mg/m2 on Days 1 and 8 and investigator’s choice of cisplatin70 mg/m2 or carboplatin (AUC 4.5 or 5 mg/mL/min according to local guidelines) on

Day 1 of each 21-day cycle.

Treatment with pembrolizumab and enfortumab vedotin continued until RECIST v1.1-definedprogression of disease, unacceptable toxicity, or for pembrolizumab a maximum of 35 cycles (up toapproximately 2 years). Assessment of tumour status was performed every 9 weeks for 18 months, andthen every 12 weeks thereafter.

Among 886 patients with urothelial carcinoma, baseline characteristics were: median age of 69 years;77% male; and 67% White. Ninety-five percent had M1 disease, and 5% had M0 disease.

Seventy-three percent had a primary tumour in the lower tract, and 27% in the upper tract. Fifty-fourpercent was cisplatin-eligible, 58% had PD-L1 CPS ≥ 10, and 72% had visceral metastases, including22% with liver metastases. Twenty percent had normal renal function, and 37%, 41% and 2% werecharacterised with mild, moderate, or severe renal impairment, respectively. Ninety-seven percent had

ECOG PS of 0-1 and 3% had ECOG PS of 2. Eighty-five percent had transitional cell carcinoma(TCC) histology, 2% had TCC with other histology and 6% had TCC with squamous differentiation.

Thirty-two percent of patients in the gemcitabine and platinum-based chemotherapy arm receivedmaintenance immunotherapy.

The primary efficacy outcome measures were PFS as assessed by BICR according to RECIST v1.1and OS. Secondary outcome measures were ORR and DoR as assessed by BICR according to RECISTv1.1 and time to pain progression (TTPP).

The study demonstrated a statistically significant improvement in OS, PFS and ORR in patientsrandomised to pembrolizumab in combination with enfortumab vedotin compared with patientsrandomised to gemcitabine and platinum-based chemotherapy.

The median follow-up time for 442 patients treated with pembrolizumab and enfortumab vedotin was17.3 months (range: 0.3 to 37.2 months). Key efficacy results are summarised in Table 24 and

Figures 22 and 23.

Table 24: Efficacy results in KEYNOTE-A39

Endpoint Pembrolizumab Gemcitabine +200 mg every Platinum3 weeks in chemotherapy withcombination with or without

Enfortumab maintenancevedotin immunotherapyn=442 n=444

OS

Number (%) of patients with event 133 (30%) 226 (51%)

Median in months (95% CI) 31.5 (25.4, NR) 16.1 (13.9, 18.3)

Hazard ratio* (95% CI) 0.47 (0.38, 0.58)p-Value† < 0.00001

PFS

Number (%) of patients with event 223 (50%) 307 (69%)

Median in months (95% CI) 12.5 (10.4, 16.6) 6.3 (6.2, 6.5)

Hazard ratio* (95% CI) 0.45 (0.38, 0.54)p-Value† < 0.00001

Objective response rate‡

ORR§ % (95% CI) 68% (63.1, 72.1) 44% (39.7, 49.2)p-Value¶ < 0.00001

Response duration

Median in months (range) NR 7.0(2.0+, 28.3+) (1.5+, 30.9+)

* Based on the stratified Cox proportional hazard regression model† Two-sided p-Value based on stratified log-rank test‡ Includes only patients with measurable disease at baseline§ Based on patients with a best overall response as confirmed complete or partial response¶ Two-sided p-Value based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression,cisplatin eligibility and liver metastases

NR = not reached

Figure 22: Kaplan-Meier curve for overall survival in KEYNOTE-A39

Treatment arm OS Rate at 6 months OS Rate at 12 months HR (95% CI) p-value

Pembrolizumab + EV 90% 78% 0.47 (0.38, 0.58) < 0.00001

Chemotherapy 82% 61%

Time in Months

Number at Risk

Pembrolizumab + EV

Chemotherapy

Overall Survival (%)

Figure 23: Kaplan-Meier curve for progression-free survival in KEYNOTE-A39

Treatment arm PFS Rate at 6 months PFS Rate at 12 months HR (95% CI) p-value

Pembrolizumab + EV 73% 51% 0.45 (0.38, 0.54) < 0.00001

Chemotherapy 61% 22%

Time in Months

Number at Risk

Pembrolizumab + EV

Chemotherapy

KEYNOTE-045: Controlled study in urothelial carcinoma patients who have received priorplatinum-containing chemotherapy

The safety and efficacy of pembrolizumab were evaluated in KEYNOTE-045, a multicentre,open-label, randomised (1:1), controlled study for the treatment of locally advanced or metastaticurothelial carcinoma in patients with disease progression on or after platinum-containingchemotherapy. Patients must have received first-line platinum-containing regimen for locallyadvanced/metastatic disease or as neoadjuvant/adjuvant treatment, with recurrence/progression≤ 12 months following completion of therapy. Patients were randomised (1:1) to receive eitherpembrolizumab 200 mg every 3 weeks (n=270) or investigator’s choice of any of the followingchemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=84),docetaxel 75 mg/m2 (n=84), or vinflunine 320 mg/m2 (n=87). Patients were treated withpembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyondprogression if the patient was clinically stable and was considered to be deriving clinical benefit by theinvestigator. Patients without disease progression could be treated for up to 24 months. The studyexcluded patients with autoimmune disease, a medical condition that required immunosuppression andpatients with more than 2 prior lines of systemic chemotherapy for metastatic urothelial carcinoma.

Patients with an ECOG performance status of 2 had to have a haemoglobin ≥ 10 g/dL, could not haveliver metastases, and must have received the last dose of their last prior chemotherapy regimen≥ 3 months prior to enrolment. Assessment of tumour status was performed at 9 weeks after the firstdose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Progression-Free Survival (%)

Among the 542 randomised patients in KEYNOTE-045, baseline characteristics were: median age66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 56% ECOGperformance status of 1 and 1% ECOG performance status of 2; and 96% M1 disease and 4% M0disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases.

Eighty-six percent had a primary tumour in the lower tract and 14% had a primary tumour in the uppertract. Fifteen percent of patients had disease progression following prior platinum-containingneoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 prior systemic regimens inthe metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had priorcarboplatin, and 1% was treated with other platinum-based regimens.

The primary efficacy outcomes were OS and PFS as assessed by BICR using RECIST v1.1.

Secondary outcome measures were ORR (as assessed by BICR using RECIST v1.1) and duration ofresponse. Table 25 summarises the key efficacy measures for the ITT population at the final analysis.

The Kaplan-Meier curve based on the final analysis for OS is shown in Figure 24. The studydemonstrated statistically significant improvements in OS and ORR for patients randomised topembrolizumab as compared to chemotherapy. There was no statistically significant differencebetween pembrolizumab and chemotherapy with respect to PFS.

Table 25: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelialcarcinoma previously treated with chemotherapy in KEYNOTE-045

Endpoint Pembrolizumab Chemotherapy200 mg every3 weeks n=272n=270

OS

Number (%) of patients with event 200 (74%) 219 (81%)

Hazard ratio* (95% CI) 0.70 (0.57, 0.85)p-Value† < 0.001

Median in months (95% CI) 10.1 (8.0, 12.3) 7.3 (6.1, 8.1)

PFS‡

Number (%) of patients with event 233 (86%) 237 (87%)

Hazard ratio* (95% CI) 0.96 (0.79, 1.16)p-Value† 0.313

Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.4, 3.6)

Objective response rate‡

ORR % (95% CI) 21% (16, 27) 11% (8, 15)p-Value§ < 0.001

Complete response 9% 3%

Partial response 12% 8%

Stable disease 17% 34%

Response duration‡,¶

Median in months (range) Not reached 4.4(1.6+, 30.0+) (1.4+, 29.9+)

Number (%#) of patients with duration ≥ 6 months 46 (84%) 8 (47%)

Number (%#) of patients with duration 35 (68%) 5 (35%)≥ 12 months

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model† Based on stratified log-rank test‡ Assessed by BICR using RECIST 1.1§ Based on method by Miettinen and Nurminen¶ Based on patients with a best objective response as confirmed complete or partial response# Based on Kaplan-Meier estimation

Figure 24: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-045 (intentto treat population)

Treatment arm OS rate at 6 months OS rate at 12 months HR (95% CI) p-value

Pembrolizumab 64% 44% 0.70 (0.57, 0.85) 0.0001590 Control 57% 30%0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Time in Months

Number at Risk

Pembrolizumab: 270 226 195 170 148 132 116 105 98 86 80 76 67 52 33 14 7 0 0 0 0

Control: 272 234 173 140 109 91 73 62 59 47 42 35 34 24 18 10 4 0 0 0 0

An analysis was performed in KEYNOTE-045 in patients who had PD-L1 CPS < 10 [pembrolizumab:n=186 (69%) vs. chemotherapy: n=176 (65%)] or ≥ 10 [pembrolizumab: n=74 (27%) vs.chemotherapy: n=90 (33%)] in both pembrolizumab- and chemotherapy-treated arms (see Table 26).

Table 26: OS by PD-L1 expression

PD-L1 Expression Pembrolizumab Chemotherapy

OS by PD-L1 Expression Hazard

Number (%) of patients with event* Ratio† (95% CI)

CPS < 10 140 (75%) 144 (82%) 0.75 (0.59, 0.95)

CPS ≥ 10 53 (72%) 72 (80%) 0.55 (0.37, 0.81)

* Based on final analysis† Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model

Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time todeterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated withpembrolizumab compared to investigator’s choice chemotherapy (HR 0.70; 95% CI 0.55-0.90). Over15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL,while those treated with investigator’s choice chemotherapy had a decline in global health status/QoL.

These results should be interpreted in the context of the open-label study design and therefore takencautiously.

KEYNOTE-052: Open-label study in urothelial carcinoma patients ineligible for cisplatin-containingchemotherapy

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-052, a multicentre,open-label study for the treatment of locally advanced or metastatic urothelial carcinoma in patients

Overall Survival (%)who were not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab at adose of 200 mg every 3 weeks until unacceptable toxicity or disease progression. Treatment couldcontinue beyond progression if the patient was clinically stable and was considered to be derivingclinical benefit by the investigator. Patients without disease progression could be treated for up to24 months. The study excluded patients with autoimmune disease or a medical condition that requiredimmunosuppression. Assessment of tumour status was performed at 9 weeks after the first dose, thenevery 6 weeks through the first year, followed by every 12 weeks thereafter.

Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containingchemotherapy baseline characteristics were: median age 74 years (82% age 65 or older); 77% male;and 89% White and 7% Asian. Eighty-eight percent had M1 disease and 12% had M0 disease.

Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasonsfor cisplatin ineligibility included: baseline creatinine clearance of < 60 mL/min (50%), ECOGperformance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of< 60 mL/min (9%), and other (Class III heart failure, Grade 2 or greater peripheral neuropathy, and

Grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10%received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had aprimary tumour in the lower tract, and 19% of patients had a primary tumour in the upper tract.

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondaryefficacy outcome measures were duration of response, PFS, and OS. Table 27 summarises the keyefficacy measures for the study population at the final analysis based on a median follow-up time of11.4 months (range: 0.1, 41.2 months) for all patients.

Table 27: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelialcarcinoma ineligible for cisplatin-containing chemotherapy in KEYNOTE-052

Endpoint n=370

Objective response rate*

ORR % (95% CI) 29% (24, 34)

Disease control rate† 47%

Complete response 9%

Partial response 20%

Stable disease 18%

Response duration

Median in months (range) 30.1(1.4+, 35.9+)% with duration ≥ 6-months 81%‡

Time to response

Median in months (range) 2.1 (1.3, 9.0)

PFS*

Median in months (95% CI) 2.2 (2.1, 3.4)6-month PFS rate 33%12-month PFS rate 22%

OS

Median in months (95% CI) 11.3 (9.7, 13.1)6-month OS rate 67%12-month OS rate 47%

* Assessed by BICR using RECIST 1.1† Based on best response of stable disease or better‡ Based on Kaplan-Meier estimates; includes 84 patients with response of 6 months or longer

An analysis was performed in KEYNOTE-052 in patients who had tumours that expressed PD-L1with a CPS < 10 (n=251; 68%) or ≥ 10 (n=110; 30%) based on the PD-L1 IHC 22C3 pharmDxTM Kit(see Table 28).

Table 28: ORR and OS by PD-L1 expression

Endpoint CPS < 10 CPS ≥ 10n=251 n=110

Objective response rate*

ORR % (95% CI) 20% (16, 26) 47% (38, 57)

OS

Median in months (95% CI) 10 (8, 12) 19 (12, 29)12-month OS rate 41% 61%

* BICR using RECIST 1.1

KEYNOTE-361 is a Phase III, randomised, controlled, open-label clinical study of pembrolizumabwith or without platinum-based combination chemotherapy (i.e. either cisplatin or carboplatin withgemcitabine) versus chemotherapy as first-line treatment in subjects with advanced or metastaticurothelial carcinoma. Results of KEYNOTE-361 for pembrolizumab in combination withchemotherapy did not show statistically significant improvement in PFS as assessed by BICR using

RECIST 1.1 (HR 0.78; 95% CI: 0.65, 0.93; p=0.0033), and OS (HR 0.86; 95% CI: 0.72, 1.02;p=0.0407) versus chemotherapy alone. Per the pre-specified hierarchical testing order no formal testsfor statistical significance of pembrolizumab versus chemotherapy could be performed. The keyefficacy results of pembrolizumab monotherapy in patients for whom carboplatin rather than cisplatinwas selected by the investigator as the better choice of chemotherapy were consistent with

KEYNOTE-052 results. Efficacy results in patients whose tumours express PD-L1 with CPS ≥ 10were similar to the overall population for whom carboplatin was selected as the choice ofchemotherapy. See Table 29 and Figures 25 and 26.

Table 29: Response to pembrolizumab 200 mg every 3 weeks or chemotherapy in patients withpreviously untreated urothelial carcinoma for whom carboplatin rather than cisplatin wasselected by the investigator as the better choice of chemotherapy in KEYNOTE-361

Endpoint Pembrolizumab Chemotherapy Pembrolizumab Chemotherapy

CPS ≥ 10 CPS ≥ 10n=170 n=196n=84 n=89

Objective responserate*

ORR % (95% CI) 28% (21.1, 35.0) 42% (34.8, 49.1) 30% (20.3, 40.7) 46% (35.4, 57.0)

Complete 10% 11% 12% 18%response

Partial 18% 31% 18% 28%response

Response duration*

Median in months NR (3.2+, 36.1+) 6.3 (1.8+, 33.8+) NR (4.2, 36.1+) 8.3 (2.1+, 33.8+)(range)% with duration 57% 30% 63% 38%≥ 12 months†

PFS*

Median in months 3.2 (2.2, 5.5) 6.7 (6.2, 8.1) 3.9 (2.2, 6.8) 7.9 (6.1, 9.3)(95% CI)12-month PFS rate 25% 24% 26% 31%

OS

Median in months 14.6 (10.2, 17.9) 12.3 (10.0, 15.5) 15.6 (8.6, 19.7) 13.5 (9.5, 21.0)(95% CI)12-month OS rate 54% 51% 57% 54%

* Assessed by BICR using RECIST 1.1† Based on Kaplan-Meier estimation

NR = not reached

Figure 25: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-361 (intent to treat population, choice of carboplatin)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab 54% 36% 0.83 (0.65, 1.06) 0.0693

Standard Therapy 51% 29%

Time in Months

Number at Risk

Pembrolizumab:

Standard Therapy:

Overall Survival (%)

Figure 26: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-361(patients with PD-L1 expression CPS ≥ 10, intent to treat population, choice of carboplatin)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab 57% 39% 0.82 (0.57, 1.17) 0.1324

Standard Therapy 54% 35%

Time in Months

Number at Risk

Pembrolizumab:

Standard Therapy:

KEYNOTE-048: Controlled study of monotherapy and combination therapy in HNSCC patients naïveto treatment in the recurrent or metastatic setting

The efficacy of pembrolizumab was investigated in KEYNOTE-048, a multicentre, randomised,open-label, active-controlled study in patients with histologically confirmed metastatic or recurrent

HNSCC of the oral cavity, pharynx or larynx, who had not previously received systemic therapy forrecurrent or metastatic disease and who were considered incurable by local therapies. Patients withnasopharyngeal carcinoma, active autoimmune disease that required systemic therapy within two yearsof treatment or a medical condition that required immunosuppression were ineligible for the study.

