Keytruda - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

KEYTRUDA 25 mg/mL concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

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

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Melanoma

KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection (see section 5.1).

Non-small cell lung carcinoma (NSCLC)

KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a > 50% tumour proportion score (TPS) with no 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 tumours have no EGFR or ALK positive mutations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the 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 metastatic non-small cell lung carcinoma in adults whose tumours express PD-L1 with a > 1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA.

Classical Hodgkin lymphoma (cHL)

KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged

3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option.

Urothelial carcinoma

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

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

Head and neck squamous cell carcinoma (HNSCC)

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 and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS > 1 (see section 5.1).

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

Renal cell carcinoma (RCC)

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

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

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

Colorectal cancer (CRC)

KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults.

Oesophageal carcinoma

KEYTRUDA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS > 10 (see section 5.1).

Triple-negative breast cancer (TNBC)

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable 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).

Endometrial carcinoma (EC)

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

4.2 Posology and method of administration

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

PD-L1 testing

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

MSI -H/dMMR testing for patients with CRC

For treatment with KEYTRUDA as monotherapy, testing for MSI-H/dMMR tumour status using a validated test is recommended to select patients with CRC (see sections 4.1 and 5.1).

Posology

The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (bw) (up to a maximum 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 concomitant therapies.

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

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

Dose delay or discontinuation (see also section 4.4)

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

Table 1: Recommended treatment modifications for KEYTRUDA

Immune-related adverse reactions	Severity	Treatment modification
Pneumonitis	Grade 2	Withhold until adverse reactions recover to Grades 0–1*
	Grades 3 or 4, or recurrent Grade 2	Permanently discontinue
Colitis	Grades 2 or 3	Withhold until adverse reactions recover to Grades 0–1*
	Grade 4 or recurrent Grade 3	Permanently discontinue
Nephritis	Grade 2 with creatinine > 1.5 to < 3 times upper limit of normal (ULN)	Withhold until adverse reactions recover to Grades 0–1*
	Grade > 3 with creatinine > 3 times ULN	Permanently discontinue
Endocrinopathies	Grade 2 adrenal insufficiency and hypophysitis	Withhold treatment until controlled by hormone replacement

Immune-related adverse reactions	Severity	Treatment modification
	Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis Type 1 diabetes associated with Grade > 3 hyperglycaemia (glucose > 250 mg/dL or > 13.9 mmol/L) or associated with ketoacidosis Hyperthyroidism Grade > 3	Withhold until adverse reactions recover to Grades 0–1* For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued.
	Hypothyroidism	Hypothyroidism may be managed with replacement therapy without treatment interruption.
Hepatitis NOTE: for RCC patients treated with pembrolizumab in combination with axitinib with liver enzyme elevations, see dosing guidelines following this table.	Grade 2 with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 to 5 times ULN or total bilirubin > 1.5 to 3 times ULN	Withhold until adverse reactions recover to Grades 0–1*
	Grade > 3 with AST or ALT > 5 times ULN or total bilirubin > 3 times ULN	Permanently discontinue
	In case of liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT increases > 50% and lasts > 1 week	Permanently discontinue
Skin reactions	Grade 3 or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)	Withhold until adverse reactions recover to Grades 0–1*
	Grade 4 or confirmed SJS or TEN	Permanently discontinue
Other immune-related adverse reactions	Based on severity and type of reaction (Grade 2 or Grade 3)	Withhold until adverse reactions recover to Grades 0–1*
	Grades 3 or 4 myocarditis Grades 3 or 4 encephalitis Grades 3 or 4 Guillain-Barre syndrome	Permanently discontinue
	Grade 4 or recurrent Grade 3	Permanently discontinue
Infusion-related reactions	Grades 3 or 4	Permanently discontinue

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 if

corticosteroid 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 experiencing immune-related myocarditis is not known.

KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued for Grade 4 or recurrent Grade 3 immune-related adverse reactions, unless otherwise specified in Table 1.

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

KEYTRUDA in combination with axitinib in RCC

For RCC patients treated with KEYTRUDA in combination with axitinib, see the SmPC regarding dosing of axitinib. When used in combination with pembrolizumab, dose escalation of axitinib above the 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 with axitinib:

• • 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 or sequential rechallenge with both medicines after recovery may be considered. If rechallenging with 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 corticosteroid therapy may be considered.

KEYTRUDA in combination with lenvatinib

When used in combination with lenvatinib, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued in accordance with the instructions in the lenvatinib SmPC for combination with pembrolizumab. No dose reductions are recommended for KEYTRUDA.

Patients treated with KEYTRUDA must be given the patient alert card and be informed about the risks of KEYTRUDA (see also package leaflet).

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

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

Method of administration

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.

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Traceability

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

Assessment of PD-L1 status

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

Immune-related adverse reactions

Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously.

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude other causes should be ensured. Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered. Upon improvement to Grade < 1, corticosteroid taper should be initiated and continued over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction recovers to Grade < 1 and corticosteroid dose has been reduced to < 10 mg prednisone or equivalent per day.

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

Immune-related pneumonitis

Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with 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-related colitis

Colitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for signs and symptoms of colitis, 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 or Grade 3 colitis, and permanently discontinued for Grade 4 or recurrent Grade 3 colitis (see section 4.2). The potential risk of gastrointestinal perforation should be taken into consideration.

Immune-related hepatitis

Hepatitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated 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) and 1 –2 mg/kg/day (for Grade > 3 events) prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, pembrolizumab should be withheld or discontinued (see section 4.2).

Immune-related nephritis

Nephritis has been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored 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 prednisone or equivalent followed by a taper) and, based on severity of creatinine elevations, pembrolizumab should be withheld for Grade 2, and permanently discontinued for Grade 3 or Grade 4 nephritis (see section 4.2).

Immune-related endocrinopathies

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

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

Adrenal insufficiency (primary and secondary) has been reported in patients receiving pembrolizumab. Hypophysitis has also been reported in patients receiving pembrolizumab (ee section 4.8). Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and other causes excluded. Corticosteroids to treat adrenal insufficiency and other hormone replacement should be administered as clinically indicated. Pembrolizumab should be withheld for Grade 2 adrenal insufficiency or hypophysitis until the event is controlled with hormone replacement. Pembrolizumab should be withheld or discontinued for Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis. Continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should be monitored to ensure appropriate hormone replacement.

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

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should be withheld for Grade > 3 until recovery to Grade < 1 hyperthyroidism. Thyroid function and hormone levels 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 are controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued (see sections 4.2 and 4.8).

Immune-related skin adverse reactions

Immune-related severe skin reactions have been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should be 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 skin reactions, and corticosteroids should be administered (see section 4.2).

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

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

Other immune-related adverse reactions

The following additional clinically significant, immune-related adverse reactions have been reported in 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 and cystitis noninfective (see sections 4.2 and 4.8).

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

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction recovers to Grade < 1 and corticosteroid dose has been reduced to < 10 mg prednisone or equivalent per day.

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

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

Transplant-related adverse reactions

Solid organ transplant rejection

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 organ transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT)

Allogeneic HSCT after treatment with pembrolizumab

Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with cHL undergoing allogeneic HSCT after previous exposure to pembrolizumab. 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 reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Infusion-related reactions

Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in patients receiving pembrolizumab (see section 4.8). For Grades 3 or 4 infusion reactions, infusion should 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.