Randomisation was stratified by tumour PD-L1 expression (TPS ≥ 50% or < 50%), HPV status(positive or negative), and ECOG PS (0 vs. 1). Patients were randomised 1:1:1 to one of the followingtreatment arms:

* Pembrolizumab 200 mg every 3 weeks

* Pembrolizumab 200 mg every 3 weeks, carboplatin AUC 5 mg/mL/min every 3 weeksor cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1 000 mg/m2/d 4 days continuousevery 3 weeks (maximum of 6 cycles of platinum and 5-FU)

* Cetuximab 400 mg/m2 load then 250 mg/m2 once weekly, carboplatin AUC5 mg/mL/min every 3 weeks or cisplatin 100 mg/m2 every 3 weeks, and 5-FU1 000 mg/m2/d 4 days continuous every 3 weeks (maximum of 6 cycles of platinumand 5-FU)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease asdetermined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration ofpembrolizumab was permitted beyond RECIST-defined disease progression if the patient wasclinically stable and considered to be deriving clinical benefit by the investigator. Assessment of

Overall Survival (%)tumour status was performed at Week 9 and then every 6 weeks for the first year, followed by every9 weeks through 24 months.

Among the 882 patients in KEYNOTE-048, 754 (85%) had tumours that expressed PD-L1 with a

CPS ≥ 1 based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these754 patients included: median age of 61 years (range: 20 to 94); 36% age 65 or older; 82% male; 74%

White and 19% Asian; 61% ECOG performance status of 1; and 77% former/current smokers. Diseasecharacteristics were: 21% HPV positive and 95% had stage IV disease (stage IVa 21%, stage IVb 6%,and stage IVc 69%).

The primary efficacy outcome measures were OS and PFS (assessed by BICR according to

RECIST 1.1). The study demonstrated a statistically significant improvement in OS for all patientsrandomised to pembrolizumab in combination with chemotherapy compared to standard treatment(HR 0.72; 95% CI 0.60-0.87) and in patients whose tumours expressed PD-L1 CPS ≥ 1 randomised topembrolizumab monotherapy compared to standard treatment. Tables 30 and 31 summarise keyefficacy results for pembrolizumab in patients whose tumours expressed PD-L1 with a CPS ≥ 1 in

KEYNOTE-048 at the final analysis performed at a median follow-up of 13 months forpembrolizumab in combination with chemotherapy and at a median follow-up of 11.5 months forpembrolizumab monotherapy. Kaplan-Meier curves for OS based on the final analysis are shown in

Figures 27 and 28.

Table 30: Efficacy results for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1expression (CPS ≥ 1)

Endpoint Pembrolizumab + Standard

Platinum Treatment*

Chemotherapy + n=2355-FUn=242

OS

Number (%) of patients with event 177 (73%) 213 (91%)

Median in months (95% CI) 13.6 (10.7, 15.5) 10.4 (9.1, 11.7)

Hazard ratio† (95% CI) 0.65 (0.53, 0.80)p-Value‡ 0.00002

PFS

Number (%) of patients with event 212 (88%) 221 (94%)

Median in months (95% CI) 5.1 (4.7, 6.2) 5.0 (4.8, 6.0)

Hazard ratio† (95% CI) 0.84 (0.69, 1.02)p-Value‡ 0.03697

Objective response rate

ORR§ % (95% CI) 36% (30.3, 42.8) 36% (29.6, 42.2)

Complete response 7% 3%

Partial response 30% 33%p-Value¶ 0.4586

Response duration

Median in months (range) 6.7 (1.6+, 39.0+) 4.3 (1.2+, 31.5+)% with duration ≥ 6 months 54% 34%

* Cetuximab, platinum, and 5-FU† Based on the stratified Cox proportional hazard model‡ Based on stratified log-rank test§ Response: Best objective response as confirmed complete response or partial response¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive vs.negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 27: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in

KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab + Chemo 55% 31% 0.65 (0.53, 0.80) 0.00002

Standard 44% 17%0 5 10 15 20 25 30 35 40 45 50

Time in Months

Number at Risk

Pembrolizumab + Chemo: 242 197 144 109 84 70 52 29 5 0 0

Standard: 235 191 122 83 54 35 17 5 1 0 0

Overall Survival (%)

Table 31: Efficacy results for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1expression (CPS ≥ 1)

Endpoint Pembrolizumab Standardn=257 Treatment*n=255

OS

Number (%) of patients with event 197 (77%) 229 (90%)

Median in months (95% CI) 12.3 (10.8, 14.3) 10.3 (9.0, 11.5)

Hazard ratio† (95% CI) 0.74 (0.61, 0.90)p-Value‡ 0.00133

PFS

Number (%) of patients with event 228 (89%) 237 (93%)

Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 6.0)

Hazard ratio† (95% CI) 1.13 (0.94, 1.36)p-Value‡ 0.89580

Objective response rate

ORR§ % (95% CI) 19.1% (14.5, 24.4) 35% (29.1, 41.1)

Complete response 5% 3%

Partial response 14% 32%p-Value¶ 1.0000

Response duration

Median in months (range) 23.4 (1.5+, 43.0+) 4.5 (1.2+, 38.7+)% with duration ≥ 6 months 81% 36%

* Cetuximab, platinum, and 5-FU† Based on the stratified Cox proportional hazard model‡ Based on stratified log-rank test§ Response: Best objective response as confirmed complete response or partial response¶ Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positivevs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 28: Kaplan-Meier curve for overall survival for pembrolizumab as monotherapy in

KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab 50% 29% 0.74 (0.61, 0.90) 0.00133

Standard 44% 17%0 5 10 15 20 25 30 35 40 45 50

Time in Months

Number at Risk

Pembrolizumab: 257 197 152 110 91 70 43 21 13 1 0

Standard: 255 207 131 89 59 40 21 9 5 0 0

An analysis was performed in KEYNOTE-048 in patients whose tumours expressed PD-L1 CPS ≥ 20[pembrolizumab plus chemotherapy: n=126 (49%) vs. standard treatment: n=110 (43%) andpembrolizumab monotherapy: n=133 (52%) vs. standard treatment: n=122 (48%)] (see Table 32).

Table 32: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab asmonotherapy by PD-L1 expression in KEYNOTE-048 (CPS ≥ 20)

Endpoint Pembrolizumab + Standard Pembrolizumab Standard

Platinum Treatment* Monotherapy Treatment*

Chemotherapy +5-FU n=110 n=133 n=122n=126

OS

Number (%) of patients 84 (66.7%) 98 (89.1%) 94 (70.7%) 108 (88.5%)with event

Median in months (95% 14.7 (10.3, 19.3) 11.0 (9.2, 13.0) 14.8 (11.5, 20.6) 10.7 (8.8, 12.8)

CI)

Hazard ratio† (95% CI) 0.60 (0.45, 0.82) 0.58 (0.44, 0.78)p-Value‡ 0.00044 0.00010

OS rate at 6 months (95% 74.6 (66.0, 81.3) 80.0 (71.2, 86.3) 74.4 (66.1, 81.0) 79.5 (71.2, 85.7)

CI)

OS rate at 12 months 57.1 (48.0, 65.2) 46.1 (36.6, 55.1) 56.4 (47.5, 64.3) 44.9 (35.9, 53.4)(95% CI)

OS rate at 24 months 35.4 (27.2, 43.8) 19.4 (12.6, 27.3) 35.3 (27.3, 43.4) 19.1 (12.7, 26.6)(95% CI)

Overall Survival (%)

Endpoint Pembrolizumab + Standard Pembrolizumab Standard

Platinum Treatment* Monotherapy Treatment*

Chemotherapy + n=110 n=1335-FU n=122n=126

PFS

Number (%) of patients 106 (84.1%) 104 (94.5%) 115 (86.5%) 114 (93.4%)with event

Median in months (95% 5.8 (4.7, 7.6) 5.3 (4.9, 6.3) 3.4 (3.2, 3.8) 5.3 (4.8, 6.3)

CI)

Hazard ratio† (95% CI) 0.76 (0.58, 1.01) 0.99 (0.76, 1.29)p-Value‡ 0.02951 0.46791

PFS rate at 6 months 49.4 (40.3, 57.9) 47.2 (37.5, 56.2) 33.0 (25.2, 41.0) 46.6 (37.5, 55.2)(95% CI)

PFS rate at 12 months 23.9 (16.7, 31.7) 14.0 (8.2, 21.3) 23.5 (16.6, 31.1) 15.1 (9.3, 22.2)(95% CI)

PFS rate at 24 months 14.6 (8.9, 21.5) 5.0 (1.9, 10.5) 16.8 (10.9, 23.8) 6.1 (2.7, 11.6)(95% CI)

Objective response rate

ORR§ % (95% CI) 42.9 (34.1, 52.0) 38.2 (29.1, 47.9) 23.3 (16.4, 31.4) 36.1 (27.6, 45.3)

Response duration

Number of responders 54 42 31 44

Median in months 7.1 (2.1+, 39.0+) 4.2 (1.2+, 31.5+) 22.6 (2.7+, 43.0+) 4.2 (1.2+, 31.5+)(range)

* Cetuximab, platinum, and 5-FU† Based on the stratified Cox proportional hazard model‡ Based on stratified log-rank test§ Response: Best objective response as confirmed complete response or partial response

An exploratory subgroup analysis was performed in KEYNOTE-048 in patients whose tumoursexpressed PD-L1 CPS ≥ 1 to < 20 [pembrolizumab plus chemotherapy: n=116 (45%) vs. standardtreatment: n=125 (49%) and pembrolizumab monotherapy: n=124 (48%) vs. standard treatment:n=133 (52%)] (see Table 33).

Table 33: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab asmonotherapy by PD-L1 expression in KEYNOTE-048 (CPS ≥ 1 to < 20)

Endpoint Pembrolizumab + Standard Pembrolizumab Standard

Platinum Treatment* Monotherapy Treatment*

Chemotherapy +5-FU n=125 n=124 n=133n=116

OS

Number (%) of patients 93 (80.2%) 115 (92.0%) 103 (83.1%) 121 (91.0%)with event

Median in months (95% 12.7 (9.4, 15.3) 9.9 (8.6, 11.5) 10.8 (9.0, 12.6) 10.1 (8.7, 12.1)

CI)

Hazard ratio† (95% CI) 0.71 (0.54, 0.94) 0.86 (0.66, 1.12)

OS rate at 6 months 76.7 (67.9, 83.4) 77.4 (69.0, 83.8) 67.6 (58.6, 75.1) 78.0 (70.0, 84.2)(95% CI)

OS rate at 12 months 52.6 (43.1, 61.2) 41.1 (32.4, 49.6) 44.0 (35.1, 52.5) 42.4 (33.9, 50.7)(95% CI)

OS rate at 24 months 25.9 (18.3, 34.1) 14.5 (9.0, 21.3) 22.0 (15.1, 29.6) 15.9 (10.3, 22.6)(95% CI)

PFS

Number (%) of patients 106 (91.4%) 117 (93.6%) 113 (91.1%) 123 (92.5%)with event

Median in months (95% 4.9 (4.2, 5.3) 4.9 (3.7, 6.0) 2.2 (2.1, 2.9) 4.9 (3.8, 6.0)

CI)

Hazard ratio† (95% CI) 0.93 (0.71, 1.21) 1.25 (0.96, 1.61)

PFS rate at 6 months 40.1 (31.0, 49.0) 40.0 (31.2, 48.5) 24.2 (17.1, 32.0) 41.4 (32.8, 49.7)(95% CI)

PFS rate at 12 months 15.1 (9.1, 22.4) 11.3 (6.4, 17.7) 17.5 (11.4, 24.7) 12.1 (7.2, 18.5)(95% CI)

PFS rate at 24 months 8.5 (4.2, 14.7) 5.0 (1.9, 10.1) 8.3 (4.3, 14.1) 6.3 (2.9, 11.5)(95% CI)

Objective response rate

ORR‡ % (95% CI) 29.3 (21.2, 38.5) 33.6 (25.4, 42.6) 14.5 (8.8, 22.0) 33.8 (25.9,42.5)

Response duration

Number of responders 34 42 18 45

Median in months 5.6 (1.6+, 25.6+) 4.6 (1.4+, 31.4+) NR (1.5+, 38.9+) 5.0 (1.4+, 38.7+)(range)

* Cetuximab, platinum, and 5-FU† Based on the stratified Cox proportional hazard model‡ Response: Best objective response as confirmed complete response or partial response

NR = not reached

KEYNOTE-040: Controlled study in HNSCC patients previously treated with platinum-containingchemotherapy

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-040, a multicentre,open-label, randomised, controlled study for the treatment of histologically confirmed recurrent ormetastatic HNSCC of the oral cavity, pharynx or larynx in patients who had disease progression on orafter platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or followingplatinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy,and were not amenable to local therapy with curative intent. Patients were stratified by PD-L1expression (TPS ≥ 50%), HPV status and ECOG performance status and then randomised (1:1) toreceive either pembrolizumab 200 mg every 3 weeks (n=247) or one of three standard treatments(n=248): methotrexate 40 mg/m2 once weekly (n=64), docetaxel 75 mg/m2 once every 3 weeks (n=99),or cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once weekly (n=71). Treatment couldcontinue beyond progression if the patient was clinically stable and was considered to be derivingclinical benefit by the investigator. The study excluded patients with nasopharyngeal carcinoma, activeautoimmune disease that required systemic therapy within 2 years of treatment, a medical conditionthat required immunosuppression, or who were previously treated with 3 or more systemic regimensfor recurrent and/or metastatic HNSCC. Assessment of tumour status was performed at 9 weeks, thenevery 6 weeks through Week 52, followed by every 9 weeks through 24 months.

Among the 495 patients in KEYNOTE-040, 129 (26%) had tumours that expressed PD-L1 with a

TPS ≥ 50% based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these129 patients included: median age 62 years (40% age 65 or older); 81% male; 78% White, 11% Asian,and 2% Black; 23% and 77% with an ECOG performance status 0 or 1, respectively; and 19% with

HPV positive tumours. Sixty-seven percent (67%) of patients had M1 disease and the majority hadstage IV disease (stage IV 32%, stage IVa 14%, stage IVb 4%, and stage IVc 44%). Sixteenpercent (16%) had disease progression following platinum-containing neoadjuvant or adjuvantchemotherapy, and 84% had received 1-2 prior systemic regimens for metastatic disease.

The primary efficacy outcome was OS in the ITT population. The initial analysis resulted in a HR for

OS of 0.82 (95% CI: 0.67, 1.01) with a one-sided p-Value of 0.0316. The median OS was 8.4 monthsfor pembrolizumab compared to 7.1 months for standard treatment. Table 34 summarises the keyefficacy measures for the TPS ≥ 50% population. The Kaplan-Meier curve for OS for the TPS ≥ 50%population is shown in Figure 29.

Table 34: Efficacy of pembrolizumab 200 mg every 3 weeks in HNSCC patients with TPS ≥ 50%who were previously treated with platinum chemotherapy in KEYNOTE-040

Endpoint Pembrolizumab Standard Treatment*200 mg every 3 weeks n=65n=64

OS

Number (%) of patients with event 41 (64%) 56 (86%)

Hazard ratio† (95% CI) 0.53 (0.35, 0.81)p-Value‡ 0.001

Median in months (95% CI) 11.6 (8.3, 19.5) 6.6 (4.8, 9.2)

PFS§

Number (%) of patients with event 52 (81%) 58 (89%)

Hazard ratio† (95% CI) 0.58 (0.39, 0.86)p-Value‡ 0.003

Median in months (95% CI) 3.5 (2.1, 6.3) 2.1 (2.0, 2.4)

Rate (%) at 6 months (95% CI) 40.1 (28.1, 51.9) 17.1 (8.8, 27.7)

Objective response rate§

ORR % (95% CI) 26.6 (16.3, 39.1) 9.2 (3.5, 19.0)p-Value¶ 0.0009

Complete response 5% 2%

Partial response 22% 8%

Stable disease 23% 23%

Response duration§,#

Median in months (range) Not reached (2.7, 13.8+) 6.9 (4.2, 18.8)

Number (%Þ) of patients with duration9 (66%) 2 (50%)≥ 6 months

* Methotrexate, docetaxel, or cetuximab† Hazard ratio (pembrolizumab compared to standard treatment) based on the stratified Cox proportional hazardmodel‡ One-sided p-Value based on log-rank test§ Assessed by BICR using RECIST 1.1¶ Based on method by Miettinen and Nurminen# Based on patients with a best objective response as confirmed complete or partial response

Þ Based on Kaplan-Meier estimation

Figure 29: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-040patients with PD-L1 expression (TPS ≥ 50%)

Treatment arm OS rate at 12 months HR (95% CI) p-value

Pembrolizumab 47% 0.53 (0.35, 0.81) 0.0013690 Standard Treatment 25%0 5 10 15 20 25

Time in Months

Number at Risk

Pembrolizumab: 64 49 35 19 7 1

Standard Treatment: 65 38 22 9 2 0

KEYNOTE-426: Controlled study of combination therapy with axitinib in RCC patients naïve totreatment

The efficacy of pembrolizumab in combination with axitinib was investigated in KEYNOTE-426,a randomised, multicentre, open-label, active-controlled study conducted in patients with advanced

RCC with clear cell component, regardless of PD-L1 tumour expression status and International

Metastatic RCC Database Consortium (IMDC) risk group categories. The study excluded patients withautoimmune disease or a medical condition that required immunosuppression. Randomisation wasstratified by risk categories (favourable versus intermediate versus poor) and geographic region (North

America versus Western Europe versus “Rest of the World”). Patients were randomised (1:1) to one ofthe following treatment arms:

* pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for2 consecutive treatment cycles (i.e. 6 weeks) with no > Grade 2 treatment-relatedadverse events to axitinib and with blood pressure well controlled to ≤ 150/90 mm Hgwere permitted dose escalation of axitinib to 7 mg twice daily. Dose escalation ofaxitinib to 10 mg twice daily was permitted using the same criteria. Axitinib could beinterrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily tomanage toxicity.

* sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with pembrolizumab and axitinib continued until RECIST v1.1-defined progression ofdisease as verified by BICR or confirmed by the investigator, unacceptable toxicity, or forpembrolizumab, a maximum of 24 months. Administration of pembrolizumab and axitinib waspermitted beyond RECIST-defined disease progression if the patient was clinically stable andconsidered to be deriving clinical benefit by the investigator. Assessment of tumour status was

Overall Survival (%)performed at baseline, after randomisation at Week 12, then every 6 weeks thereafter until Week 54,and then every 12 weeks thereafter.

A total of 861 patients were randomised. The study population characteristics were: median age of62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 80% had a

Karnofsky Performance Score (KPS) 90-100 and 20% had KPS 70-80; patient distribution by IMDCrisk categories was 31% favourable, 56% intermediate and 13% poor.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1).

Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using

RECIST 1.1. The study demonstrated a statistically significant improvement in OS (HR 0.53; 95% CI0.38, 0.74; p-Value = 0.00005) and PFS (HR 0.69; 95% CI 0.56, 0.84; p-Value = 0.00012) for patientsrandomised to the pembrolizumab combination arm compared with sunitinib at its pre-specifiedinterim analysis. Table 35 summarises key efficacy measures and Figures 30 and 31 show the

Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up time of37.7 months.

Table 35: Efficacy results in KEYNOTE-426

Endpoint Pembrolizumab Sunitinib

Axitinib n=429n=432

OS

Number (%) of patients with 193 (45%) 225 (52%)event

Median in months (95% CI) 45.7 (43.6, NA) 40.1 (34.3, 44.2)

Hazard ratio* (95% CI) 0.73 (0.60, 0.88)p-Value† 0.00062

PFS‡

Number (%) of patients with 286 (66%) 301 (70%)event

Median in months (95% CI) 15.7 (13.6, 20.2) 11.1 (8.9, 12.5)

Hazard ratio* (95% CI) 0.68 (0.58, 0.80)p-Value† < 0.00001

Objective response rate

ORR§ % (95% CI) 60 (56, 65) 40 (35, 44)

Complete response 10% 3%

Partial response 50% 36%p-Value¶ < 0.0001

Response duration

Median in months (range) 23.6 (1.4+, 43.4+) 15.3 (2.3, 42.8+)

Number (%#) of patients with 87 (45%) 29 (32%)duration ≥ 30 months

* Based on the stratified Cox proportional hazard model† Nominal p-Value based on stratified log-rank test‡ Assessed by BICR using RECIST 1.1§ Based on patients with a best objective response as confirmed complete or partial response¶ Nominal p-Value based on Miettinen and Nurminen method stratified by IMDC risk group and geographicregion. At the pre-specified interim analysis of ORR (median follow-up time of 12.8 months), statisticallysignificant superiority was achieved for ORR comparing pembrolizumab plus axitinib with sunitinibp-Value < 0.0001# Based on Kaplan-Meier estimation

NA = not available

Figure 30: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-426 (intent to treat population)

Treatment arm OS rate at 12 months OS rate at 36 months HR (95% CI) p-value

Pembrolizumab + Axitinib 90% 63% 0.73 (0.60, 0.88) 0.00062

Sunitinib 79% 54%

Time in Months

Number at Risk

Pembrolizumab + Axitinib

Sunitinib

Overall Survival (%)

Figure 31: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-426 (intent to treat population)

Treatment arm PFS rate at 12 months PFS rate at 36 months HR (95% CI) p-value

Pembrolizumab + Axitinib 60% 29% 0.68 (0.58, 0.80) <0.00001

Sunitinib 47% 15%

Time in Months

Number at Risk

Pembrolizumab + Axitinib

Sunitinib

Subgroup analyses were performed in KEYNOTE-426 in patients with PD-L1 CPS ≥ 1[pembrolizumab/axitinib combination: n=243 (56%) vs. sunitinib: n=254 (59%)] and CPS < 1[pembrolizumab/axitinib combination: n=167 (39%) vs. sunitinib: n=158 (37%)]. OS and PFS benefitswere observed regardless of PD-L1 expression level.

The KEYNOTE-426 study was not powered to evaluate efficacy of individual subgroups.

Table 36 summarises the efficacy measures by IMDC risk category based on the final OS analysis at amedian follow-up of 37.7 months.

Table 36: Efficacy results in KEYNOTE-426 by IMDC risk category

Endpoint* Pembrolizumab + Sunitinib Pembrolizumab + Axitinib

Axitinib n=429 vs. Sunitinibn=432

OS 12-month OS rate, % (95% CI) OS HR (95% CI)

Favourable 95.6 (90.5, 98.0) 94.6 (89.0, 97.4) 1.17 (0.76, 1.80)

Intermediate 90.7 (86.2, 93.8) 77.6 (71.8, 82.3) 0.67 (0.52, 0.86)

Poor 69.6 (55.8, 79.9) 45.1 (31.2, 58.0) 0.51 (0.32, 0.81)

PFS Median (95% CI), months PFS HR (95% CI)

Favourable 20.7 (15.2, 28.9) 17.8 (12.5, 20.7) 0.76 (0.56, 1.03)

Progression-Free Survival (%)

Endpoint* Pembrolizumab + Sunitinib Pembrolizumab + Axitinib

Axitinib n=429 vs. Sunitinibn=432

Intermediate 15.3 (12.5, 20.8) 9.7 (8.0, 12.4) 0.69 (0.55, 0.86)

Poor 4.9 (2.8, 12.4) 2.9 (2.7, 4.2) 0.53 (0.33, 0.84)

Confirmed ORR % (95% CI) ORR difference,% (95% CI)

Favourable 68.8 (60.4, 76.4) 50.4 (41.5, 59.2) 18.5 (6.7, 29.7)

Intermediate 60.5 (54.0, 66.8) 39.8 (33.7, 46.3) 20.7 (11.8, 29.2)

Poor 39.3 (26.5, 53.2) 11.5 (4.4, 23.4) 27.7 (11.7, 42.8)

* n (%) for favourable, intermediate and poor risk categories for pembrolizumab/axitinib vs. sunitinib were: 138 (32%) vs.131 (31%); 238 (55%) vs. 246 (57%); 56 (13%) vs. 52 (12%), respectively

KEYNOTE-581 (CLEAR): Controlled study of combination therapy with lenvatinib in RCC patientsnaïve to treatment

The efficacy of pembrolizumab in combination with lenvatinib was investigated in KEYNOTE-581(CLEAR), a multicentre, open-label, randomised study conducted in 1 069 patients with advanced

RCC with clear cell component including other histological features such as sarcomatoid and papillaryin the first-line setting. Patients were enrolled regardless of PD-L1 tumour expression status. Thestudy excluded patients with active autoimmune disease or a medical condition that requiredimmunosuppression. Randomisation was stratified by geographic region (North America versus

Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC)prognostic groups (favourable versus intermediate versus poor).

Patients were randomised (1:1:1) to one of the following treatment arms:

* pembrolizumab 200 mg intravenously every 3 weeks up to 24 months in combination withlenvatinib 20 mg orally once daily.

* lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily.

* sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks.

Treatment continued until unacceptable toxicity or disease progression as determined by theinvestigator and confirmed by BICR using RECIST 1.1. Administration of pembrolizumab withlenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinicallystable and considered by the investigator to be deriving clinical benefit. Pembrolizumab was continuedfor a maximum of 24 months; however, treatment with lenvatinib could be continued beyond24 months. Assessment of tumour status was performed at baseline and then every 8 weeks.

Among the study population (355 patients in the pembrolizumab with lenvatinib arm and 357 in thesunitinib arm), the baseline characteristics were: median age of 62 years (range: 29 to 88 years), 41%age 65 or older; 74% male; 75% White, 21% Asian, 1% Black, and 2% other races; 17% and 83% ofpatients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC riskcategories was 33% favourable, 56% intermediate and 10% poor, and by MSKCC prognostic groupswas 27% favourable, 64% intermediate and 9% poor. Metastatic disease was present in 99% of thepatients and locally advanced disease was present in 1%. Common sites of metastases in patients werelung (69%), lymph node (46%), and bone (26%).

The primary efficacy outcome measure was PFS based on BICR using RECIST 1.1. Key secondaryefficacy outcome measures included OS and ORR. The study demonstrated statistically significantimprovements in PFS (HR 0.39; 95% CI 0.32, 0.49; p-Value < 0.0001), OS (HR 0.66; 95% CI 0.49,0.88; p-Value 0.0049), and ORR (71%; [95% CI 66, 76] vs. 36%; [95% CI 31, 41]; p-Value < 0.0001)in patients randomised to pembrolizumab in combination with lenvatinib compared with sunitinib atthe pre-specified interim analysis, with a median survival follow-up time of 26.5 months, and medianduration of treatment for pembrolizumab plus lenvatinib of 17.0 months. The primary OS analysis wasnot adjusted to account for subsequent therapies.

Efficacy results for KEYNOTE-581 (CLEAR) at the protocol-specified final analysis with medianfollow-up time of 49.4 months are summarised in Table 37 and Figures 32 and 33. PFS results wereconsistent across pre-specified subgroups, MSKCC prognostic groups and PD-L1 tumour expressionstatus. Efficacy results by MSKCC prognostic group are summarised in Table 38.

Table 37: Efficacy results in KEYNOTE-581 (CLEAR)

Endpoint Pembrolizumab Sunitinib200 mg every3 weeksand Lenvatinib n=357n=355

PFS*

Number (%) of patients with event 207 (58%) 214 (60%)

Median in months (95% CI) 23.9 (20.8, 27.7) 9.2 (6.0, 11.0)

Hazard ratio† (95% CI) 0.47 (0.38, 0.57)p-Value‡ < 0.0001

OS

Number (%) of patients with event 149 (42%) 159 (45%)

Median in months (95% CI) 53.7 (48.7, NR) 54.3 (40.9, NR)

Hazard ratio† (95% CI) 0.79 (0.63, 0.99)p-Value‡ 0.0424

Objective response rate

ORR§ % (95% CI) 71% (66.6, 76.0) 37% (31.7, 41.7)

Complete response 18% 5%

Partial response 53% 32%p-Value¶ < 0.0001

Response duration#

Median in months (range) 26.7 (1.64+, 55.92+) 14.7 (1.64+, 54.08+)

* The primary analysis of PFS included censoring for new anti-cancer treatment. Results for

PFS with and without censoring for new anti-cancer treatment were consistent† Based on the stratified Cox proportional hazard model‡ Nominal p-Value, two-sided based on stratified log-rank test§ Response: Best objective response as confirmed complete response or partial response¶ Nominal two-sided p-Value based on the stratified Cochran-Mantel-Haenszel (CMH) test.

At the earlier pre-specified final analysis of ORR (median follow-up time of 17.3 months),statistically significant superiority was achieved for ORR comparing pembrolizumab pluslenvatinib with sunitinib, (odds ratio: 3.84 [95% CI: 2.81, pct. 5.26], p-Value < 0.0001)# Based on Kaplan-Meier estimates

NR = not reached

The final OS analysis was not adjusted to account for subsequent therapies, with 195/357 (54.6%)patients in the sunitinib arm and 56/355 (15.8%) patients in the pembrolizumab plus lenvatinib armreceiving subsequent anti-PD-1/PD-L1 therapy.

Figure 32: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-581 (CLEAR)

Treatment arm PFS Rate at 24 months PFS Rate at 36 months HR (95% CI)

Pembrolizumab + Lenvatinib 49% 37% 0.47 (0.38, 0.57)

Sunitinib 23% 18%

Time in Months

Number at Risk

Pembrolizumab + Lenvatinib

Sunitinib

Progression-Free Survival (%)

Figure 33: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-581 (CLEAR)

Treatment arm OS Rate at 24 months OS Rate at 36 months HR (95% CI)

Pembrolizumab + Lenvatinib 80% 66% 0.79 (0.63, 0.99)

Sunitinib 70% 60%

Time in Months

Number at Risk

Pembrolizumab + Lenvatinib

Sunitinib

The KEYNOTE-581 (CLEAR) study was not powered to evaluate efficacy of individual subgroups.

Subgroup analyses were performed by MSKCC prognostic group.

Table 38 summarises the efficacy measures by MSKCC prognostic group based on the final OSanalysis at a median follow-up of 49.4 months.

Overall Survival (%)

Table 38: Efficacy results in KEYNOTE-581 (CLEAR) by MSKCC prognostic group

Pembrolizumab +

Sunitinib Pembrolizumab +

Lenvatinib(n=357) Lenvatinib vs.

(n=355) Sunitinib

Number of Number Number of Number

Patients of Events Patients of Events

Progression-Free Survival (PFS) by BICR* PFS HR (95% CI)

Favourable 96 56 97 65 0.46 (0.32, 0.67)

Intermediate 227 129 228 130 0.51 (0.4 0, 0.65)

Poor 32 22 32 19 0.18 (0.08, 0.42)

Overall Survival (OS)* OS HR (95% CI)

Favourable 96 27 97 31 0.89 (0.5 3, 1.50)

Intermediate 227 104 228 108 0.81 (0.6 2, 1.06)

Poor 32 18 32 20 0.59 (0.3 1, 1.12)

* Median follow-up: 49.4 months (data cutoff - 31 July 2022)

KEYNOTE-B61: Open-label single arm Phase II study

Additional data are available from the open-label single arm Phase II study KEYNOTE-B61 ofpembrolizumab (400 mg every 6 weeks) in combination with lenvatinib (20 mg OD) for the first-linetreatment of patients with advanced or metastatic RCC with non-clear cell histology (n=158),including 59% papillary, 18% chromophobe, 4% translocation, 1% medullary, 13% unclassified, and6% other. The ORR was 50.6% (95% CI: 42.6, 58.7) and the median duration of response was19.5 months (95% CI: 15.3, NR).

KEYNOTE-564: Placebo-controlled study for the adjuvant treatment of patients with resected RCC

The efficacy of pembrolizumab was investigated as adjuvant therapy for RCC in KEYNOTE-564, amulticentre, randomised, double-blind, placebo-controlled study in 994 patients with increased risk ofrecurrence defined as intermediate-high or high risk, or M1 with no evidence of disease (NED). Theintermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Gradewithout nodal involvement (N0) or distant metastases (M0). The high risk category included: pT4, any

Grade N0 and M0; any pT, any Grade with nodal involvement and M0. The M1 NED categoryincluded patients with metastatic disease who had undergone complete resection of primary andmetastatic lesions. Patients must have undergone a partial nephroprotective or radical completenephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NEDparticipants) with negative surgical margins ≥ 4 weeks prior to the time of screening. The studyexcluded patients with active autoimmune disease or a medical condition that requiredimmunosuppression. Patients with RCC with clear cell component were randomised (1:1) to receivepembrolizumab 200 mg every 3 weeks (n=496) or placebo (n=498) for up to 1 year until diseaserecurrence or unacceptable toxicity. Randomisation was stratified by metastasis status (M0, M1 NED),and within M0 group, further stratified by ECOG PS (0,1), and geographic region (US, non-US).