Use of pembrolizumab in combination with chemotherapy

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

Disease-specific precautions

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

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

Use of pembrolizumab in urothelial carcinoma for patients who are considered ineligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 with CPS > 10 The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit has been assessed in a comparative study (KEYNOTE-361). In KEYNOTE-361, a higher number of deaths within 6 months of treatment initiation followed by a long-term survival benefit was observed with 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 of pembrolizumab effect before initiating treatment in patients with urothelial carcinoma who are considered eligible for carboplatin-based combination chemotherapy. KEYNOTE-052 also included patients eligible for mono-chemotherapy, for whom no randomised data are available. In addition, no safety and efficacy data are available in frailer patients (e.g. ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these data, pembrolizumab should be used with caution in this population after careful consideration of the potential risk-benefit on an individual basis.

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

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

Physicians should consider the benefit/risk balance of the available treatment options (pembrolizumab monotherapy or pembrolizumab in combination with chemotherapy) before initiating treatment in previously 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 a long-term survival benefit was observed with pembrolizumab monotherapy compared to chemotherapy (see section 5.1).

Use of pembrolizumab , for, first-line treatment of patients with HNSCC

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

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

Use of pembrolizumab , for adjuvant treatment of patients with melanoma

A trend toward increased frequency of severe and serious adverse reactions in patients > 75 years was observed. Safety data of pembrolizumab in the adjuvant melanoma setting in patients > 75 years are limited.

Use of pembrolizumab in combination with axitinib , for, first-line treatment of patients with RCC When pembrolizumab is given with axitinib, higher than expected frequencies of Grades 3 and 4 ALT and AST elevations have been reported in patients with advanced RCC (see section 4.8). Liver enzymes should be monitored before initiation of and periodically throughout treatment. More frequent monitoring of liver enzymes as compared to when the medicines are used in monotherapy may be considered. Medical management guidelines for both medicines should be followed (see section 4.2 and refer to the SmPC for axitinib).

Use of pembrolizumab, for, first-line treatment of patients with MSI-H/dMMR CRC

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

Patients excluded from clinical studies

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 C infection; active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring systemic corticosteroid therapy; a history of severe hypersensitivity to another monoclonal antibody; receiving immunosuppressive therapy and a history of severe immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring 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 their infection treated prior to receiving pembrolizumab. Patients with active infections occurring during treatment with pembrolizumab were managed with appropriate medical therapy. Patients with clinically 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 clinical studies, therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

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 with appropriate medical management in these patients.

Patient alert card

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 patient will be provided with the patient alert card with each prescription.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signalling 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, that administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates of 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 the developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab.

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

Summary of the safety profile

Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of pembrolizumab (see “Description of selected adverse reactions” below). The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.

Pembrolizumab in monotherapy (see section 4.2)

The safety of pembrolizumab as monotherapy has been evaluated in 7,148 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, HNSCC, CRC, endometrial, gastric, small intestine, biliary, pancreatic cancer or adjuvant therapy of RCC across four doses (2 mg/kg bw every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bw every 2 or 3 weeks) in clinical studies. In this patient population, the median observation time was 7.9 months (range: 1 day to 39 months) and the most frequent adverse reactions with pembrolizumab were fatigue (31%), diarrhoea (22%), and nausea (21%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions (see section 4.4). The incidences of immune-related adverse reactions were 36.1% all Grades and 8.9% for Grades 3–5 for pembrolizumab monotherapy in the adjuvant setting (n=1,480) and 24.2% all Grades and 6.4% for Grades 3–5 in the metastatic setting (n=5,375). No new immune-related adverse reactions were identified in the adjuvant setting.

Pembrolizumab in combination with chemotherapy (see section 4.2)

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

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 2,033 patients with NSCLC, HNSCC, oesophageal carcinoma or TNBC receiving 200 mg, 2 mg/kg bw or 10 mg/kg bw pembrolizumab every 3 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were anaemia (52%), nausea (52%), fatigue (37%), constipation (34%), neutropenia (33%), diarrhoea (32%), decreased appetite (30%), and vomiting (28%). Incidences of Grades 3–5 adverse reactions in patients with NSCLC were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone, in patients with HNSCC were 85% for pembrolizumab combination therapy and 84% for chemotherapy plus cetuximab, and in patients with oesophageal carcinoma were 86% for pembrolizumab combination therapy and 83% for chemotherapy alone, and in patients with TNBC were 78% for pembrolizumab combination therapy and 74% for chemotherapy alone.

Pembrolizumab in combination with tyrosine kinase inhibitor (TKI) (see section 4.2)

When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related 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 in combination with lenvatinib in advanced EC has been evaluated in a total of 1,456 patients with advanced RCC or advanced EC receiving 200 mg pembrolizumab every 3 weeks with either axitinib 5 mg twice daily or lenvatinib 20 mg once daily in clinical studies, as appropriate. In these patient populations, 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 3–5 adverse reactions in patients with RCC were 80% for pembrolizumab in combination with either axitinib or lenvatinib and 71% for sunitinib alone. In patients with EC, Grades 3–5 adverse reactions were 89% for pembrolizumab in combination with lenvatinib and 73% for chemotherapy alone.

Tabulated summary of adverse reactions

Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy or other anti-tumour medicines or reported from post-marketing use of pembrolizumab are listed in Table 2. These reactions are presented by system organ class and by frequency. 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 not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Adverse reactions known to occur with pembrolizumab or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with 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*

	Monotherapy	In combination with chemotherapy	In combination with axitinib or lenvatinib
Infections and infestations
Very common		pneumonia	urinary tract infection
Common	pneumonia		pneumonia
Blood and lymphatic system disorders
Very common	anaemia	neutropenia, anaemia, thrombocytopenia, leukopenia	anaemia
Common	thrombocytopenia, neutropenia, lymphopenia	febrile neutropenia, lymphopenia	neutropenia, thrombocytopenia, lymphopenia, leukopenia
Uncommon	leukopenia, eosinophilia	eosinophilia	eosinophilia
Rare	immune thrombocytopenia, haemolytic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis
Immune system disorders
Common	infusion- related reactiona	infusion- related reactiona	infusion- related reactiona
Uncommon	sarcoidosis
Not known	solid organ transplant rejection
Endocrine disorders
Very common	hypothyroidismb	hypothyroidism	hypothyroidism
Common	hyperthyroidism	hyperthyroidism0	adrenal insufficiency* hyperthyroidism, thyroiditise
Uncommon	adrenal insufficiency*, hypophysitisd, thyroiditise	adrenal insufficiency* hypophysitisd, thyroiditise	hypophysitisd
Metabolism and nutrition disorders
Very common	decreased appetite	hypokalaemia, decreased appetite	decreased appetite
Common	hyponatraemia, hypokalaemia, hypocalcaemia	hyponatraemia, hypocalcaemia	hyponatraemia, hypokalaemia, hypocalcaemia
Uncommon	type 1 diabetes mellitusg	type 1 diabetes mellitus	type 1 diabetes mellitusg
Psychiatric disorders
Very common		insomnia
Common	insomnia		insomnia
Nervous system disorders
Very common	headache	neuropathy peripheral, headache, dizziness	headache, dysgeusia
Common	dizziness, neuropathy peripheral, lethargy, dysgeusia	lethargy, dysgeusia	dizziness, neuropathy peripheral, lethargy

	Monotherapy	In combination with chemotherapy	In combination with axitinib or lenvatinib
Uncommon	epilepsy	epilepsy	myasthenic syndromeh, encephalitis1
Rare	Guillain-Barre syndromei, encephalitis-1', myelitisk, myasthenic syndromeh, meningitis (aseptic)	encephalitis, Guillain-Barré syndrome1
Eye disorders
Common	dry eye	dry eye	dry eye
Uncommon	uveitism		uveitism
Rare	V ogt-Koyanagi-Har ada syndrome	uveitis	V ogt-Koyanagi-Harad a syndrome
Cardiac disorders
Common	cardiac arrhythmia^ (including atrial fibrillation)	cardiac arrhythmia^ (including atrial fibrillation)	cardiac arrhythmia^ (including atrial fibrillation)
Uncommon	myocarditis, pericardial effusion, pericarditis	myocarditisn, pericardial effusion, pericarditis	myocarditis, pericardial effusion
Vascular disorders
Very common			hypertension
Common	hypertension	hypertension
Uncommon		vasculitiso	vasculitiso
Rare	vasculitiso
Respiratory, thoracic and mediastinal disorders
Very common	dyspnoea, cough	dyspnoea, cough	dyspnoea, cough
Common	pneumonitisp	pneumonitisp	pneumonitisp
Gastrointestinal disorders
Very common	diarrhoea, abdominal painq, nausea, vomiting, constipation	nausea, vomiting, diarrhoea, abdominal painq, constipation	diarrhoea, abdominal painq, nausea, vomiting, constipation
Common	colitisr, dry mouth	colitisr, dry mouth, gastritis	colitisr, pancreatitiss, gastritis, dry mouth
Uncommon	pancreatitiss, gastritis, gastrointestinal ulcerationt	pancreatitiss, gastrointestinal ulcerationt	gastrointestinal ulcerationt
Rare	small intestinal perforation		small intestinal perforation
Hepatobiliary disorders
Common		hepatitisu	hepatitisu
Uncommon	hepatitisu
Rare	cholangitis sclerosing	cholangitis sclerosing
Skin and subcutaneous tissue disorders
Very common	pruritusv, rashw	alopecia, rashw, pruritusv	rashw, pruritusv

	Monotherapy	In combination with chemotherapy	In combination with axitinib or lenvatinib
Common	severe skin reactionsx, erythema, dermatitis, dry skin, vitiligoy, alopecia, eczema, dermatitis acneiform	severe skin reactionsx, erythema, dermatitis, dry skin	severe skin reactionsx, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia
Uncommon	psoriasis, lichenoid keratosisz, papule, hair colour changes	psoriasis, eczema, lichenoid keratosis, dermatitis acneiform, vitiligoy	eczema, lichenoid keratosisz, psoriasis, vitiligoy, papule, hair colour changes
Rare	Stevens-Johnson syndrome, erythema nodosum, toxic epidermal necrolysis	erythema nodosum, papule, hair colour changes	toxic epidermal necrolysis, Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders
Very common	musculoskeletal painaa, arthralgia	musculoskeletal painaa, arthralgia	arthralgia, musculoskeletal painaa, myositisbb, pain in extremity
Common	pain in extremity, myositisbb, arthritiscc	myositisbb, pain in extremity, arthritiscc	arthritiscc
Uncommon	tenosynovitisdd	tenosynovitisdd	tenosynovitisdd
Rare	Sjogren’s syndrome	Sjogren’s syndrome	Sjogren’s syndrome
Renal and urinary d	lisorders
Common		acute kidney injury	nephritisee
Uncommon	nephritisee	nephritisee
Rare	cystitis noninfective		cystitis noninfective
General disorders and administration site conditions
Very common	fatigue, asthenia, oedemaff, pyrexia	fatigue, asthenia, pyrexia, oedemaff	fatigue, asthenia, oedemaff, pyrexia
Common	influenza-like illness, chills	influenza-like illness, chills	influenza-like illness, chills
Investigations
Very common		alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased	lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased
Common	alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased, blood creatinine increased	hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased	amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia
Uncommon	amylase increased	amylase increased

*Adverse reaction frequencies presented in Table 2 may not be fully attributable to pembrolizumab alone but may contain contributions 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:

• a. infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, infusion-related hypersensitivity reaction, and cytokine release syndrome)

• b. hypothyroidism (myxoedema)

• c. hyperthyroidism (Basedow’s disease)

• d. hypophysitis (hypopituitarism, lymphocytic hypophysitis)

• e. thyroiditis (autoimmune thyroiditis, thyroid disorder, and thyroiditis acute)

• f. adrenal insufficiency (Addison’s disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency)

• g. type 1 diabetes mellitus (diabetic ketoacidosis)

• h. myasthenic syndrome (myasthenia gravis, including exacerbation)

• i. Guillain-Barre syndrome (axonal neuropathy and demyelinating polyneuropathy)

• j. encephalitis (autoimmune encephalitis, noninfective encephalitis)

• k. myelitis (transverse myelitis)

• l. meningitis aseptic (meningitis, meningitis noninfective)

• m. uveitis (chorioretinitis, iritis and iridocyclitis)

n. myocarditis (autoimmune myocarditis)

• o. vasculitis (central nervous system vasculitis, aortitis, giant cell arteritis)

• p. pneumonitis (interstitial lung disease, organising pneumonia, immune-mediated pneumonitis)

• q. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)

• r. colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, autoimmune colitis, and immune-mediated enterocolitis)

• s. pancreatitis (autoimmune pancreatitis, pancreatitis acute and immune-mediated pancreatitis)

• t. gastrointestinal ulceration (gastric ulcer and duodenal ulcer)

• u. hepatitis (autoimmune hepatitis, immune-mediated hepatitis, drug induced liver injury and acute hepatitis)

• v. pruritus (urticaria, urticaria papular and pruritus genital)

• w. rash (rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)

• x. severe skin reactions (dermatitis exfoliative generalised, exfoliative rash, pemphigus, and Grade > 3 of the following: acute febrile neutrophilic dermatosis, contusion, decubitus ulcer, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption, erythema multiforme, jaundice, lichen planus, oral lichen planus, pemphigoid, pruritus, pruritus genital, rash, rash erythematous, rash maculo-papular, rash pruritic, rash pustular, skin lesion, skin necrosis and toxic skin eruption)

y.   vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)

z. lichenoid keratosis (lichen planus and lichen sclerosus)

aa. musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)

bb. myositis (myalgia, myopathy, necrotising myositis, polymyalgia rheumatica and rhabdomyolysis)

cc. arthritis (joint swelling, polyarthritis and joint effusion)

dd. tenosynovitis (tendonitis, synovitis and tendon pain)

ee. nephritis (autoimmune nephritis, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome, glomerulonephritis and glomerulonephritis membranous)

ff. oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema)

Description of selected adverse reactions

Data for the following immune-related adverse reactions are based on patients who received pembrolizumab across four doses (2 mg/kg bw every 3 weeks, 10 mg/kg bw every 2 or 3 weeks, or 200 mg every 3 weeks) in clinical studies (see section 5.1). The management guidelines for these adverse reactions are described in section 4.4.

Immune-related adverse reactions (see section 4.4)

Immune-related pneumonitis

Pneumonitis occurred in 314 (4.4%) patients, including Grade 2, 3, 4 or 5 cases in 138 (1.9%), 80 (1.1%), 19 (0.3%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.7 months (range 2 days to 27.2 months). The median duration was 2.0 months (range 1 day to 51.0+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (4.1%). Pneumonitis led to discontinuation of pembrolizumab in 129 (1.8%) patients. Pneumonitis resolved in 188 patients, 6 with sequelae.

In patients with NSCLC, pneumonitis occurred in 160 (5.7%), including Grade 2, 3, 4 or 5 cases in 62 (2.2%), 47 (1.7%), 14 (0.5%) and 10 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.9% with a history of prior thoracic radiation. In patients with 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-related colitis

Colitis occurred in 140 (2.0%) patients, including Grade 2, 3 or 4 cases in 42 (0.6%), 74 (1.0%) and

6 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was

4.5 months (range 2 days to 24.3 months). The median duration was 1.0 month (range 1 day to

45.2+ months). Colitis led to discontinuation of pembrolizumab in 41 (0.6%) patients. Colitis resolved in 115 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-related hepatitis

Hepatitis occurred in 70 (1.0%) patients, including Grade 2, 3 or 4 cases in 11 (0.2%), 47 (0.7%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 3.9 months (range 8 days to 26.3 months). The median duration was 1.2 months (range 1 day to 22.5+ months). Hepatitis led to discontinuation of pembrolizumab in 29 (0.4%) patients. Hepatitis resolved in 54 patients.