Starting from randomisation, patients underwent imaging every 12 weeks for the first 2 years, thenevery 16 weeks from year 3 to 5, and then every 24 weeks annually.

Among the 994 patients, the baseline characteristics were: median age of 60 years (range: 25 to 84),33% age 65 or older; 71% male; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-fourpercent were N0; 83% had no sarcomatoid features; 86% were pT2 with Grade 4 or sarcomatoidfeatures or pT3; 8% were pT4 or with nodal involvement; and 6% were M1 NED. Baselinecharacteristics and demographics were generally comparable between the pembrolizumab and placeboarms.

The primary efficacy outcome measure was investigator-assessed disease-free survival (DFS). The keysecondary outcome measure was OS. The study demonstrated statistically significant improvements in

DFS and OS for patients randomised to the pembrolizumab arm compared with placebo. At thepre-specified interim analysis with a median follow-up time of 23.9 months, the DFS HRwas 0.68 (95% CI 0.53, 0.87; p-Value = 0.0010). Efficacy results with a median follow-up time of55.8 months are summarised in Table 39 and Figures 34 and 35.

Table 39: Efficacy results in KEYNOTE-564

Endpoint Pembrolizumab Placebo200 mg every3 weeksn=496 n=498

DFS

Number (%) of patients with 174 (35%) 224 (45%)event

Median in months (95% CI) NR (NR, NR) NR (54.9, NR)

Hazard ratio* (95% CI) 0.72 (0.59, 0.87)

OS

Number (%) of patients with 55 (11%) 86 (17%)event

Median in months (95% CI) NR (NR, NR) NR (NR, NR)

Hazard ratio* (95% CI) 0.62 (0.44, 0.87)p-Value† 0.0024

* Based on the stratified Cox proportional hazard model† One-sided p-Value based on stratified log-rank test

NR = not reached

Figure 34: Kaplan-Meier curve for disease-free survival by treatment arm in KEYNOTE-564(intent to treat population)

Treatment arm DFS rate at 24 months DFS rate at 48 months HR (95% CI)

Pembrolizumab 78% 65% 0.72 (0.59, 0.87)

Placebo 67% 57%

Time in Months

Number at Risk

Pembrolizumab

Placebo

Disease-Free Survival (%)

Figure 35: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-564 (intentto treat population)

Treatment arm OS rate at 24 months OS rate at 48 months HR (95% CI) p-value

Pembrolizumab 96% 91% 0.62 (0.44, 0.87) 0.0024

Placebo 94% 86%

Time in Months

Number at Risk

Pembrolizumab

Placebo

MSI-H or dMMR cancers

KEYNOTE-177: Controlled study in MSI-H or dMMR CRC patients naïve to treatment in themetastatic setting

The efficacy of pembrolizumab was investigated in KEYNOTE-177, a multicentre, randomised, open-label, active-controlled study that enrolled patients with previously untreated metastatic MSI-H ordMMR CRC. MSI or MMR (mismatch repair) tumour status was determined locally using polymerasechain reaction (PCR) or IHC, respectively. Patients with autoimmune disease or a medical conditionthat required immunosuppression were ineligible.

Patients were randomised (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks orinvestigator’s choice of the following chemotherapy regimens given intravenously every 2 weeks:

* mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination witheither bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (orlevoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2 400 mg/m2over 46-48 hours. Bevacizumab 5 mg/kg bw on Day 1 or cetuximab 400 mg/m2 onfirst infusion, then 250 mg/m2 weekly.

Overall Survival (%)

* FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with eitherbevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2 (orlevoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2 400 mg/m2over 46-48 hours. Bevacizumab 5 mg/kg bw on Day 1 or cetuximab 400 mg/m2 onfirst infusion, then 250 mg/m2 weekly.

Treatment with pembrolizumab continued until RECIST v1.1-defined progression of disease asdetermined by the investigator or unacceptable toxicity. Patients treated with pembrolizumab withoutdisease progression could be treated for up to 24 months. Assessment of tumour status was performedevery 9 weeks. Patients randomised to chemotherapy were offered pembrolizumab at the time ofdisease progression.

A total of 307 patients were enrolled and randomised to pembrolizumab (n=153) or chemotherapy(n=154). The baseline characteristics of these patients were: median age of 63 years (range: 24 to 93),47% age 65 or older; 50% male; 75% White and 16% Asian; 52% and 48% had an ECOGperformance status of 0 or 1, respectively. Mutation status: 25% BRAF V600E, 24% KRAS/NRAS.

For 143 patients treated with chemotherapy, 56% received mFOLFOX6 with or without bevacizumabor cetuximab and 44% received FOLFIRI with or without bevacizumab or cetuximab.

The primary efficacy outcome measures were PFS assessed by BICR according to RECIST v1.1 and

OS. Secondary outcome measures were ORR and response duration. The study demonstrated astatistically significant improvement in PFS (HR 0.60; 95% CI 0.45, 0.80; p-Value 0.0002) forpatients randomised to the pembrolizumab arm compared with chemotherapy at the pre-specified finalanalysis for PFS. There was no statistically significant difference between pembrolizumab andchemotherapy in the final OS analysis in which 60% of the patients who had been randomised toreceive chemotherapy had crossed over to receive subsequent anti-PD-1/PD-L1 therapies includingpembrolizumab. Table 40 summarises the key efficacy measures and Figures 36 and 37 show the

Kaplan-Meier curves for updated PFS and OS based on the final analysis with a median follow-uptime of 38.1 months (range: 0.2 to 58.7 months).

Table 40: Efficacy results in KEYNOTE-177

Endpoint Pembrolizumab Chemotherapy200 mg every 3 weeks n=154n=153

PFS*

Number (%) of patients with event 86 (56%) 117 (76%)

Median in months (95% CI) 16.5 (5.4, 38.1) 8.2 (6.1, 10.2)

Hazard ratio† (95% CI) 0.59 (0.45, 0.79)p-Value‡ 0.0001

OS§

Number (%) of patients with event 62 (41%) 78 (51%)

Median in months (95% CI) NR (49.2, NR) 36.7 (27.6, NR)

Hazard ratio† (95% CI) 0.74 (0.53, 1.03)p-Value§ 0.0359

Objective response rate

ORR % (95% CI) 45% (37.1, 53.3) 33% (25.8, 41.1)

Complete response 13% 4%

Partial response 32% 29%

Response duration

Median in months (range) NR (2.3+, 53.5+) 10.6 (2.8, 48.3+)% with duration ≥ 24 months¶ 84% 34%

* With additional 12 months of follow-up after the pre-specified final analysis for PFS† Based on Cox regression model‡ p-Value is nominal§ Not statistically significant after adjustment for multiplicity¶ Based on Kaplan-Meier estimation

NR = not reached

Figure 36: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-177 (intent to treat population)

Treatment arm PFS rate at 24 months PFS rate at 36 months HR (95% CI) Nominal p-value

Pembrolizumab 48% 42% 0.59 (0.45, 0.79) 0.0001

Chemotherapy 20% 11%

Time in Months

Number at Risk

Pembrolizumab

Chemotherapy

Progression-Free Survival (%)

Figure 37: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-177 (intent to treat population)

Treatment arm OS rate at 24 months OS rate at 36 months HR (95% CI) p-value*

Pembrolizumab 68% 61% 0.74 (0.53, 1.03) 0.0359

Chemotherapy 60% 50%

Time in Months

Number at Risk

Pembrolizumab

Chemotherapy

* Not statistically significant after adjustment for multiplicity

KEYNOTE-164: Open-label study in patients with unresectable or metastatic MSI-H or dMMR CRCwho have received prior therapy

The efficacy of pembrolizumab was investigated in KEYNOTE-164, a multicentre, non-randomised,open-label, multi-cohort Phase II study that enrolled patients with unresectable or metastatic MSI-H ordMMR CRC that progressed following prior fluoropyrimidine-based therapy in combination withirinotecan and/or oxaliplatin.

Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or diseaseprogression. Clinically stable patients with initial evidence of disease progression were permitted toremain on treatment until disease progression was confirmed. Patients without disease progressionwere treated for up to 24 months (up to 35 cycles). Assessment of tumour status was performed every9 weeks.

Among the 124 patients enrolled in KEYNOTE-164, the baseline characteristics were: median age56 years (35% age 65 or older); 56% male; 68% White, 27% Asian; 41% and 59% had an ECOGperformance status of 0 and 1, respectively. Twelve percent of patients had BRAF mutations and 36%had RAS mutations; 39% and 34% were undetermined for BRAF and RAS mutations, respectively.

Ninety-seven percent of the patients had M1 disease and 3% had M0 disease (locally advancedunresectable). Seventy-six percent of patients received 2 or more prior lines of therapy.

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondaryefficacy outcome measures included response duration, PFS, and OS. The median follow-up time inmonths was 37.3 (range: 0.1 to 65.2). Efficacy results are summarised in Table 41.

Overall Survival (%)

Table 41: Efficacy results in KEYNOTE-164

Endpoint n=124

Objective response rate*

ORR % (95% CI) 34% (25.6, 42.9)

Complete response 10%

Partial response 24%

Response duration*

Median in months (range) NR (4.4, 58.5+)% with duration ≥ 36 months# 92%

* Based on patients with a best objective response as confirmed complete orpartial response# Based on Kaplan-Meier estimation+ Denotes there is no progressive disease by the time of last disease assessment

NR = not reached

Objective responses were observed regardless of BRAF or RAS mutation status.

Non-colorectal cancers

KEYNOTE-158: Open-label study in patients with unresectable or metastatic MSI-H or dMMRendometrial, gastric, small intestine, or biliary cancer who have received prior therapy

The efficacy of pembrolizumab was investigated in 355 patients with unresectable or metastatic

MSI-H or dMMR non-CRC solid tumours enrolled in a multicentre, non-randomised, open-label

Phase II study (KEYNOTE-158), including patients with endometrial, gastric, small intestine, orbiliary cancer. MSI or MMR tumour status was determined prospectively using PCR or IHC,respectively.

Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or diseaseprogression. Clinically stable patients with initial evidence of disease progression were permitted toremain on treatment until disease progression was confirmed. Patients without disease progressionwere treated for up to 24 months (up to 35 cycles). Assessment of tumour status was performed every9 weeks through the first year, then every 12 weeks thereafter.

Among the 83 patients with endometrial cancer, the baseline characteristics were: median age of64 years (range: 42 to 86), 46% age 65 or older; 84% White, 6% Asian, and 4% Black; and ECOG PS0 (46%) and 1 (54%). Ninety-eight percent of the patients had M1 disease and 2% had M0 disease.

Forty-seven percent of patients received 2 or more prior lines of therapy.

Among the 51 patients with gastric cancer, the baseline characteristics were: median age 67 years(range: 41 to 89); 57% age 65 or older; 65% male, 63% White, 28% Asian; and ECOG PS 0 (45%)and 1 (55%). All patients had M1 disease. Forty-five percent of patients received 2 or more prior linesof therapy.

Among the 27 patients with small intestinal cancer, the baseline characteristics were: median age58 years (range: 21 to 77); 33% age 65 or older; 63% male, 81% White, 11% Asian; and ECOG PS 0(56%) and 1 (44%). Ninety-six percent of patients had M1 disease and 4% M0 disease. Thirty-sevenpercent of patients received 2 or more prior lines of therapy. All patients had a tumour histology ofadenocarcinoma.

Among the 22 patients with biliary cancer, the baseline characteristics were: median age 61 years(range: 40 to 77); 41% age 65 or older; 73% male, 91% White, 9% Asian; ECOG PS 0 (45%) and 1(55%); and 82% M1 disease and 18% M0 disease. Forty-one percent of patients received 2 or moreprior lines of therapy.

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondaryefficacy outcome measures included response duration, PFS, and OS. The median follow-up time inmonths was 21.9 (range: 1.5 to 64.0) for endometrial, 13.9 (range: 1.1 to 66.9) for gastric, 29.1 (4.2 to67.7) for small intestine, and 19.4 (range: 1.1 to 60.8) for biliary cancer. Efficacy results aresummarised in Table 42.

Table 42: Efficacy results in KEYNOTE-158

Endpoint Endometrial Gastric Small Intestine Biliaryn=83 n=51 n=27 n=22

Objective response rate*

ORR % 51% 37% 56% 41%(95% CI) (39.4, 61.8) (24.1, 51.9) (35.3, 74.5) (20.7, 63.6)

Complete response 16% 14% 15% 14%

Partial response 35% 24% 41% 27%

Response duration*

Median in months (range) NR NR NR 30.6(2.9, 60.4+) (6.2, 63.0+) (3.7+, 57.3+) (6.2, 46.0+)% with duration ≥ 12 months# 85% 90% 93% 89%% with duration ≥ 36 months# 60% 81% 73% 42%

* Based on patients with a best objective response as confirmed complete or partial response# Based on Kaplan-Meier estimation+ Denotes there is no progressive disease by the time of last disease assessment

NR = not reached

KEYNOTE-590: Controlled study of combination therapy in oesophageal carcinoma patients naïve totreatment

The efficacy of pembrolizumab in combination with chemotherapy was investigated in

KEYNOTE-590, a multicentre, randomised, double-blind, placebo-controlled study in patients withlocally advanced unresectable or metastatic oesophageal carcinoma or GEJ carcinoma (Siewert type I).

Patients with active autoimmune disease, a medical condition that required immunosuppression, orknown HER-2 positive GEJ adenocarcinoma patients were ineligible for the study. Randomisationwas stratified by tumour histology (squamous cell carcinoma vs. adenocarcinoma), geographic region(Asia vs. ex-Asia), and ECOG performance status (0 vs. 1).

Patients were randomised (1:1) to one of the following treatment arms:

* Pembrolizumab 200 mg on Day 1 of each three-week cycle in combination withcisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and 5-FU800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per localstandard for 5-FU administration.

* Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IVon Day 1 of each three-week cycle for up to six cycles and 5-FU 800 mg/m2 IV per dayon Day 1 to Day 5 of each three-week cycle, or per local standard for 5-FUadministration.

Treatment with pembrolizumab or chemotherapy continued until unacceptable toxicity or diseaseprogression or a maximum of 24 months. Patients randomised to pembrolizumab were permitted tocontinue beyond the first RECIST v1.1-defined disease progression if clinically stable until the firstradiographic evidence of disease progression was confirmed at least 4 weeks later with repeatimaging. Assessment of tumour status was performed every 9 weeks.

Among the 749 patients in KEYNOTE-590, 383 (51%) had tumours that expressed PD-L1 with a

CPS ≥ 10 based on the PD-L1 IHC 22C3 pharmDxTM Kit. The baseline characteristics of these383 patients were: median age of 63 years (range: 28 to 89), 41% age 65 or older; 82% male;34% White and 56% Asian; 43% and 57% had an ECOG performance status of 0 and 1, respectively.

Ninety-three percent had M1 disease. Seventy-five percent had a tumour histology of squamous cellcarcinoma, and 25% had adenocarcinoma.

The primary efficacy outcome measures were OS and PFS as assessed by the investigator according to

RECIST 1.1 in squamous cell histology, CPS ≥ 10, and in all patients. The study demonstrated astatistically significant improvement in OS and PFS for all pre-specified study populations. In allpatients randomised to pembrolizumab in combination with chemotherapy, compared to chemotherapythe OS HR was 0.73 (95% CI 0.62-0.86) and the PFS HR was 0.65 (95% CI 0.55-0.76). Secondaryefficacy outcome measures were ORR and duration of response, according to RECIST 1.1 as assessedby the investigator. Table 43 summarises key efficacy measures from the pre-specified analysis inpatients whose tumours expressed PD-L1 with a CPS ≥ 10 in KEYNOTE-590 performed at a medianfollow-up time of 13.5 months (range: 0.5 to 32.7 months). The Kaplan-Meier curve for OS and PFSare shown in Figures 38 and 39.