Immune-related nephritis

Nephritis occurred in 30 (0.4%) patients, including Grade 2, 3 or 4 cases in 8 (0.1%), 16 (0.2%) and

2 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 4.6 months (range 12 days to 21.4 months). The median duration was 6.9 months (range 6 days to 28.2+ months). Nephritis led to discontinuation of pembrolizumab in 13 (0.2%) patients. Nephritis resolved in 18 patients, 5 with sequelae. In patients with non-squamous NSCLC treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), the incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.

Immune-related endocrinopathies

Adrenal insufficiency occurred in 62 (0.9%) patients, including Grade 2, 3 or 4 cases in 27 (0.4%), 27 (0.4%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of adrenal insufficiency was 5.5 months (range 1 day to 23.7 months). The median duration was not reached (range 3 days to 40.1+ months). Adrenal insufficiency led to discontinuation of pembrolizumab in 10 (0.1%) patients. Adrenal insufficiency resolved in 24 patients, 10 with sequelae.

Hypophysitis occurred in 40 (0.6%) patients, including Grade 2, 3 or 4 cases in 15 (0.2%), 21 (0.3%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 5.9 months (range 1 day to 17.7 months). The median duration was 3.3 months (range 3 days to 48.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 10 (0.1%) patients. Hypophysitis resolved in 19 patients, 8 with sequelae.

Hyperthyroidism occurred in 344 (4.8%) patients, including Grade 2 or 3 cases in 93 (1.3%) and

8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism 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 in

3 (< 0.1%) patients. Hyperthyroidism resolved in 282 (82.0%) patients, 11 with sequelae. In patients with RCC and melanoma treated with pembrolizumab monotherapy in the adjuvant setting (n=1,480), the incidence of hyperthyroidism was 10.9%, the majority of which were Grade 1 or 2.

Hypothyroidism occurred in 856 (12.0%) patients, including Grade 2 or 3 cases in 630 (8.8%) and

8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.4 months (range 1 day to 25.9 months). The median duration was not reached (range 2 days to 62.9+ months). Four patients ( 0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 199 (23.2%) 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 was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab in combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients treated with pembrolizumab in combination with axitinib or lenvatinib (n=1,456), the incidence of hypothyroidism was 46.2% (all Grades) with 0.8% Grade 3 or 4. In patients with RCC and melanoma treated with pembrolizumab monotherapy in the adjuvant setting (n=1,480), the incidence of hypothyroidism was 17.7%, the majority of which were Grade 1 or 2.

Immune-related skin adverse reactions

Immune-related severe skin reactions occurred in 116 (1.6%) patients, including Grade 2, 3 or 5 cases in 11 (0.2%), 91 (1.3%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 3.3 months (range 3 days to 25.5 months). The median duration was 1.9 months (range 1 day to 47.1+ months). Severe skin reactions led to discontinuation of pembrolizumab in 15 (0.2%) patients. Severe skin reactions resolved in 83 patients, 2 with sequelae.

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

Complications of allogeneic HSCT in cHL

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

Of 32 patients in KEYNOTE-087 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 16 patients reported acute GVHD and 7 patients reported chronic GVHD, two of which were fatal. No patients experienced hepatic VOD. No patients experienced engraftment syndrome post-transplant.

Of 14 patients in KEYNOTE-204 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 8 patients reported acute GVHD and 3 patients reported chronic GVHD, none of which were fatal. No patients experienced hepatic VOD. One patient experienced engraftment syndrome post-transplant.

Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC

In a clinical study of previously untreated patients with RCC receiving pembrolizumab in combination with axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and AST increased (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 systemic corticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with either pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% had no 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.

Laboratory abnormalities

In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.9% for lymphocytes decreased, 7.9% for sodium decreased, 6.2% for haemoglobin decreased, 5.5% for glucose increased, 5.4% for phosphate decreased, 3.3% for ALT increased, 3.2% for AST increased, 2.7% for alkaline phosphatase increased, 2.4% for potassium decreased, 2.1% for potassium increased, 2.0% for neutrophils decreased, 1.9% for platelets decreased, 1.9% for calcium increased, 1.8% for bilirubin increased, 1.5% for albumin decreased, 1.5% for calcium decreased, 1.4% for creatinine increased, 1.0% for glucose decreased, 0.9% for leucocytes decreased, 0.8% for magnesium increased, 0.5% for haemoglobin increased, 0.5% for sodium increased, and 0.2% for magnesium decreased.

In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 37.7% for neutrophils decreased, 25.8% for lymphocytes decreased, 25.2% for leucocytes decreased, 20.3% for haemoglobin decreased, 13.3% for platelets decreased, 11.3% for sodium decreased, 8.9% for phosphate decreased, 7.2% for potassium decreased, 6.7% for glucose increased, 5.8% for ALT increased, 5.4% for AST increased, 3.6% for calcium decreased, 3.4% for potassium increased, 2.8% for albumin decreased, 2.7% for creatinine increased, 2.3% for alkaline phosphatase increased, 1.9% for bilirubin increased, 1.7% for calcium increased, 1.0% for glucose decreased, 0.6% for sodium increased, and 0.1% for haemoglobin increased.

In patients treated with pembrolizumab in combination with axitinib or lenvatinib, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 23.0% for lipase increased (not measured in patients treated with pembrolizumab and axitinib), 12.0% for lymphocyte decreased, 11.4% for sodium decreased, 11.2% for amylase increased, 11.2% for triglycerides increased, 10.4% for ALT increased, 8.9% for AST increased, 7.8% for glucose increased, 7.3% for phosphorus decreased, 6.8% for phosphate decreased, 6.1% for potassium decreased, 5.1% for potassium increased, 4.5% for cholesterol increased, 4.4% for creatinine increased, 4.2% for haemoglobin decreased, 4.0% for magnesium decreased, 3.5% for neutrophils decreased, 3.1% for alkaline phosphatase increased, 3.0% for platelets decreased, 2.8% for bilirubin increased, 2.2% for calcium decreased, 1.7% for white blood cells decreased, 1.6% for magnesium increased, 1.5% for prothrombin INR increased, 1.4% for glucose decreased, 1.2% for albumin decreased, 1.2% for calcium increased, 0.4% for sodium increased, and 0.1% for haemoglobin increased.

Immunogenicity

In clinical studies in patients treated with pembrolizumab 2 mg/kg bw every three weeks, 200 mg every three weeks, or 10 mg/kg bw every two or three weeks as monotherapy, 36 (1.8%) of 2,034 evaluable patients tested positive for treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) patients had neutralising antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development.

Paediatric population

The safety of pembrolizumab as monotherapy has been evaluated in 161 paediatric patients aged 9 months to 17 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg bw every 3 weeks in the Phase I/II study KEYNOTE-051. The cHL population (n=22) included patients 11 to 17 years of age. The safety profile in paediatric patients was generally similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (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%). The majority 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%) patients had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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

Mechanism of action

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 a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune 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 presenting cells 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-stimulatory effect of pembrolizumab (anti-PD-1) results in a tumour microenvironment with greater T-cell activation to help overcome primary and acquired resistance to immunotherapy and may improve tumour responses compared to either treatment alone. In preclinical murine models, PD-1 plus TKI inhibitors have demonstrated enhanced anti-tumour activity compared to either agent alone.

Clinical efficacy and safety

Pembrolizumab doses of 2 mg/kg bw every 3 weeks, 10 mg/kg bw every 3 weeks, and 10 mg/kg bw every 2 weeks were evaluated in melanoma or previously treated NSCLC clinical studies. Based on the modelling and simulation of dose/exposure relationships for efficacy and safety for pembrolizumab, there are no clinically significant differences in efficacy or safety among the doses of 200 mg every 3 weeks, 2 mg/kg bw every 3 weeks, and 400 mg every 6 weeks (see section 4.2).

Melanoma

KEYNOTE-006: Controlled study in melanoma patients naïve to treatment with ipilimumab

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 were naïve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg bw every 2 (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 on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 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 brain metastases, 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. BRAF mutations 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 outcome measures were objective response rate (ORR) and response duration. Table 3 summarises key efficacy measures in patients naïve to treatment with ipilimumab at the final analysis performed after a minimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysis are shown in Figures 1 and 2.

Table 3: Efficacy results in KEYNOTE-006

Endpoint	Pembrolizumab 10 mg/kg bw every 3 weeks n=277	Pembrolizumab 10 mg/kg bw every 2 weeks n=279	Ipilimumab 3 mg/kg bw every 3 weeks n=278
OS
Number (%) of patients with event	119 (43%)	122 (44%)	142 (51%)
Hazard ratio* (95% CI)	0.68 (0.53, 0.86)	0.68 (0.53, 0.87)
p-Value*	< 0.001	< 0.001
Median in months (95% CI)	Not reached (24, NA)	Not reached (22, NA)	16 (14, 22)
PFS
Number (%) of patients with event	183 (66%)	181 (65%)	202 (73%)
Hazard ratio* (95% CI)	0.61 (0.50, 0.75)	0.61 (0.50, 0.75)
p-Value*	< 0.001	< 0.001
Median in months (95% CI)	4.1 (2.9, 7.2)	5.6 (3.4, 8.2)	2.8 (2.8, 2.9)
Best objective response
ORR % (95% CI)	36% (30, 42)	37% (31, 43)	13% (10, 18)
Complete response %	13%	12%	5%
Partial response %	23%	25%	8%
Response duration
Median in months (range)	Not reached (2.0, 22.8+)	Not reached (1.8, 22.8+)	Not reached (1.1+, 23.8+)
% ongoing at 18 months	68%§	71%§	70%§

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

t Based on stratified log-rank test

i 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) 0.00085

Pembrolizumab 10 mg/kg every 3 weeks       55.3%         0.68 (0.53, 0.86) 0.00083

ipilimumab                                 ­43.0%

0 Number at Risk	4	8	12 Time in Months	16	20	24	28
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	0
ipilimumab:                                2­78	213	170	145	122	110	28	0

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	0
ipilimumab:	278	88	48	34	29	16	5	0

KEYNOTE-002: Controlled study in melanoma patients previously treated with ipilimumab

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 treated with ipilimumab and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor. Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=180) or 10 mg/kg bw (n=181) every 3 weeks or chemotherapy (n=179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or carboplatin+pa­clitaxel). The study excluded patients with autoimmune disease or those receiving immunosuppression; further exclusion criteria were a history of severe or life-threatening immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent dose) for greater 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 interstitial lung 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 on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced independently- verified progression of disease after the first scheduled disease assessment were able to crossover and receive 2 mg/kg bw or 10 mg/kg bw of pembrolizumab every 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 had three 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 key efficacy 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 to chemotherapy for PFS, and there was no difference between pembrolizumab doses. There was no statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised to the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

Table 4: Efficacy results in KEYNOTE-002

Endpoint	Pembrolizumab 2 mg/kg bw every 3 weeks n=180	Pembrolizumab 10 mg/kg bw every 3 weeks n=181	Chemotherapy n=179
PFS
Number (%) of patients with event	150 (83%)	144 (80%)	172 (96%)
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, 5.2)	2.8 (2.6, 2.8)
OS
Number (%) of patients with event	123 (68%)	117 (65%)	128 (72%)
Hazard ratio* (95% CI)	0.86 (0.67, 1.10)	0.74 (0.57, 0.96)
p-Value^	0.1173	0.0106t
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 (1.4+, 25.3+)	Not reached (1.1+, 28.3+)	6.8 (2.8, 11.3)
% ongoing at 12 months	73% 1	79% 1	0% 1

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

proportional hazard model

t Based on stratified log-rank test

i 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

1 Based on Kaplan-Meier estimation

KEYNOTE-001: Open-label study in melanoma patients naïve and previously treated with ipilimumab The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated in an uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from two defined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve to treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 2 mg/kg bw every 3 weeks or 10 mg/kg bw every 3 weeks. Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease 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 with ipilimumab, 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 a history of brain metastases. Seventy percent had at least two and 35% of patients had three or more prior systemic therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population. 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 with ipilimumab, 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 a history of brain metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations 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; including complete response, partial response and stable disease), response duration, PFS and OS. Tumour response was assessed at 12-week intervals. Table 5 summarises key efficacy measures in patients previously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at a dose of 2 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 every 3 weeks in patients previously treated with ipilimumab n=89	Pembrolizumab 2 mg/kg bw every 3 weeks in patients naïve to treatment with ipilimumab 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 months1	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

t IRO = Integrated radiology and oncologist assessment using RECIST 1.1

i 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 first recorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab

1 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 in patients who received 2 mg/kg bw of pembrolizumab every 3 weeks.

Sub-population analyses

BRAF mutation status in melanoma

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

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

	BRAF wild type		BRAF mutant with prior BRAF treatment
Endpoint	Pembrolizumab 2 mg/kg bw every 3 weeks (n=136)	Chemotherapy (n=137)	Pembrolizumab 2 mg/kg bw every 3 weeks (n=44)	Chemotherapy (n=42)
PFS Hazard ratio* (95% CI)	0.50 (0.39, 0.66)	^B ^B ^B	0.79 (0.50, 1.25)	^B ^B ^B
OS Hazard ratio* (95% CI)	0.78 (0.58, 1.04)	—	1.07 (0.64, 1.78)	—
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 who were 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 treatment		BRAF mutant with prior BRAF treatment
Endpoint	Pembrolizumab 10 mg/kg bw every 2 or 3 weeks (pooled)	Ipilimumab (n=170)	Pembrolizumab 10 mg/kg bw every 2 or 3 weeks (pooled)	Ipilimumab (n=55)	Pembrolizumab 10 mg/kg bw every 2 or 3 weeks (pooled)	Ipilimumab (n=52)
PFS Hazard ratio* (95% CI)	0.61 (0.49, 0.76)	—	0.52 (0.35, 0.78)	—	0.76 (0.51, 1.14)	—
OS Hazard ratio* (95% CI)	0.68 (0.52, 0.88)	—	0.70 (0.40, 1.22)	—	0.66 (0.41, 1.04)	—
ORR %	38%	14%	41%	15%	24%	10%

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

PD-L1 status in melanoma

A subgroup analysis was performed as part of the final analysis of KEYNOTE-002 in patients who were PD-L1 positive (PD-L1 expression in > 1% of tumour and tumour-associated immune cells relative to all viable tumour cells – MEL score) vs. PD-L1 negative. PD-L1 expression was tested retrospectively by immunohistoche­mistry (IHC) assay with the 22C3 anti-PD-L1 antibody. Among patients 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 2 mg/kg bw every 3 weeks	Chemotherapy	Pembrolizumab 2 mg/kg bw every 3 weeks	Chemotherapy
	PD-L1 positive		PD-L1 negative
PFS Hazard ratio* (95% CI)	0.55 (0.40, 0.76)	^B ^B ^B	0.81 (0.50, 1.31)	^B ^B ^B
OS Hazard ratio* (95% CI)	0.90 (0.63, 1.28)	^B ^B ^B	1.18 (0.70, 1.99)	^B ^B ^B
ORR %	25%	4%	10%	8%