Table 43: Efficacy results for pembrolizumab plus chemotherapy in KEYNOTE-590 with PD-L1expression (CPS ≥ 10)

Endpoint Pembrolizumab Standard

Cisplatin Chemotherapy Treatment*5-FUn=186 n=197

OS

Number (%) of patients with event 124 (66.7%) 165 (83.8%)

Median in months† (95% CI) 13.5 (11.1, 15.6) 9.4 (8.0, 10.7)

Hazard ratio‡ (95% CI) 0.62 (0.49, 0.78)p-Value§ < 0.0001

PFS¶

Number (%) of patients with event 140 (75.3%) 174 (88.3%)

Median in months† (95% CI) 7.5 (6.2, 8.2) 5.5 (4.3, 6.0)

Hazard ratio‡ (95% CI) 0.51 (0.41, 0.65)p-Value§ < 0.0001

Objective response rate¶

ORR§ % (95% CI) 51.1 (43.7, 58.5) 26.9 (20.8, 33.7)

Complete response 5.9% 2.5%

Partial response 45.2% 24.4%p-Value# < 0.0001

Response duration¶,Þ

Median in months (range) 10.4 (1.9, 28.9+) 5.6 (1.5+, 25.0+)% with duration ≥ 6 months† 80.2% 47.7%% with duration ≥ 12 months† 43.7% 23.2%% with duration ≥ 18 months† 33.4% 10.4%

* Cisplatin and 5-FU† Based on Kaplan-Meier estimation‡ Based on the stratified Cox proportional hazard model§ One-sided p-Value based on log-rank test stratified by geographic region (Asia versus Rest of the World) andtumour histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0versus 1)¶ Assessed by investigator using RECIST 1.1# One-sided p-Value for testing. H0: difference in % = 0 versus H1: difference in % > 0

Þ Best objective response as confirmed complete response or partial response

A total of 32 patients aged ≥ 75 years for PD-L1 CPS ≥ 10 were enrolled in KEYNOTE-590 (18 in thepembrolizumab combination and 14 in the control). Data about efficacy of pembrolizumab incombination with chemotherapy are too limited in this patient population.

Figure 38: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-590 with PD-L1 expression (CPS ≥ 10)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab+SOC 54% 31% 0.62 (0.49, 0.78) <0.0001

SOC 37% 15%

Time in Months

Number at Risk

Pembrolizumab+SOC

SOC

Overall Survival (%)

Figure 39: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-590 with PD-L1 expression (CPS ≥ 10)

Treatment arm PFS rate at 12 months PFS rate at 18 months HR (95% CI) p-value

Pembrolizumab+SOC 30% 21% 0.51 (0.41, 0.65) <0.0001

SOC 9% 5%

Time in Months

Number at Risk

Pembrolizumab+SOC

SOC

KEYNOTE-522: Controlled study of neoadjuvant and adjuvant therapy in patients with locallyadvanced, inflammatory, or early-stage triple-negative breast cancer at high risk of recurrence

The efficacy of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and thencontinued as monotherapy as adjuvant treatment after surgery was investigated in the randomised,double-blind, multicentre, placebo-controlled study KEYNOTE-522. If indicated, patients receivedadjuvant radiation therapy prior to or concurrent with adjuvant pembrolizumab or placebo. The keyeligibility criteria for this study were locally advanced, inflammatory, or early-stage TNBC at highrisk of recurrence (tumour size > 1 cm but ≤ 2 cm in diameter with nodal involvement or tumoursize > 2 cm in diameter regardless of nodal involvement), regardless of tumour PD-L1 expression.

Patients with active autoimmune disease that required systemic therapy within 2 years of treatment ora medical condition that required immunosuppression were ineligible for the study. Randomisationwas stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice ofcarboplatin (dosed every 3 weeks vs. weekly). Patients were randomised (2:1) to receive eitherpembrolizumab or placebo via intravenous infusion:

o Four cycles of neoadjuvant pembrolizumab 200 mg every 3 weeks or placebo on Day 1of cycles 1-4 of treatment regimen in combination with:

▪ Carboplatin

* AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatmentregimen

Progression-Free Survival (%)or AUC 1.5 mg/mL/min every week on Day 1, 8, and 15 of cycles 1-4 oftreatment regimen and▪ Paclitaxel 80 mg/m2 every week on Day 1, 8, and 15 of cycles 1-4 of treatmentregimeno Followed by four additional cycles of neoadjuvant pembrolizumab 200 mg every3 weeks or placebo on Day 1 of cycles 5-8 of treatment regimen in combination with:

▪ Doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks on Day 1 ofcycles 5-8 of treatment regimen and▪ Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatmentregimeno Following surgery, 9 cycles of adjuvant pembrolizumab 200 mg every 3 weeks orplacebo were administered.

Treatment with pembrolizumab or placebo continued until completion of the treatment (17 cycles),disease progression that precludes definitive surgery, disease recurrence in the adjuvant phase, orunacceptable toxicity.

A total of 1 174 patients were randomised. The study population characteristics were: median age of49 years (range: 22 to 80); 11% age 65 or older; 99.9% female; 64% White; 20% Asian, 5% Black,and 2% American Indian or Alaska Native; ECOG performance status of 0 (87%) and 1 (13%);56% were pre-menopausal status and 44% were post-menopausal status; 7% were primary

Tumour 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1,11% N2, and 0.2% N3; 1.4% of patients had inflammatory breast cancer; 75% of patients were overall

Stage II and 25% were Stage III.

The dual primary efficacy outcome measures were pCR rate and EFS. pCR was defined as absence ofinvasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded localpathologist at the time of definitive surgery. EFS was defined as the time from randomisation to thefirst occurrence of any of the following events: progression of disease that precludes definitivesurgery, local or distant recurrence, second primary malignancy, or death due to any cause. Asecondary efficacy outcome measure was OS.

The study demonstrated a statistically significant improvement in pCR rate difference at itspre-specified primary analysis (n=602), the pCR rates were 64.8% (95% CI: 59.9%, 69.5%) in thepembrolizumab arm and 51.2 % (95% CI: 44.1%, 58.3%) in the placebo arm, with a treatmentdifference of 13.6 % (95% CI: 5.4%, 21.8%; p-Value 0.00055). The study also demonstrated astatistically significant improvement in EFS at its pre-specified interim analysis (median follow-uptime for all patients of 37.8 months (range: 2.7-48.0 months), HR=0.63 (95% CI: 0.48, 0.82;p-Value 0.00031)). At a median follow-up time for all patientsof 73.1 months (range: 2.7-83.9 months), the study also demonstrated a statistically significantimprovement in OS.

Results reported from the pre-specified pCR final analysis (n=1002) and key efficacy measures fromthe EFS and OS pre-specified interim analysis at median follow-up time for all patients of73.1 months (range: 2.7-83.9 months) are summarised in Table 44. The Kaplan-Meier curves for EFSand OS are shown in Figures 40 and 41.

Table 44: Efficacy results in KEYNOTE-522

Endpoint Pembrolizumab with Placebo with

Chemotherapy/Pembrolizumab Chemotherapy/PlacebopCR (ypT0/Tis ypN0)* n=669 n=333

Number of patients with pCR 428 182pCR Rate (%) (95% CI) 64.0 (60.2, 67.6) 54.7 (49.1, 60.1)

Treatment difference (%) 9.2 (2.8, 15.6)estimate (95% CI)†p-Value‡ 0.00221

EFS n=784 n=390

Number (%) of patients with 123 (15.7%) 93 (23.8%)event

Hazard ratio (95% CI)¶ 0.65 (0.51, 0.83)

OSÞ n=784 n=390

Number (%) of patients with 115 (14.7%) 85 (21.8%)event

Hazard ratio (95% CI)¶ 0.66 (0.50, 0.87)p-Value# 0.00150

* Based on a pre-specified pCR final analysis (compared to a significance level of 0.0028)† Based on Miettinen and Nurminen method stratified by nodal status, tumour size, and choice of carboplatin‡ One-sided p-Value for testing. H0: difference in % = 0 versus H1: difference in % > 0¶ Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by nodalstatus, tumour size, and choice of carboplatin

Þ Based on a pre-specified OS interim analysis (compared to a significance level of 0.00503)#

One-sided p-Value based on log-rank test stratified by nodal status, tumour size, and choice of carboplatin

Figure 40: Kaplan-Meier curve for event-free survival by treatment arm in

KEYNOTE-522 (intent to treat population)

Treatment arm EFS Rate at 36 months EFS Rate at 60 months HR (95% CI)

Pembrolizumab + Chemo/Pembrolizumab 85% 81% 0.65 (0.51, 0.83)

Placebo + Chemo/Placebo 76% 72%

Time in Months

Number at Risk

Pembrolizumab + Chemo/Pembrolizumab

Placebo + Chemo/Placebo

Event-Free Survival (%)

Figure 41: Kaplan-Meier curve for overall survival by treatment arm in

KEYNOTE-522 (intent to treat population)

Treatment arm OS Rate at 36 months OS Rate at 60 months HR (95% CI) p-Value

Pembrolizumab + Chemo/Pembrolizumab 90% 87% 0.66 (0.50, 0.87) 0.00150

Placebo + Chemo/Placebo 87% 82%

Time in Months

Number at Risk

Pembrolizumab + Chemo/Pembrolizumab

Placebo + Chemo/Placebo

KEYNOTE-355: Controlled study of combination therapy in TNBC patients previously untreated formetastatic disease

The efficacy of pembrolizumab in combination with paclitaxel, nab-paclitaxel, or gemcitabine andcarboplatin was investigated in KEYNOTE-355, a randomised, double-blind, multicentre,placebo-controlled study. Key eligibility criteria were locally recurrent unresectable or metastatic

TNBC, regardless of tumour PD-L1 expression, not previously treated with chemotherapy in theadvanced setting. Patients with active autoimmune disease that required systemic therapy within2 years of treatment or a medical condition that required immunosuppression were ineligible.

Randomisation was stratified by chemotherapy treatment (paclitaxel or nab-paclitaxel vs. gemcitabineand carboplatin), tumour PD-L1 expression (CPS ≥ 1 vs. CPS < 1), and prior treatment with the sameclass of chemotherapy in the neoadjuvant setting (yes vs. no). Patients were randomised (2:1) to one ofthe following treatment arms via intravenous infusion:

* Pembrolizumab 200 mg on Day 1 every 3 weeks in combination with nab-paclitaxel100 mg/m2 on Days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on Days 1, 8,and 15 every 28 days, or gemcitabine 1 000 mg/m2 and carboplatin AUC 2 mg/mL/minon Days 1 and 8 every 21 days.

* Placebo on Day 1 every 3 weeks in combination with nab-paclitaxel 100 mg/m2 on

Days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on Days 1, 8, and 15 every

Overall Survival (%)28 days, or gemcitabine 1 000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1and 8 every 21 days.

Treatment with pembrolizumab or placebo, both in combination with chemotherapy, continued until

RECIST 1.1-defined progression of disease as determined by the investigator, unacceptable toxicity,or a maximum of 24 months. Chemotherapy could continue per standard of care. Administration ofpembrolizumab was permitted beyond RECIST-defined disease progression if the patient wasclinically stable and deriving clinical benefit as determined by the investigator. Assessment of tumourstatus was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeksthereafter.

Among the 847 patients randomised in KEYNOTE-355, 636 (75%) had tumours that expressed PD-L1with a CPS ≥ 1 and 323 (38%) had tumour PD-L1 expression CPS ≥ 10 based on the PD-L1

IHC 22C3 pharmDxTM Kit. The baseline characteristics of the 323 patients with tumour PD-L1expression CPS ≥ 10 included: median age of 53 years (range: 22 to 83); 20% age 65 or older;100% female; 69% White, 20% Asian, and 5% Black; ECOG performance status of 0 (61%) and1 (39%); 67% were post-menopausal status; 3% had a history of brain metastases; and 20% haddisease-free interval of < 12 months.

The dual primary efficacy outcome measures were PFS as assessed by BICR using RECIST 1.1 and

OS. Secondary efficacy outcome measures were ORR and response duration as assessed by BICRusing RECIST 1.1. The study demonstrated a statistically significant improvement in PFS at itspre-specified interim analysis (HR 0.65; 95% CI 0.49, 0.86; p-Value 0.0012) and OS at final analysisfor patients with tumour PD-L1 expression CPS ≥ 10 randomised to the pembrolizumab incombination with chemotherapy arm compared with placebo in combination with chemotherapy.

Table 45 summarises key efficacy measures and Figures 42 and 43 show the Kaplan-Meier curves for

PFS and OS based on the final analysis with a median follow-up time of 20.2 months (range: 0.3 to53.1 months) for patients with tumour PD-L1 expression CPS ≥ 10.

Table 45: Efficacy results in KEYNOTE-355 patients with CPS ≥ 10

Endpoint Pembrolizumab Placebowith chemotherapy* with chemotherapy*n=220 n=103

PFS†

Number (%) of patients with 144 (65%) 81 (79%)event

Hazard ratio‡ (95% CI) 0.66 (0.50, 0.88)p-Value§ 0.0018

Median in months (95% CI) 9.7 (7.6, 11.3) 5.6 (5.3, 7.5)

OS

Number (%) of patients with 155 (70%) 84 (82%)event

Hazard ratio‡ (95% CI) 0.73 (0.55, 0.95)p-Value¶ 0.0093

Median in months (95% CI) 23.0 (19.0, 26.3) 16.1 (12.6, 18.8)

Objective response rate†

ORR % (95% CI) 53% (46, 59) 41% (31, 51)

Complete response 17% 14%

Partial response 35% 27%

Response duration†

Median in months (range) 12.8 (1.6+, 45.9+) 7.3 (1.5, 46.6+)% with duration ≥ 6 months# 82% 60%% with duration ≥ 12 months# 56% 38%

* Chemotherapy: paclitaxel, nab-paclitaxel, or gemcitabine and carboplatin† Assessed by BICR using RECIST 1.1‡ Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratifiedby chemotherapy on study (taxane vs. gemcitabine and carboplatin) and prior treatment with same class ofchemotherapy in the neoadjuvant setting (yes vs. no)§ Nominal p-Value based on log-rank test stratified by chemotherapy on study (taxane vs. gemcitabine andcarboplatin) and prior treatment with same class of chemotherapy in the neoadjuvant setting (yes vs. no). Atthe pre-specified interim analysis of PFS (median follow-up time of 19.2 months), statistically significantsuperiority was achieved for PFS comparing pembrolizumab/chemotherapy with placebo/chemotherapy p-

Value 0.0012¶ One-sided p-Value based on log-rank test stratified by chemotherapy on study (taxane vs. gemcitabine andcarboplatin) and prior treatment with same class of chemotherapy in the neoadjuvant setting (yes vs. no). OSresults met the pre-specified efficacy boundary of 0.0113 for statistical significance# From product-limit (Kaplan-Meier) method for censored data+ Denotes there is no progressive disease by the time of last disease assessment

Figure 42: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-355 patients with PD-L1 expression (CPS ≥ 10)

Treatment arm PFS rate at 12 months HR (95% CI) p-value

Pembrolizumab + Chemotherapy 39% 0.66 (0.50, 0.88) 0.0018

Placebo + Chemotherapy 23%

Time in Months

Number at Risk

Pembrolizumab + Chemotherapy

Placebo + Chemotherapy

Progression-Free Survival (%)

Figure 43: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-355patients with PD-L1 expression (CPS ≥ 10)

Treatment arm OS rate at 24 months HR (95% CI) p-value

Pembrolizumab + Chemotherapy 48% 0.73 (0.55, 0.95) 0.0093

Placebo + Chemotherapy 34%

Time in Months

Number at Risk

Pembrolizumab + Chemotherapy

Placebo + Chemotherapy

KEYNOTE-868 (NRG-GY018): Controlled study of combination therapy for treatment of patients withprimary advanced or recurrent EC

The efficacy of pembrolizumab in combination with paclitaxel and carboplatin was investigated in

KEYNOTE-868 (NRG-GY018), a randomised, multicentre, double-blind, placebo-controlled study in810 patients with advanced or recurrent endometrial carcinoma including those with dMMR andpMMR tumours. Patients had not received prior systemic therapy or had received prior chemotherapyin the adjuvant setting. Patients who had received prior adjuvant chemotherapy were eligible if theirchemotherapy-free interval was at least 12 months. Patients with endometrial sarcoma, includingcarcinosarcoma or patients with active autoimmune disease or a medical condition that requiredimmunosuppression were ineligible. Randomisation was stratified according to MMR status, ECOG

PS (0 or 1 vs. 2), and prior adjuvant chemotherapy. Patients were randomised (1:1) to one of thefollowing treatment arms:

* Pembrolizumab 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC5 mg/mL/min for 6 cycles, followed by pembrolizumab 400 mg every 6 weeks for upto 14 cycles.

* Placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for6 cycles, followed by placebo every 6 weeks for up to 14 cycles.

Overall Survival (%)

All study medications were administered as an intravenous infusion on Day 1 of each treatment cycle.

Treatment continued until disease progression, unacceptable toxicity or a maximum of 20 cycles (upto approximately 24 months). Patients with measurable disease who had RECIST-defined stabledisease or partial response at the completion of cycle 6 were permitted to continue receiving paclitaxeland carboplatin with pembrolizumab or placebo for up to 10 cycles as determined by the investigator.

Assessment of tumour status was performed every 9 weeks for the first 9 months and then every12 weeks thereafter.

Among the 810 randomised patients, 222 (27%) had dMMR tumour status and 588 (73%) had pMMRtumour status.

The dMMR population characteristics were: median age of 66 years (range: 37 to 86), 55% age 65 orolder; 79% White, 9% Black and 3% Asian; 5% Hispanic or Latino; 64% ECOG PS of 0, 33% ECOG

PS of 1 and 3% ECOG PS of 2; 61% had recurrent disease and 39% had primary or persistent disease;5% received prior adjuvant chemotherapy and 43% received prior radiotherapy. The histologicsubtypes were endometrioid carcinoma (24% grade 1, 43% grade 2, and 14% grade 3),adenocarcinoma Not Otherwise Specified (NOS) (11%), and other (8% includingdedifferentiated/undifferentiated, serous and mixed epithelial).

The pMMR population characteristics were: median age of 66 years (range: 29 to 94), 54% age 65 orolder; 72% White, 16% Black, and 5% Asian; 6% Hispanic or Latino; 67% ECOG PS of 0, 30%

ECOG PS of 1 and 3% ECOG PS of 2; 56% had recurrent disease and 44% had primary or persistentdisease; 26% received prior adjuvant chemotherapy and 41% received prior radiotherapy. Thehistologic subtypes were endometrioid carcinoma (17% grade 1, 19% grade 2, and 16% grade 3),serous (26%), adenocarcinoma NOS (10%), clear cell carcinoma (7%), and other (5% including mixedepithelial and dedifferentiated/undifferentiated).

The primary efficacy outcome measure was PFS as assessed by the investigator according to RECIST1.1 in the dMMR and pMMR populations. Secondary efficacy outcome measures included OS, ORRand response duration in the dMMR and pMMR populations. The study demonstrated statisticallysignificant improvements in PFS for patients randomised to pembrolizumab in combination withchemotherapy compared to placebo in combination with chemotherapy in both the dMMR and pMMRpopulations. The median follow-up time was 13.6 months (range: 0.6 to 39.4 months) and 8.7 months(range: 0.1 to 37.2 months) in the dMMR and pMMR populations, respectively. OS endpoint was notformally assessed within multiplicity control. OS results were not mature. Efficacy results by MMRstatus are summarised in Table 46. The Kaplan-Meier curves for PFS by MMR status are shown in

Figures 44 and 45, respectively.

Table 46: Efficacy results in KEYNOTE-868 (NRG-GY018)

Endpoint dMMR Population pMMR Population

Pembrolizumab Placebo Pembrolizumab Placebowith with with withchemotherapy* chemotherapy* chemotherapy* chemotherapy*n=110 n=112 n=294 n=294

PFS

Number (%) of 29 (26%) 60 (54%) 95 (32%) 138 (47%)patients with event

Median in months NR 8.3 13.1 8.7(95% CI) (30.7, NR) (6.5, 12.3) (10.6, 19.5) (8.4, 11.0)

Hazard ratio† (95% CI) 0.34 (0.22, 0.53) 0.57 (0.44, 0.74)p-Value‡ < 0.0001 < 0.0001

OS

Number (%) of 10 (9%) 17 (15%) 45 (15%) 54 (18%)patients with event

Median in months NR NR 28.0 27.4(95% CI) (NR, NR) (NR, NR) (21.4, NR) (19.5, NR)

Hazard ratio† (95% CI) 0.55 (0.25, 1.19) 0.79 (0.53, 1.17)

Objective response rate

Number of participants n=95 n=95 n=220 n=235with measurabledisease at baseline

ORR¶ % (95% CI) 78% (68, 86) 69% (59, 79) 61% (55, 68) 51% (45, 58)

Response duration

Median in months NR 4.4 7.1 6.4(range) (0.0+, 33.0+) (0.0+, 32.8+) (0.0+, 32.8+) (0.0+, 20.1+)

* Chemotherapy (paclitaxel and carboplatin)† Based on the stratified Cox proportional hazard model‡ One-sided p-value based on stratified log-rank test (compared to an alpha boundary of 0.00207 for dMMR and 0.00116for pMMR)¶ Response: Best objective response as confirmed complete response or partial response

NR = not reached

Figure 44: Kaplan-Meier curve for progression-free survivalin KEYNOTE-868 (NRG-GY018) in dMMR population

Treatment arm HR (95% CI)

Pembrolizumab + Chemotherapy 0.34 (0.22, 0.53)

Chemotherapy

Time in Months

Number at Risk

Pembrolizumab + Chemotherapy

Chemotherapy

Progression-Free Survival (%)

Figure 45: Kaplan-Meier curve for progression-free survivalin KEYNOTE-868 (NRG-GY018) in pMMR population

Treatment arm HR (95% CI)

Pembrolizumab + Chemotherapy 0.57 (0.44, 0.74)

Chemotherapy

Time in Months

Number at Risk

Pembrolizumab + Chemotherapy

Chemotherapy

KEYNOTE-775: Controlled study of combination therapy in advanced EC patients previously treatedwith systemic chemotherapy

The efficacy of pembrolizumab in combination with lenvatinib was investigated in KEYNOTE-775, arandomised, multicentre, open-label, active-controlled study conducted in patients with advanced ECwho had been previously treated with at least one prior platinum-based chemotherapy regimen in anysetting, including in the neoadjuvant and adjuvant settings. Participants may have received up to2 platinum-containing therapies in total, as long as one was given in the neoadjuvant or adjuvanttreatment setting. The study excluded patients with endometrial sarcoma, carcinosarcoma, pre-existing

Grade ≥ 3 fistula, uncontrolled BP (> 150/90 mmHg), significant cardiovascular impairment or eventwithin previous 12 months, or patients who had active autoimmune disease or a medical condition thatrequired immunosuppression. Randomisation was stratified by MMR status (dMMR or pMMR[mismatch repair proficient]) using a validated IHC test. The pMMR stratum was further stratified by

ECOG performance status, geographic region, and history of pelvic radiation. Patients wererandomised (1:1) to one of the following treatment arms:

* pembrolizumab 200 mg intravenously every 3 weeks in combination with lenvatinib20 mg orally once daily.

* investigator’s choice consisting of either doxorubicin 60 mg/m2 every 3 weeks, orpaclitaxel 80 mg/m2 weekly, 3 weeks on/1 week off.

Treatment with pembrolizumab and lenvatinib continued until RECIST v1.1-defined progression ofdisease as verified by BICR, unacceptable toxicity, or for pembrolizumab, a maximum of 24 months.

Progression-Free Survival (%)

Administration of study treatment was permitted beyond RECIST-defined disease progression if thetreating investigator considered the patient to be deriving clinical benefit and the treatment wastolerated. A total of 121/411 (29%) of the pembrolizumab and lenvatinib-treated patients receivedcontinued study therapy beyond RECIST-defined disease progression. The median duration of thepost-progression therapy was 2.8 months. Assessment of tumour status was performed every 8 weeks.

A total of 827 patients were enrolled and randomised to pembrolizumab in combination withlenvatinib (n=411) or investigator’s choice of doxorubicin (n=306) or paclitaxel (n=110). The baselinecharacteristics of these patients were: median age of 65 years (range: 30 to 86), 50% age 65 or older;61% White, 21% Asian, and 4% Black; ECOG PS of 0 (59%) or 1 (41%), and 84% with pMMRtumour status and 16% with dMMR tumour status. The histologic subtypes were endometrioidcarcinoma (60%), serous (26%), clear cell carcinoma (6%), mixed (5%), and other (3%). All 827 ofthese patients received prior systemic therapy for EC: 69% had one, 28% had two, and 3% had threeor more prior systemic therapies. 37% of patients received only prior neoadjuvant or adjuvant therapy.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1).

Secondary efficacy outcome measures included ORR, as assessed by BICR using RECIST 1.1. At thepre-specified interim analysis, with a median follow-up time of 11.4 months (range: 0.3 to26.9 months), the study demonstrated a statistically significant improvement in OS and PFS. The pre-specified final OS analysis with approximately 16 months of additional follow-up duration from theinterim analysis (overall median follow-up time of 14.7 months [range: 0.3 to 43.0 months]) wasperformed without multiplicity adjustment. Efficacy results by MMR subgroups were consistent withoverall study results. PFS, ORR and response duration results at the interim analysis and OS results atfinal analysis are summarised in Table 47. Kaplan-Meier curves for final OS and interim PFS analysesare shown in Figures 46 and 47, respectively.

Table 47: Efficacy results in KEYNOTE-775

Endpoint Pembrolizumab Chemotherapy*200 mg every 3 weeks

Lenvatinibn=411 n=416

OS

Number (%) of patients with 276 (67%) 329 (79%)event

Median in months (95% CI) 18.7 (15.6, 21.3) 11.9 (10.7, 13.3)

Hazard ratio† (95% CI) 0.65 (0.55, 0.77)p-ValueÞ < 0.0001

PFSß

Number (%) of patients 281 (68%) 286 (69%)with event

Median in months (95% CI) 7.2 (5.7, 7.6) 3.8 (3.6, 4.2)

Hazard ratio† (95% CI) 0.56 (0.47, 0.66)p-Value‡ < 0.0001

Objective response rateß

ORR§ % (95% CI) 32% (27, 37) 15% (11, 18)

Complete response 7% 3%

Partial response 25% 12%p-Value¶ < 0.0001

Response durationß

Median in months# (range) 14.4 (1.6+, 23.7+) 5.7 (0.0+, 24.2+)

* Doxorubicin or Paclitaxel† Based on the stratified Cox regression model

Þ One-sided nominal p-Value for final analysis based on stratified log-rank test. At the pre-specified interim analysis of OS with a median follow-up time of 11.4 months (range: 0.3to 26.9 months), statistically significant superiority was achieved for OS comparing thecombination of pembrolizumab and lenvatinib with chemotherapy (HR: 0.62 [95% CI:0.51, 0.75] p-Value < 0.0001)ß At pre-specified interim analysis‡ One-sided p-Value based on stratified log-rank test§ Response: Best objective response as confirmed complete response or partial response¶ Based on Miettinen and Nurminen method stratified by MMR Status, ECOG performancestatus, geographic region, and history of pelvic radiation# Based on Kaplan-Meier estimation

Figure 46: Kaplan-Meier curve for overall survival by treatment armin KEYNOTE-775 (intent to treat population)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) nominal p-value

Pembrolizumab + Lenvatinib 63% 41% 0.65 (0.55, 0.77) <0.0001

Chemotherapy 49% 23%

Time in Months

Number at Risk

Pembrolizumab + Lenvatinib

Chemotherapy

Overall Survival (%)

Figure 47: Kaplan-Meier curve for progression free-survival by treatment armin KEYNOTE-775 (intent to treat population)

Treatment arm PFS rate at 6 months PFS rate at 12 months HR (95% CI) p-value

Pembrolizumab + Lenvatinib 54% 31% 0.56 (0.47, 0.66) <0.0001

Chemotherapy 34% 13%

Time in Months

Number at Risk

Pembrolizumab + Lenvatinib:

Chemothe rapy:

Cervical cancer

KEYNOTE-A18: Controlled study of combination therapy with CRT in patients with locally advancedcervical cancer

The efficacy of pembrolizumab in combination with cisplatin and external beam radiation therapy(EBRT) followed by brachytherapy (BT) was investigated in KEYNOTE-A18, a multicentre,randomised, double-blind, placebo-controlled study that enrolled 1 060 patients with locally advancedcervical cancer who had not previously received any definitive surgery, radiation, or systemic therapyfor cervical cancer. There were 601 patients with FIGO (International Federation of Gynaecology and

Obstetrics) 2014 Stage III - IVA (tumour involvement of the lower vagina with or without extensiononto pelvic sidewall or hydronephrosis/non-functioning kidney or has spread to adjacent pelvicorgans) with either node-positive or node-negative disease and 459 patients with FIGO 2014

Stage IB2 - IIB (tumour lesions >4 cm or clinically visible lesions that have spread beyond the uterusbut have not extended onto the pelvic wall or to the lower third of vagina) with node-positive disease.

Patients with autoimmune disease that required systemic therapy within 2 years of treatment or amedical condition that required immunosuppression were ineligible. Randomisation was stratified byplanned type of EBRT (Intensity-modulated radiation therapy [IMRT] or volumetric modulated arctherapy [VMAT] vs. non-IMRT and non-VMAT), stage at screening of cervical cancer (FIGO 2014

Stage IB2 - IIB vs. Stage III - IVA) and planned total radiotherapy dose ([EBRT + BT dose] of< 70 Gy vs. ≥ 70 Gy as per equivalent dose [EQD2]). Patients were randomised (1:1) to one of the twotreatment arms:

* Pembrolizumab 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2

IV weekly (5 cycles, an optional sixth infusion could be administered per local practice)and radiotherapy (EBRT followed by BT), followed by pembrolizumab 400 mg IV every6 weeks (15 cycles).

Progression-Free Survival (%)

* Placebo IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly(5 cycles, an optional sixth infusion could be administered per local practice) andradiotherapy (EBRT followed by BT), followed by placebo IV every 6 weeks (15 cycles).

Treatment continued until RECIST v1.1-defined progression of disease as determined by theinvestigator or unacceptable toxicity. Assessment of tumour status was performed every 12 weeks forthe first two years, every 24 weeks in year 3, and then annually.

Among the 601 patients with FIGO 2014 Stage III - IVA disease enrolled in KEYNOTE-A18, thebaseline characteristics were: median age of 51 years (range: 22 to 87), 16% age 65 or older;36% White, 1% Black, 34% Asian, 38% Hispanic or Latino; 68% ECOG performance status of 0 and32% ECOG performance status of 1; 93% with CPS ≥ 1; 71% had positive pelvic and/or positivepara-aortic lymph node(s), 29% had neither positive pelvic nor para-aortic lymph node, 86% IMRT or

VMAT EBRT, 90% ≥ 70 Gy (EQD2). Eighty-four percent had squamous cell carcinoma and 16% hadnon-squamous histology.

The primary efficacy outcomes were PFS (as assessed by investigator according to RECIST v1.1 orhistopathologic confirmation) and OS. The study demonstrated statistically significant improvementsin PFS [0.70 (95% CI 0.55, 0.89; p-Value 0.0020)] from the first pre-specified interim analysis and

OS [0.67 (95% CI 0.50, 0.90; p-Value 0.0040)] from the second pre-specified interim analysis in theoverall population for patients randomised to pembrolizumab with CRT compared to placebo with

CRT. Table 48 summarises key efficacy measures from the second pre-specified interim analysis inpatients with FIGO 2014 Stage III - IVA disease with median follow-up time of 26.6 months(range: 0.9 to 41.7 months). The Kaplan-Meier curves in patients with FIGO 2014 Stage III - IVAdisease for OS and PFS based on this analysis are shown in Figures 48 and 49, respectively.