* 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 who were PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who were evaluable 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 10 mg/kg bw every 2 or 3 weeks (pooled)	Ipilimumab	Pembrolizumab 10 mg/kg bw every 2 or 3 weeks (pooled)	Ipilimumab
	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

Ocular melanoma

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

KEYNOTE-054: Placebo-controlled study for the adjuvant treatment of patients with completely resected 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 lymph node metastasis), IIIB or IIIC melanoma. A total of 1,019 adult patients were randomised (1:1) to receive pembrolizumab 200 mg every three weeks (n=514) or placebo (n=505), for up to one year until disease recurrence or unacceptable toxicity. Randomisation was stratified by American Joint Committee on Cancer (AJCC) 7th edition stage (IIIA vs. IIIB vs. IIIC 1–3 positive lymph nodes vs. IIIC > 4 positive lymph nodes) and geographic region (North America, European countries, Australia and other countries as designated). Patients must have undergone lymph node dissection, and if indicated, radiotherapy within 13 weeks prior to starting treatment. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Patients who received prior therapy for melanoma other than surgery or interferon for thick primary melanomas without evidence of lymph node involvement were ineligible. Patients underwent imaging every 12 weeks after the first dose of pembrolizumab for the first two years, then every 6 months from year 3 to 5, and then annually.

Among the 1,019 patients, the baseline characteristics were: median age of 54 years (25% age 65 or older); 62% male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% had stage IIIB; 18% had stage IIIC (1–3 positive lymph nodes) and 20% had stage IIIC (> 4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type. PD-L1 expression 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 cells relative to all viable tumour cells). The same scoring system was used for metastatic melanoma (MEL score).

The primary efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumours, where RFS was defined as the time between the date of randomisation and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. The secondary outcome measures were distant metastasis-free survival (DMFS) and OS in the whole population and in the population with PD-L1 positive tumours. OS was not formally assessed at the time 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 arm compared with placebo at its pre-specified interim analysis. Updated efficacy results with a median follow-up time of 45.5 months are summarised in Table 10 and Figures 4 and 5.

Table 10: Efficacy results in KEYNOTE-054

Endpoint	KEYTRUDA 200 mg every 3 weeks n=514	Placebo n=505
RFS
Number (%) of patients with event	203 (40%)	288 (57%)
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 event	173 (34%)	245 (49%)
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 4: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-054 (intent to treat population)

	0	6	12	18	24	30	36	42
Number at Risk				Time in Months
Pembrolizumab	514	412	375	353	333	316	300	163
Placebo:	505	359	297	253	225	213	205	115

Figure 5: Kaplan-Meier curve for distant metastasis-free survival by treatment arm in KEYNOTE-054 (intent to treat population)

	0	6	12	18	24	30	36	42
Number at Risk			Time in Months
Pembrolizumab:	514	434	404	378	352	334	314	174
Placebo:	505	395	339	301	265	251	235	136

RFS and DMFS benefit was consistently demonstrated across subgroups, including tumour PD-L1 expression, BRAF mutation status, and stage of disease (using AJCC 7th edition). These results were consistent when reclassified in a post-hoc analysis according to the current AJCC 8th edition staging system.

NSCLC

KEYNOTE-024: Controlled study of NSCLC patients naïve to treatment

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 were randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=154) or investigator’s cho­ice platinum-containing chemotherapy (n=151; including pemetrexed+car­boplatin, pemetrexed+cis­platin, gemcitabine+cis­platin, gemcitabine+car­boplatin, or paclitaxel+car­boplatin. Patients with non- squamous NSCLC could receive pemetrexed maintenance.). Patients were treated with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy who experienced independently-verified progression of disease were able to crossover and receive pembrolizumab.

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 11 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 of 11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

Table 11: Efficacy results in KEYNOTE-024

Endpoint	Pembrolizumab 200 mg every 3 weeks n=154	Chemotherapy n=151
PFS
Number (%) of patients with event	73 (47%)	116 (77%)
Hazard ratio* (95% CI)	0.50 (0.37, 0.68)
p-Value1	< 0.001
Median in months (95% CI)	10.3 (6.7, NA)	6.0 (4.2, 6.2)
OS
Number (%) of patients with event	73 (47%)	96 (64%)
Hazard ratio* (95% CI)	0.63 (0/	17, 0.86)
p-Value1	0.002
Median in months (95% CI)	30.0 (18.3, NA)	14.2 (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 1
Median in months (range)	Not reached (1.9+, 14.5+)	6.3 (2.1+, 12.6+)
% with duration > 6 months	88%§	59%1

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

t Based on stratified log-rank test

* Based on patients with a best objective response as confirmed complete or partial response

§ Based on Kaplan-Meier estimates; includes 43 patients with responses of 6 months or longer

1 Based on Kaplan-Meier estimates; includes 16 patients with responses of 6 months or longer

NA = not available

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 was observed in the small number of patients who were never-smokers; however, due to the small number of patients, no definitive conclusions can be drawn from these data.

KEYNOTE-042: Controlled study of NSCLC patients naïve to treatment

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 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 receive pembrolizumab 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 tumour status 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 these 599 patients included: median age 63 years (45% age 65 or older); 69% male; 63% White and 32% 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 significant improvement in OS for patients whose tumours expressed PD- L1 TPS > 1% randomised to pembrolizumab monotherapy compared to chemotherapy (HR 0.82; 95% CI 0.71, 0.93 at the final analysis) and in patients whose tumours expressed PD- L1 TPS > 50% randomised to pembrolizumab monotherapy compared to chemotherapy. Table 12 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 8.

Table 12: Efficacy results (PD-L1 TPS > 50%) in KEYNOTE-042

Endpoint	Pembrolizumab 200 mg every 3 weeks n=299	Chemotherapy n=300
OS
Number (%) of patients with event	180 (60%)	220 (73%)
Hazard ratio* (95% CI)	0.70 (0.58, 0.86)
p-Valuet	0.0003
Median in months (95% CI)	20.0 (15.9, 24.2)	12.2 (10.4, 14.6)
PFS
Number (%) of patients with event	238 (80%)	250 (83%)
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 (2.1+, 36.5+)	10.8 (1.8+, 30.4+)
% with duration > 18 months	57%	34%

t t

Hazard ratio (pembrolizumab compared to chemotherapy) 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 partial response

Figure 8: 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 survival benefit of pembrolizumab compared to chemotherapy, during both the first 4 months and throughout the entire duration of treatment, in patients who were never-smokers. However, due to the exploratory nature of this subgroup analysis, no definitive conclusions can be drawn.

KEYNOTE-189: Controlled study of combination therapy in non-squamous NSCLC patients naive to treatment

The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was investigated in a multicentre, randomised, active-controlled, double-blind study, KEYNOTE-189. Key eligibility 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 that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 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 of

cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by pembrolizumab 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks (n=410)

• • Placebo with pemetrexed 500 mg/m2 and investigator’s cho­ice of cisplatin 75 mg/m2

or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks (n=206)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab was permitted beyond RECIST-defined disease progression by BICR or beyond discontinuation of pemetrexed if the patient was clinically stable and deriving clinical benefit as determined by the investigator. For patients who completed 24 months of therapy or had a complete response, treatment with pembrolizumab could be reinitiated for disease progression and administered for 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 experienced independently-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 status of 0 or 1 respectively; 31% PD-L1 negative (TPS < 1%); and 18% with treated or untreated brain metastases 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 13 summarises key efficacy measures and Figures 9 and 10 show the Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of 18.8 months.

Table 13: Efficacy results in KEYNOTE-189

Endpoint	Pembrolizumab + Pemetrexed + Platinum Chemotherapy n=410	Placebo + Pemetrexed + Platinum Chemotherapy n=206
OS
Number (%) of patients with event	258 (63%)	163 (79%)
Hazard ratic/ (95% CI)	0.56 (0.46, 0.69)
p-Value^	< 0.00001
Median in months (95% CI)	22.0 (19.5, 24.5)	10.6 (8.7, 13.6)
PFS
Number (%) of patients with event	337 (82%)	197 (96%)
Hazard ratic/ (95% CI)	0.49 (0.41, 0.59)
p-Value1	< 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-Value1	< 0.0001
Response duration
Median in months (range)	12.5 (1.1+, 34.9+)	7.1 (2.4, 27.8+)
% with duration > 12 months#	53%	27%

t t §

A total of 113 patients (57%) who discontinued study treatment in the placebo plus chemotherapy arm crossed over to receive monotherapy pembrolizumab or received a checkpoint 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 partial

response

• 1 Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status

• # Based on Kaplan-Meier estimation

  p-value

  0.56 (0.46, 0.69) < 0.00001

  
  

  Treatment arm Pembrolizumab Control

  0		6	12	18	24	30	36	42
  Number at Risk Pembrolizumab:	410	347	283	Time in Months 234	184	86	12
  Control:	206	149	98	72	55	25	5

  
  

Figure 10: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-189 (intent to treat population)

Control:

Number at Risk

Pembrolizumab:

Treatment arm

Pembrolizumab

Control

p-value

0.49 (0.41, 0.59) < 0.00001

An analysis was performed in KEYNOTE-189 in patients who had PD-L1 TPS < 1% [pembrolizumab combination: n=127 (31%) vs. chemotherapy: n=63 (31%)], TPS 1–49% [pembrolizumab combination: n=128 (31%) vs. chemotherapy: n=58 (28%)] or > 50% [pembrolizumab combination: n=132 (32%) vs. chemotherapy: n=70 (34%)] (see Table 14).

Table 14: Efficacy results by PD-L1 Expression in KEYNOTE-189 

Endpoint	Pembrolizumab combination therapy	Chemotherapy	Pembrolizumab combination therapy	Chemotherapy	Pembrolizumab combination therapy	Chemotherapy
	TPS <1%		TPS 1 to 49%		TPS > 50%
OS Hazard ratio': (95% CI)	0.51 (0.36, 0.71)		0.66 (0.46, 0.96)		0.59 (0.40, 0.86)
PFS Hazard ratio': (95% CI)	0.67 (0.49, 0.93)		0.53 (0.38, 0.74)		0.35 (0.25, 0.49)
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 hazard model

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 OS and HR=1.12 [95% CI 0.56, 2.22] in PFS for pembrolizumab combination vs. chemotherapy was reported within this study subgroup. Data about efficacy of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

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

The efficacy of pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel was 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; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1 expression (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 the following treatment arms via intravenous infusion:

• • Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day

cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab was administered prior to chemotherapy on Day 1.

• • Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or nab-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 disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically 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 disease progression.

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 of 65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of 0 (29%) and 1 (71%); and 8% with treated brain metastases at baseline. Thirty-five percent had tumour 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 15 summarises key efficacy measures and Figures 11 and 12 show the Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of 14.3 months.

Table 15: Efficacy Results in KEYNOTE-407

Endpoint	Pembrolizumab Carboplatin Paclitaxel/Nab-paclitaxel n=278	Placebo Carboplatin Paclitaxel/Nab-paclitaxel n=281
OS
Number of events (%)	168 (60%)	197 (70%)
Median in months (95% CI)	17.1 (14.4, 19.9)	11.6 (10.1, 13.7)
Hazard ratio1 (95% CI)	0.71 (0.58, 0.88)
p-ValuC	0.0006
PFS
Number of events (%)	217 (78%)	252 (90%)
Median in months (95% CI)	8.0 (6.3, 8.4)	5.1 (4.3, 6.0)
Hazard rath/ (95% CI)	0.57 (0.47, 0.69)
p-Value1	< 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 duration of response in months (range)	8.8 (1.3+, 28.4+)	4.9 (1.3+, 28.3+)
% with duration > 12 months1	38%	25%

A total of 138 patients (51%) who discontinued study treatment in the placebo plus chemotherapy arm

t t

§

1

crossed over to receive monotherapy pembrolizumab or received a checkpoint inhibitor as subsequent therapy

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

0     3     6     9    12    15    18    21    24    27    30 33

Time in Months

Number at Risk

Pembrolizumab:	278	256	232	203	180	150	119	80	46	14	4	0
Control:	281	245	210	163	137	113	91	61	36	16	3	0

Number at Risk

Pembrolizumab:

An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS < 1% [pembrolizumab plus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to 49% [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 plus chemotherapy arm: n=73 (26%)] (see Table 16).

Table 16: Efficacy results by PD-L1 Expression in KEYNOTE-407 

Endpoint	Pembrolizumab combination therapy	Chemotherapy	Pembrolizumab combination therapy	Chemotherapy	Pembrolizumab combination therapy	Chemotherapy
	TPS <1%		TPS 1 to 49%		TPS > 50%
OS Hazard ratio': (95% CI)	0.79 (0.56, 1.11)		0.59 (0.42, 0.84)		0.79 (0.52, 1.21)
PFS Hazard ratio': (95% CI)	0.67 (0.49, 0.91)		0.52 (0.38, 0.71)		0.43 (0.29, 0.63)
ORR %	67%	41%	55%	42%	64%	30%

Based on final analysis

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

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 pembrolizumab combination vs. chemotherapy was reported within this study subgroup. Data about efficacy of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

KEYNOTE-010: Controlled study of NSCLC patients previously treated with chemotherapy

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 with platinum-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 also had 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 disease progression or unacceptable toxicity. The study excluded patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation 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 received one (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 17 summarises key efficacy measures for the entire population (TPS > 1%) and for the-patients with TPS > 50%, and Figure 13 shows the Kaplan-Meier curve for OS (TPS > 1%), based on a final analysis with median follow-up of 42.6 months.

Table 17: Response to pembrolizumab 2 or 10 mg/kg bw every 3 weeks in previously treated patients with NSCLC in KEYNOTE-010

Endpoint	Pembrolizumab 2 mg/kg bw every 3 weeks	Pembrolizumab 10 mg/kg bw every 3 weeks	Docetaxel 75 mg/m every 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-Valuet	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-Valuet	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 (2.8, 46.2+)	37.8 (2.0+, 49.3+)	7.1 (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-Valuet	< 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-Valuet	< 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 (2.8, 44.0+)	37.5 (2.0+, 49.3+)	8.1 (2.6, 16.8)
% ongoing	55%	47%	8%

t t §

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

Number at Risk

Pembrolizumab 2 mg/kg:

Pembrolizumab 10 mg/kg: Docetaxel:

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

In subgroup analyses, a reduced survival benefit of pembrolizumab compared to docetaxel was observed for patients who were never-smokers or patients with tumours harbouring EGFR activating mutations 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 these data.

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

Classical Hodgkin lymphoma

KEYNOTE-204: Controlled study in patients with relapsed or refractory classical Hodgkin lymphoma (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 with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, 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 more after 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 or documented disease progression, or a maximum of 35 cycles. Limited data are currently available on response duration following pembrolizumab discontinuation at cycle 35. Response was assessed every 12 weeks, with the first planned post-baseline assessment at Week 12.

Among the 304 patients in KEYNOTE-204, there is a subpopulation consisting of 112 patients who failed a transplant before enrolling and 137 who failed 2 or more prior therapies and were ineligible for ASCT at the time of enrolment. The baseline characteristics of these 249 patients were: median age 34 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 frontline chemotherapy and ~ 45% had received prior ASCT. Nodular-sclerosis was the more represented cHL histological subtype (~ 81%) and bulky disease, B symptoms and bone marrow involvement were present in approximately 21%, 28% and 4% of patients, respectively.