Table 48: Efficacy results in KEYNOTE-A18 for patients with FIGO 2014 Stage III - IVAcervical cancer

Endpoint Pembrolizumab Placebo200 mg every 3 weeksand 400 mg every6 weeks with CRT with CRTn=296 n=305

OS

Number (%) of patients with event 43 (15%) 73 (24%)

Median in months (95% CI) NR (NR, NR) NR (NR, NR)

Hazard ratio* (95% CI) 0.57 (0.39, 0.83)

PFS by investigator

Number (%) of patients with event 79 (27%) 125 (41%)

Median in months (95% CI) NR (NR, NR) NR (26.3, NR)

Hazard ratio* (95% CI) 0.57 (0.43, 0.76)

* Based on the unstratified Cox proportional hazard model

CRT = Chemoradiotherapy

NR = not reached

Figure 48: Kaplan-Meier curve for overall survival by treatment armin KEYNOTE-A18 for patients with FIGO 2014 Stage III - IVA cervical cancer

Treatment arm HR (95% CI)

Pembrolizumab + CRT 0.57 (0.39, 0.83)

CRT

Time in Months

Number at Risk

Pembrolizumab + CRT

CRT

Overall Survival (%)

Figure 49: Kaplan-Meier curve for progression-free survival by treatment armin KEYNOTE-A18 for patients with FIGO 2014 Stage III - IVA cervical cancer

Treatment arm HR (95% CI)

Pembrolizumab + CRT 0.57 (0.43, 0.76)

CRT

Time in Months

Number at Risk

Pembrolizumab + CRT

CRT

KEYNOTE-826: Controlled study of combination therapy in patients with persistent, recurrent, ormetastatic cervical cancer

The efficacy of pembrolizumab in combination with paclitaxel and cisplatin or paclitaxel andcarboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicentre,randomised, double-blind, placebo-controlled study that enrolled 617 patients with persistent,recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy exceptwhen used concurrently as a radio-sensitising agent. Patients were enrolled regardless of tumour

PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within2 years of treatment or a medical condition that required immunosuppression were ineligible.

Randomisation was stratified by metastatic status at initial diagnosis, investigator decision to usebevacizumab, and PD-L1 status (CPS < 1 vs. CPS 1 to < 10 vs. CPS ≥ 10). Patients were randomised(1:1) to one of the two treatment groups:

* Treatment Group 1: Pembrolizumab 200 mg plus chemotherapy with or withoutbevacizumab

* Treatment Group 2: Placebo plus chemotherapy with or without bevacizumab

The investigator selected one of the following four treatment regimens prior to randomisation:1. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m22. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg3. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min4. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg

Progression-Free Survival (%)

All study medications were administered as an intravenous infusion. All study treatments wereadministered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 ofeach 3-week treatment cycle. The option to use bevacizumab was by investigator choice prior torandomisation. Treatment with pembrolizumab continued until RECIST v1.1-defined progression ofdisease, unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab waspermitted beyond RECIST-defined disease progression if the patient was clinically stable andconsidered to be deriving clinical benefit by the investigator. Assessment of tumour status wasperformed at Week 9 and then every 9 weeks for the first year, followed by every 12 weeks thereafter.

Of the 617 enrolled patients, 548 patients (89%) had tumours expressing PD-L1with a CPS ≥ 1 basedon the PD-L1 IHC 22C3 pharmDxTM Kit. Among these 548 enrolled patients with tumours expressing

PD-L1, 273 patients were randomised to pembrolizumab in combination with chemotherapy with orwithout bevacizumab, and 275 patients were randomised to placebo in combination withchemotherapy with or without bevacizumab. The baseline characteristics of these 548 patients were:median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, and 1% Black;37% Hispanic or Latino; 56% and 43% ECOG performance status of 0 or 1, respectively; 63%received bevacizumab as study treatment; 21% with adenocarcinoma and 5% with adenosquamoushistology; for patients with persistent or recurrent disease with or without distant metastases, 39% hadreceived prior chemoradiation only and 17% had received prior chemoradiation plus surgery.

The primary efficacy outcome measures were OS and PFS as assessed by investigator according to

RECIST v1.1. Secondary efficacy outcome measures were ORR and duration of response, accordingto RECIST v1.1, as assessed by investigator. At a pre-specified interim analysis, the studydemonstrated statistically significant improvements in OS (HR 0.64; 95% CI 0.50, 0.81;p-Value = 0.0001) and PFS (HR 0.62; 95% CI 0.50, 0.77; p-Value < 0.0001) for patients whosetumours expressed PD-L1 with a CPS ≥ 1 randomised to pembrolizumab in combination withchemotherapy with or without bevacizumab compared to placebo in combination with chemotherapywith or without bevacizumab. The study also demonstrated statistically significant improvements in

OS and PFS in the overall population. Table 49 summarises key efficacy measures for patients whosetumours expressed PD-L1 with a CPS ≥ 1 in KEYNOTE-826 at the final analysis with a medianduration of follow-up of 21.3 months. The Kaplan-Meier curves for OS and PFS based on the finalanalysis are shown in Figures 50 and 51.

Table 49: Efficacy results in KEYNOTE-826 for patients with PD-L1 expression (CPS ≥ 1)

Endpoint Pembrolizumab Placebo200 mg every 3 weeks plus Chemotherapy* with orplus Chemotherapy* with without bevacizumabor without bevacizumabn=273 n=275

OS

Number (%) of patients with event 153 (56%) 201 (73%)

Median in months (95% CI) 28.6 (22.1, 38.0) 16.5 (14.5, 20.0)

Hazard ratio† (95% CI) 0.60 (0.49, 0.74)p-Value‡ < 0.0001

PFS

Number (%) of patients with event 171 (63%) 220 (80%)

Median in months (95% CI) 10.5 (9.7, 12.3) 8.2 (6.3, 8.5)

Hazard ratio† (95% CI) 0.58 (0.47, 0.71)p-Value‡ < 0.0001

Objective response rate

ORR¶ % (95% CI) 69% (63, 74) 51% (45, 57)

Complete response 26% 15%

Partial response 43% 36%

Response duration

Median in months (range) 19.2 (1.3+, 40.9+) 10.4 (1.5+, 40.7+)% with duration ≥ 12 months# 56 45% with duration ≥ 24 months# 48 30

* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)† Based on the stratified Cox proportional hazard model‡ Nominal p-Value based on stratified log-rank test¶ Response: Best objective response as confirmed complete response or partial response# Based on Kaplan-Meier estimation

Figure 50: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-826patients with PD-L1 expression (CPS ≥ 1)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab+Chemotherapy* 76% 54% 0.60 (0.49, 0.74) <0.0001

Chemotherapy* 63% 39%

Time in Months

Number at Risk

Pembrolizumab+Chemotherapy*

Chemotherapy*

* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab

Overall Survival (%)

Figure 51: Kaplan-Meier curve for progression free survival by treatment arm in

KEYNOTE-826 patients with PD-L1 expression (CPS ≥ 1)

Treatment arm PFS rate at 12 months PFS rate at 24 months HR (95% CI) p-value

Pembrolizumab+Chemotherapy* 46% 36% 0.58 (0.47, 0.71) <0.0001

Chemotherapy* 34% 19%

Time in Months

Number at Risk

Pembrolizumab+Chemotherapy*

Chemotherapy*

* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab

Gastric or gastro-oesophageal junction (GEJ) adenocarcinoma

KEYNOTE-811: Controlled study of combination therapy in locally advanced unresectable ormetastatic HER2-positive gastric or gastro-oesophageal junction adenocarcinoma patients naïve totreatment

The efficacy of pembrolizumab in combination with trastuzumab plus fluoropyrimidine and platinum-containing chemotherapy was investigated in KEYNOTE-811, a multicentre, randomised, double-blind, placebo-controlled study that enrolled 698 patients with HER2-positive advanced gastric or GEJadenocarcinoma regardless of PD-L1 expression status, who had not previously received systemictherapy for metastatic disease. Patients with an autoimmune disease that required systemic therapywithin 2 years of treatment or a medical condition that required immunosuppression were ineligible.

Randomisation was stratified by PD-L1 expression (CPS ≥ 1 or < 1), chemotherapy regimen (5-FUplus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region(Europe/Israel/North America/Australia, Asia or Rest of the World). Patients were randomised (1:1) toone of the following treatment arms; all study medications, except oral capecitabine, wereadministered as an intravenous infusion for every 3-week treatment cycle:

* Pembrolizumab 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg insubsequent cycles, followed by investigator’s choice of combination chemotherapy ofcisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) oroxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1 000 mg/m2 bid for 14 days(CAPOX). Pembrolizumab was administered prior to trastuzumab and chemotherapyon Day 1 of each cycle.

Progression-Free Survival (%)

* Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles,followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2up to 6-8 cycles and capecitabine 1 000 mg/m2 bid for 14 days (CAPOX). Placebo wasadministered prior to trastuzumab and chemotherapy on Day 1 of each cycle.

Treatment with pembrolizumab, trastuzumab and chemotherapy or placebo, trastuzumab andchemotherapy continued until RECIST v1.1-defined progression of disease as determined by BICR,unacceptable toxicity, or a maximum of 24 months. Assessment of tumour status was performed every6 weeks.

Among the 698 patients randomised in KEYNOTE-811, 594 (85%) had tumours that expressed PD-L1with a CPS ≥ 1 based on the PD-L1 IHC 22C3 pharmDxTM kit. The baseline characteristics of the594 patients with tumour PD-L1 expression CPS ≥ 1 included: median age of 63 years (range: 19 to85), 43% age 65 or older; 80% male; 63% White, 33% Asian, and 0.7 % Black; 42% ECOG PS of 0and 58% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease (stage IV) and 2%had locally advanced unresectable disease. Ninety-five percent (n=562) had tumours that were not

MSI H, 1% (n=8) had tumours that were MSI H, and in 4% (n=24) the status was not known. Eighty-five percent of patients received CAPOX.

The primary efficacy outcome measures were PFS based on BICR using RECIST 1.1, and OS.

Secondary efficacy outcome measures included ORR and DoR based on BICR using RECIST 1.1.

At the second interim analysis in the overall population, the study demonstrated a statisticallysignificant improvement in PFS (HR 0.72; 95% CI 0.60, 0.87; p-Value 0.0002) for patientsrandomised to the pembrolizumab arm in combination with trastuzumab and chemotherapy comparedwith placebo in combination with trastuzumab and chemotherapy. At this interim analysis, there wasno statistically significant difference with respect to OS. The median follow-up time was 15.4 months(range: 0.3 to 41.6 months). At the first interim analysis conducted on the first 264 patientsrandomised in the overall population (133 patients in the pembrolizumab arm and 131 in the placeboarm), a statistically significant improvement was observed in ORR (74.4% vs. 51.9%, representing a22.7% difference in ORR, [95%CI: 11.2, 33.7]; p-Value 0.00006).

Table 50 summarises key efficacy results at the second interim analysis for the pre-specified subgroupof patients whose tumours expressed PD-L1 with a CPS ≥ 1 and Figures 52 and 53 show the

Kaplan-Meier curves for PFS and OS.

Table 50: Efficacy results for KEYNOTE-811 for patients with PD-L1 expression (CPS ≥ 1)

Endpoint Pembrolizumab Placebo

Trastuzumab Trastuzumaband Chemotherapy and Chemotherapyn=298 n=296

PFS

Number (%) of patients with event 199 (67%) 215 (73%)

Median in months (95% CI) 10.8 (8.5, 12.5) 7 . 2 ( 6.8, 8.4)

Hazard ratio* (95% CI) 0.7 (0.58, 0.85)p-Value† 0.0001

OS

Number (%) of patients with event 167 (56%) 183 (62%)

Median in months (95% CI) 20.5 (18.2, 24.3) 15.6 (13.5, 18.6)

Hazard ratio* (95% CI) 0.79 (0.64, 0.98)p-Value† 0.0143

Objective response rate

ORR‡ % (95% CI) 73% (67.7, 78.1) 58% (52.6, 64.1)

Complete response 14% 10%

Partial response 59% 49%p-Value# 0.00008

Response duration

Median in months (range) 11.3 (1.1+, 40.1+) 9.5 (1.4+, 38.3+)% with duration ≥ 6 months¶ 75% 67%% with duration ≥ 12 months¶ 49% 41%

* Based on unstratified Cox proportional hazard model† Nominal p-value based on unstratified log-rank test; no formal test was performed in patients with PD-L1 expression (CPS ≥ 1)‡ Response: Best objective response as confirmed complete response or partial response# Nominal p-value based on unstratified Miettinen and Nurminen method; no formal test was performed in patients with PD-L1expression (CPS ≥ 1)¶ Based on Kaplan-Meier estimation

Figure 52: Kaplan-Meier curve for progression free survival by treatment arm in KEYNOTE-811 patients with PD-L1 expression (CPS ≥ 1)

Treatment arm PFS Rate at 12 months PFS Rate at 24 months HR (95% CI) p-value

Pembrolizumab + SOC 45.7% 27.0% 0.70 (0.58, 0.85) 0.0001

SOC 32.9% 13.3%

Time in Months

Number at Risk

Pembrolizumab + SOC

SOC

Progression-Free Survival (%)

Figure 53: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-811patients with PD-L1 expression (CPS ≥ 1)

Treatment arm OS Rate at 12 months OS Rate at 18 months HR (95% CI) p-value

Pembrolizumab + SOC 69.2% 56.9% 0.79 (0.64, 0.98) 0.0143

SOC 60.6% 45.6%

Time in Months

Number at Risk

Pembrolizumab + SOC

SOC

KEYNOTE-859: Controlled study of combination therapy in locally advanced unresectable ormetastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma patients naïve totreatment

The efficacy of pembrolizumab in combination with fluoropyrimidine and platinum chemotherapywas investigated in KEYNOTE-859, a multicentre, randomised, double-blind, placebo-controlledstudy that enrolled 1 579 patients with HER2-negative advanced gastric or GEJ adenocarcinomaregardless of PD-L1 expression status, who had not previously received systemic therapy formetastatic disease. Prior neoadjuvant and/or adjuvant therapy was allowed if it was completed at least6 months prior to randomisation. Patients with an autoimmune disease that required systemic therapywithin 2 years of treatment, a medical condition that required immunosuppression, or patients who hadreceived prior treatment with immune checkpoint inhibitors were ineligible.

Randomisation was stratified by PD-L1 expression (CPS ≥ 1 or < 1), chemotherapy regimen (5-FUplus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region(Europe/Israel/North America/Australia, Asia or Rest of the World).

Patients were randomised (1:1) to one of the following treatment arms; all study medications, exceptoral capecitabine, were administered as an intravenous infusion for every 3-week treatment cycle:

* Pembrolizumab 200 mg, investigator’s choice of combination chemotherapy ofcisplatin 80 mg/m2 and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2and capecitabine 1 000 mg/m2 bid for 14 days (CAPOX) for up to 35 cycles. Duration

Overall Survival (%)of cisplatin or oxaliplatin treatment could be capped at 6 cycles as per local countryguidelines. Pembrolizumab was administered prior to chemotherapy on Day 1 of eachcycle.

* Placebo, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 andcapecitabine 1 000 mg/m2 bid for 14 days (CAPOX) for up to 35 cycles. Duration ofcisplatin or oxaliplatin treatment could be capped at 6 cycles as per local countryguidelines. Placebo was administered prior to chemotherapy on Day 1 of each cycle.

Treatment with pembrolizumab and chemotherapy or placebo and chemotherapy continued until

RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or amaximum of 24 months. Assessment of tumour status was performed every 6 weeks.

Among the 1 579 patients in KEYNOTE-859, 1 235 (78%) had tumours that expressed PD-L1 with a

CPS ≥ 1 based on the PD-L1 IHC 22C3 pharmDxTM kit. The baseline characteristics of the1 235 patients with tumour PD-L1 expression CPS ≥ 1 included: median age of 62 years (range: 24 to86), 40% age 65 or older; 70.4% male; 55.5% White; 33.1% Asian; 36.5% ECOG PS of 0 and 63.5%

ECOG PS of 1. Ninety-six percent of patients had metastatic disease (stage IV) and 4% had locallyadvanced unresectable disease. Five percent (n=66) had tumours that were MSI-H. Eighty-six percentof patients received CAPOX.

The primary efficacy outcome measure was OS. Additional secondary efficacy outcome measuresincluded PFS, ORR, and DOR as assessed by BICR using RECIST 1.1.

The study demonstrated a statistically significant improvement in OS (HR 0.78; 95% CI 0.70, 0.87; p-

Value < 0.0001), PFS (HR 0.76; 95% CI 0.67, 0.85; p-Value < 0.0001) and ORR (51% [95% CI 47.7,54.8] vs 42% [95% CI 38.5, 45.5]; p-Value 0.00009) in patients randomised to pembrolizumab incombination with chemotherapy compared with placebo in combination with chemotherapy in theoverall population. The median follow-up time was 12 months (range: 0.1 to 45.9 months). Table 51summarises key efficacy results for the pre-specified subgroup of patients whose tumours expressed

PD-L1 with a CPS ≥ 1 and Figures 54 and 55 show the Kaplan-Meier curves for OS and PFS.

Table 51: Efficacy results in KEYNOTE-859 for patients with PD L1 expression (CPS ≥ 1)

Endpoint Pembrolizumab Placebo

Fluoropyrimidine Fluoropyrimidine andand Platinum Platinum

Chemotherapy Chemotherapyn=618 n=617

OS

Number (%) of patients with event 464 (75%) 526 (85%)

Median in months* (95% CI) 13.0 (11.6, 14.2) 11.4 (10.5, 12.0)

Hazard ratio† (95% CI) 0.74 (0.65, 0.84)p-Value‡ < 0.0001

PFS

Number (%) of patients with event 443 (72%) 483 (78%)

Median in months* (95% CI) 6.9 (6.0, 7.2) 5.6 (5.4, 5.7)

Hazard ratio† (95% CI) 0.72 (0.63, 0.82)p-Value‡ < 0.0001

Objective response rate

ORR§ (95% CI) 52% (48.1, 56.1) 43% (38.7, 46.6)

Complete response 10% 6%

Partial response 42% 37%p-Value¶ 0.00041

Response duration

Median in months* (range) 8.3 (1.2+, 41.5+) 5.6 (1.3+, 34.2+)% with duration ≥ 12 months* 41% 26%

* Based on Kaplan-Meier estimation† Based on the stratified Cox proportional hazard model‡ One sided p-Value based on stratified log-rank test§ Response: Best objective response as confirmed complete response or partial response¶ One sided p-Value based on stratified Miettinen and Nurminen method

Figure 54: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-859patients with PD-L1 expression (CPS ≥ 1)

Treatment arm OS Rate at 12 months OS Rate at 24 months HR (95% CI) p-value

Pembro + Chemo 52% 30% 0.74 (0.65, 0.84) <0.0001

Chemo 46% 18%

Time in Months

Number at Risk

Pembro + Chemo

Chemo

Overall Survival (%)

Figure 55: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-859 patients with PD-L1 expression (CPS ≥ 1)

Treatment arm PFS Rate at 12 months PFS Rate at 24 months HR (95% CI) p-value

Pembro + Chemo 29% 20% 0.72 (0.63, 0.82) <0.0001

Chemo 18% 8%

Time in Months

Number at Risk

Pembro + Chemo

Chemo

An analysis was performed in KEYNOTE-859 in patients whose tumours expressed PD-L1 with a

CPS ≥ 1 to < 10 or CPS ≥ 10 in both arms (see Table 52).

Table 52: Efficacy results by PD-L1 expression in KEYNOTE-859

Endpoint Pembrolizumab Chemotherapy Pembrolizumab Chemotherapycombination n=345 combination n=272therapy therapyn=337 n=279

CPS ≥ 1 to < 10 CPS ≥ 10

OS HR0.83 (0.70, 0.98)* 0.65 (0.53, 0.79)†(95% CI)

PFS HR0.83 (0.70, 0.99)* 0.62 (0.51, 0.76)†(95% CI)

ORR§45% (39.7, 50.6) 42% (37.0, 47.7) 61% (54.6, 66.3) 43% (37.1, 49.1)(95% CI)

* Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on unstratified Cox proportionalhazard model† Hazard ratio (pembrolizumab combination therapy compared to chemotherapy) based on stratified Cox proportionalhazard model§ Response: Best objective response as confirmed complete response or partial response

Progression-Free Survival (%)

Biliary tract carcinoma

KEYNOTE-966: Controlled study of combination therapy in patients with locally advancedunresectable or metastatic BTC

The efficacy of pembrolizumab in combination with gemcitabine and cisplatin was investigated in

KEYNOTE-966, a multicentre, randomised, double-blind, placebo-controlled study that enrolled1 069 patients with locally advanced unresectable or metastatic BTC, who had not received priorsystemic therapy in the advanced disease setting. Patients were enrolled regardless of tumour PD-L1expression. Patients must have had acceptable serum bilirubin levels (≤ 1.5 x ULN or directbilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN) and any clinically significantbiliary obstruction had to be resolved before randomisation. Patients with autoimmune disease thatrequired systemic therapy within 2 years of treatment or a medical condition that requiredimmunosuppression were ineligible. Randomisation was stratified by geographic region (Asia vs. non-

Asia), locally advanced versus metastatic, and site of origin (gallbladder, intrahepatic or extrahepaticcholangiocarcinoma).

Patients were randomised (1:1) to one of the two treatment groups:

* Pembrolizumab 200 mg on Day 1 plus gemcitabine 1 000 mg/m2 and cisplatin 25 mg/m2on Day 1 and Day 8 every 3 weeks

* Placebo on Day 1 plus gemcitabine 1 000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and

Day 8 every 3 weeks

All study medications were administered via intravenous infusion. Treatment was continued untilunacceptable toxicity or disease progression. For pembrolizumab, treatment was continued for amaximum of 35 cycles, or approximately 24 months. For cisplatin, treatment could be administeredfor a maximum of 8 cycles and for gemcitabine, treatment could be continued beyond 8 cycles.

Assessment of tumour status was performed at baseline and then every 6 weeks through 54 weeksfollowed by every 12 weeks thereafter.

The study population characteristics were median age of 64 years (range: 23 to 85), 47% age 65 orolder; 52% male; 49% White, 46% Asian; 46% ECOG PS of 0 and 54% ECOG PS of 1; 31% ofpatients had a history of hepatitis B infection, and 3% had a history of hepatitis C infection.

The primary efficacy outcome measure was OS and the secondary efficacy measures were PFS, ORRand DOR as assessed by BICR using RECIST 1.1. The study demonstrated a statistically significantimprovement in OS at final analysis for patients randomised to pembrolizumab in combination withchemotherapy compared to placebo in combination with chemotherapy. Table 53 summarises keyefficacy measures and Figures 56 and 57 show the Kaplan-Meier curves for PFS and OS based on thefinal analysis with a median follow-up time of 11.6 months (range: 0.2 to 37.5 months).

Table 53: Efficacy results in KEYNOTE-966

Endpoint Pembrolizumab Placebo with200 mg every 3 weeks gemcitabine/cisplatinwithgemcitabine/cisplatin n=536n=533

OS

Number (%) of patients with 414 (78%) 443 (83%)event

Median in months (95% CI) 12.7 (11.5, 13.6) 10.9 (9.9, 11.6)

Hazard ratio* (95% CI) 0.83 (0.72, 0.95)p-Value† 0.0034

PFS

Number (%) of patients with 428 (80%) 448 (84%)event

Median in months (95% CI) 6.5 (5.7, 6.9) 5.6 (4.9, 6.5)

Hazard ratio* (95% CI) 0.87 (0.76, 0.99)p-Value‡ 0.0171

Objective response rate

ORR% (95% CI) 29.3% (25.4, 33.3) 28.4% (24.6, 32.4)

Complete response 2.6% 1.7%

Partial response 26.6% 26.7%p-Valueα 0.3610

Response duration§, ¶

Median in months (range) 8.3 (1.2+, 33.0+) 6.8 (1.1+, 30.0+)% with duration ≥ 6 months¶ 65% 55%% with duration ≥ 12 months¶ 38% 27%

* Based on the stratified Cox proportional hazard model† One-sided p-Value based on a stratified log-rank test. The OS result met the pre-specified one-sidedsignificance level of 0.0200‡ One-sided p-Value based on stratified log-rank test. The PFS result did not meet the pre-specified one-sided significance level of 0.0125α One-sided p-Value based on the stratified Miettinen and Nurminen method. The ORR result did not meetthe pre-specified one-sided significance level of 0.0125§ Based on patients with objective response that is confirmed complete response or partial response¶ Based on Kaplan-Meier estimate

Figure 56: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-966(intent to treat population)

Treatment arm OS rate at 12 months OS rate at 24 months HR (95% CI) p-value

Pembrolizumab + Chemotherapy 52% 25% 0.83 (0.72, 0.95) 0.0034

Placebo + Chemotherapy 44% 18%

Time in Months

Number at Risk

Pembrolizumab + Chemotherapy

Placebo + Chemotherapy

Overall Survival (%)

Figure 57: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-966 (intent to treat population)

Treatment arm PFS rate at 6 months PFS rate at 12 months HR (95% CI) p-value

Pembrolizumab + Chemotherapy 52% 24% 0.87 (0.76, 0.99) 0.0171

Placebo + Chemotherapy 46% 19%

Time in Months

Number at Risk

Pembrolizumab + Chemotherapy

Placebo + Chemotherapy

No overall differences in safety were observed in patients ≥ 75 years of age compared to youngerpatients receiving pembrolizumab monotherapy. Based on limited safety data from patients ≥ 75 yearsof age, when administrated in combination with chemotherapy, pembrolizumab showed lesstolerability in patients ≥ 75 years of age compared to younger patients. For efficacy data in patients≥ 75 years of age please refer to the relevant section of each indication.

In KEYNOTE-051, 161 paediatric patients (62 children aged 9 months to less than 12 years and99 adolescents aged 12 years to 17 years) with advanced melanoma or PD-L1 positive advanced,relapsed, or refractory solid tumours or lymphoma were administered pembrolizumab 2 mg/kg bwevery 3 weeks. All patients received pembrolizumab for a median of 4 doses (range: 1-35 doses), with138 patients (85.7%) receiving pembrolizumab for 2 doses or more. Participants were enrolled across28 tumour types by primary diagnosis. The most common tumour types by histology were Hodgkinlymphoma (13.7%), glioblastoma multiforme (9.3%), neuroblastoma (6.2%), osteosarcoma (6.2%) andmelanoma (5.6%). Of the 161 patients, 137 were enrolled with solid tumours, 22 with Hodgkinlymphoma, and 2 with other lymphomas. In patients with solid tumours and other lymphomas, the

ORR was 5.8%, no patient had a complete response and 8 patients (5.8%) had a partial response. Inthe Hodgkin lymphoma population (n=22), in patients aged 11 years to 17 years, the baselinecharacteristics were median age 15 years; 64% male; 68% White; 77% had a Lansky/Karnofsky scale90-100 and 23% had scale 70-80. Eighty-six percent had two or more prior lines of therapy and 64%

Progression-Free Survival (%)had Stage 3 or higher. In these paediatric patients with cHL, the ORR assessed by BICR according tothe IWG 2007 criteria was 54.5%, 1 patient (4.5%) had a complete response and 11 patients (50.0%)had a partial response, and the ORR assessed by the Lugano 2014 criteria was 63.6%, 4 patients(18.2%) had a complete response and 10 patients (45.5%) had a partial response. Data from clinicalstudies in adolescent melanoma patients is very limited and extrapolation from adult data has beenused to establish efficacy. Among the 5 adolescent participants with advanced melanoma treated in

KEYNOTE-051, no patient had a complete or a partial response, and 1 patient had stable disease.

The European Medicines Agency has deferred the obligation to submit the results of studies withpembrolizumab in one or more subsets of the paediatric population in treatment of Hodgkin lymphoma(see section 4.2 for information on paediatric use).

The pharmacokinetics of pembrolizumab was studied in 2 993 patients with metastatic or unresectablemelanoma, NSCLC, or carcinoma who received doses in the range: of 1 to 10 mg/kg bw every2 weeks, 2 to 10 mg/kg bw every 3 weeks, or 200 mg every 3 weeks.

Pembrolizumab is administered via the intravenous route and therefore is immediately and completelybioavailable.

Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab atsteady-state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind toplasma proteins in a specific manner.

Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to itsclearance.

Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) afterachieving maximal change at steady-state compared with the first dose (252 mL/day [CV%: 37%]);this decrease in CL with time is not considered clinically meaningful. The geometric mean value(CV%) for the terminal half-life is 22 days (32%) at steady-state.

Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area under the plasmaconcentration time curve (AUC) increased dose proportionally within the dose range for efficacy.

Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with anevery 3 week regimen and the systemic accumulation was 2.1-fold. The median trough concentrations(Cmin) at steady-state were approximately 22 mcg/mL at a dose of 2 mg/kg bw every 3 weeks and29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve atsteady-state over 3 weeks (AUC0-3weeks) was 794 mcg*day/mL at a dose of 2 mg/kg bw every 3 weeksand 1 053 mcg*day/mL at a dose of 200 mg every 3 weeks.

Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observedmedian Cmin at steady-state was up to 40% higher than that in other tumour types treated with the samedosage; however, the range of trough concentrations is similar. There are no notable differences inmedian Cmax between cHL and other tumour types. Based on available safety data in cHL and othertumour types, these differences are not clinically meaningful.

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed inpopulation pharmacokinetic analyses. The following factors had no clinically important effect on theclearance of pembrolizumab: age (range: 15-94 years), gender, race, mild or moderate renalimpairment, mild or moderate hepatic impairment and tumour burden. The relationship between bodyweight and clearance supports the use of either fixed dose or body weight-based dosing to provideadequate and similar control of exposure. Pembrolizumab exposure with weight-based dosing at2 mg/kg bw every 3 weeks in paediatric patients (≥ 3 to 17 years) are comparable to those of adults atthe same dose.

The effect of renal impairment on the clearance of pembrolizumab was evaluated by populationpharmacokinetic analyses in patients with mild or moderate renal impairment compared to patientswith normal renal function. No clinically important differences in the clearance of pembrolizumabwere found between patients with mild or moderate renal impairment and patients with normal renalfunction. Pembrolizumab has not been studied in patients with severe renal impairment (seesection 4.2).

The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by populationpharmacokinetic analyses in patients with mild and moderate hepatic impairment (as defined using the

US National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepaticfunction. No clinically important differences in the clearance of pembrolizumab were found betweenpatients with mild or moderate hepatic impairment and normal hepatic function. Pembrolizumab hasnot been studied in patients with severe hepatic impairment (see section 4.2).

The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in

Cynomolgus monkeys administered intravenous doses of 6, 40 or 200 mg/kg bw once a week in the1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-freeperiod. No findings of toxicological significance were observed and the no observed adverse effectlevel (NOAEL) in both studies was ≥ 200 mg/kg bw, which produced exposure multiples of 19 and94 times the exposure in humans at doses of 10 and 2 mg/kg bw, respectively. The exposure multiplebetween the NOAEL and a human dose of 200 mg was 74.

Animal reproduction studies have not been conducted with pembrolizumab. The PD-1/PD-L1 pathwayis thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of

PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus andto result in an increase in foetal loss.

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 monthrepeat-dose toxicology studies in monkeys, there were no notable effects in the male and femalereproductive organs; however, many animals in these studies were not sexually mature.

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Unopened vial2 years.

Chemical and physical in-use stability has been demonstrated for up to 42 days at 2 °C to 8 °C or at23 °C to 27 °C.

From a microbiological point of view, the product, once diluted, should be used immediately. Thediluted solution must not be frozen. If not used immediately, in-use storage times and conditions priorto use are the responsibility of the user and would normally not be longer than 7 days at 2 °C to 8 °C,or 12 hours at room temperature, unless dilution has taken place in controlled and validated asepticconditions. If refrigerated, the vials and/or intravenous bags must be allowed to come to roomtemperature prior to use.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

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

For storage conditions after dilution of the medicinal product, see section 6.3.

4 mL of concentrate in a 10 mL Type I clear glass vial, with a coated grey chlorobutyl or bromobutylstopper and an aluminium seal with a dark blue coloured flip-off cap, containing 100 mgpembrolizumab.

Pack sizes: one or two vials per carton.

Not all pack sizes may be marketed.

* Do not shake the vial.

* Equilibrate the vial to room temperature (at or below 25 °C).

* Prior to dilution, the vial of liquid can be out of refrigeration (temperatures at or below 25 °C)for up to 24 hours.

* Parenteral medicinal products should be inspected visually for particulate matter anddiscolouration prior to administration. The concentrate is a clear to slightly opalescent,colourless to slightly yellow solution. Discard the vial if visible particles are observed.

* Withdraw the required volume up to 4 mL (100 mg) of concentrate and transfer into anintravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) toprepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Each vialcontains an excess fill of 0.25 mL (total content per vial 4.25 mL) to ensure the recovery of4 mL of concentrate. Mix diluted solution by gentle inversion.

* If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperatureprior to use. Translucent to white proteinaceous particles may be seen in diluted solution.

Administer the infusion solution intravenously over 30 minutes using a sterile, non-pyrogenic,low-protein binding 0.2 to 5 µm in-line or add-on filter.

* Do not co-administer other medicinal products through the same infusion line.

* KEYTRUDA is for single use only. Discard any unused portion left in the vial.

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

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/15/1024/002

EU/1/15/1024/003

Date of first authorisation: 17 July 2015

Date of latest renewal: 24 March 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.