The primary efficacy outcome was PFS and the secondary efficacy outcome measure was ORR, both assessed by BICR according to the 2007 revised International Working Group (IWG) criteria. The additional primary efficacy outcome measure, OS, was not formally assessed at the time of the analysis. In the ITT population, the median follow-up time for 151 patients treated with pembrolizumab 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% for pembrolizumab compared to 54% for standard treatment with a p-Value of 0.0225. Table 18 summarises the efficacy results in the subpopulation. Efficacy results in this subpopulation were consistent with the ITT population. The Kaplan-Meier curve for PFS for this subpopulation is shown in Figure 14.

Table 18: Efficacy results in cHL patients who failed a transplant before enrolling or who failed 2 or more prior therapies and were ineligible for ASCT in KEYNOTE-204

Endpoint	Pembrolizumab 200 mg every 3 weeks n=124	Brentuximab vedotin 1.8 mg/kg bw every 3 weeks n=125
PFS
Number (%) of patients with event	68 (55%)	75 (60%)
Hazard ratio* (95% CI)	0.66 (0.4	7, 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 (%1) of patients with duration > 6 months	53 (80.8%)	28 (61.2%)
Number (%1) 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

1 Based on Kaplan-Meier estimation

KEYNOTE-087 and KEYNOTE-013: Open-label studies in patients with relapsed or refractory cHL The efficacy of pembrolizumab was investigated in KEYNOTE-087 and KEYNOTE-013, two multicentre, open-label studies for the treatment of 241 patients with cHL. These studies enrolled patients who failed ASCT and BV, who were ineligible for ASCT because they were unable to achieve a complete or partial remission to salvage chemotherapy and failed BV, or who failed ASCT and did not receive BV. Five study subjects were ineligible to ASCT due to reasons other than failure to salvage chemotherapy. Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic transplant within the past 5 years (or > 5 years but with GVHD), active autoimmune disease or a medical condition that required immunosuppression were 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 toxicity or documented disease progression.

Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or older); 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% who were refractory to first line therapy. Sixty-one percent of patients had received ASCT, 38% were transplant ineligible; 17% had no prior brentuximab vedotin use; and 37% of patients had prior radiation 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 or older), 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 (range 2 to 15). Eighty-four percent were refractory to at least one prior therapy, including 35% who were refractory to first line therapy. Seventy-four percent of patients had received ASCT, 26% were transplant 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. Efficacy results are summarised in Table 19.

Table 19: Efficacy results in KEYNOTE-087 and KEYNOTE-013

	KEYNOTE-087a	KEYNOTE-013b
Endpoint	Pembrolizumab 200 mg every 3 weeks n=210	Pembrolizumab 10 mg/kg bw every 2 weeks n=31
Objective response rate c
ORR % (95% CI)	71% (64.3, 77.0)	58% (39.1, 75.5)
Complete remission	28%	19%
Partial remission	43%	39%
Response duration c
Median in months (range)	16.6 (0.0+, 39.1+)d	Not reached (0.0+, 45.6+)e
% with duration > 6-months	74%f	80%g
% with duration > 12-months	59%h	70%i
Time to response
Median in months (range)	2.8 (2.1, 16.5)d	2.8 (2.4, 8.6)e
PFS c
Number (%) of patients with event	133 (63%)	19 (61%)
Median in months (95% CI)	13.6 (11.1, 16.7)	11.4 (4.9, 27.8)
9-month PFS rate	61%
12-month PFS rate	52%	48%
24-month PFS rate	32%	30%
OS
Number (%) of patients with event	33 (16%)	6 (19%)
12-month OS rate	96%	87%
24-month OS rate	91%	87%
36-month OS rate	86%	81%

Median follow-up time of 39.5 months b Median follow-up time of 52.8 months c Assessed by BICR according to the IWG 2007 criteria by PET CT scans d Based on patients (n=149) with a response by independent review e Based on patients (n=18) with a response by independent review f Based on Kaplan-Meier estimation; includes 84 patients with responses of 6 months or longer g Based on Kaplan-Meier estimation; includes 9 patients with responses of 6 months or longer h Based on Kaplan-Meier estimation; includes 60 patients with responses of 12 months or longer i Based on Kaplan-Meier estimation; includes 7 patients with responses of 12 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 conclusion on efficacy in this population.

Urothelial carcinoma

KEYNOTE-045: Controlled study in urothelial carcinoma patients who have received prior platinum-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 metastatic urothelial carcinoma in patients with disease progression on or after platinum-containing chemotherapy. Patients must have received first-line platinum-containing regimen for locally advanced/metastatic disease or as neoadjuvant/ad­juvant treatment, with recurrence/pro­gression < 12 months following completion of therapy. Patients were randomised (1:1) to receive either pembrolizumab 200 mg every 3 weeks (n=270) or investigator’s cho­ice of any of the following chemotherapy 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 with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with autoimmune disease, a medical condition that required immunosuppression and patients 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 have liver 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 first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among the 542 randomised patients in KEYNOTE-045, baseline characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 56% ECOG performance status of 1 and 1% ECOG performance status of 2; and 96% M1 disease and 4% M0 disease. 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 upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, 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 of response. Table 20 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 15. The study demonstrated statistically significant improvements in OS and ORR for patients randomised to pembrolizumab as compared to chemotherapy. There was no statistically significant difference between pembrolizumab and chemotherapy with respect to PFS.

Table 20: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial carcinoma previously treated with chemotherapy in KEYNOTE-045

Endpoint	Pembrolizumab 200 mg every 3 weeks n=270	Chemotherapy n=272
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 ’1
Median in months (range)	Not reached (1.6+, 30.0+)	4.4 (1.4+, 29.9+)
Number (%#) of patients with duration > 6 months	46 (84%)	8 (47%)
Number (%#) of patients with duration > 12 months	35 (68%)	5 (35%)

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

t t

§

1

#

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 21).

Table 21: OS by PD-L1 Expression

PD-L1 Expression	Pembrolizumab	Chemotherapy
	OS by PD-L1 Expression Number (%) of patients with event		Hazard 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 to deterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated with pembrolizumab compared to investigator’s cho­ice chemotherapy (HR 0.70; 95% CI 0.55–0.90). Over 15 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 taken cautiously.

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

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 who were not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with autoimmune disease or a medical condition that required immunosuppression. Assessment of tumour status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy 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. Reasons for cisplatin ineligibility included: baseline creatinine clearance of < 60 mL/min (50%), ECOG performance 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 a primary 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. Secondary efficacy outcome measures were duration of response, PFS, and OS. Table 22 summarises the key efficacy measures for the study population at the final analysis based on a median follow-up time of 11.4 months (range: 0.1, 41.2 months) for all patients.

Table 22: Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial carcinoma 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

t 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-L1 with a CPS < 10 (n=251; 68%) or > 10 (n=110; 30%) based on the PD-L1 IHC 22C3 pharmDxTM Kit (see Table 23).

Table 23: ORR and OS by PD-L1 Expression

Endpoint	CPS < 10 N=251	CPS > 10 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 pembrolizumab with or without platinum-based combination chemotherapy (i.e. either cisplatin or carboplatin with gemcitabine) versus chemotherapy as first-line treatment in subjects with advanced or metastatic urothelial carcinoma. Results of KEYNOTE-361 for pembrolizumab in combination with chemotherapy 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 tests for statistical significance of pembrolizumab versus chemotherapy could be performed. The key efficacy results of pembrolizumab monotherapy in patients for whom carboplatin rather than cisplatin was 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 > 10 were similar to the overall population for whom carboplatin was selected as the choice of chemotherapy. See Table 24 and Figures 16 and 17.

Table 24: Response to pembrolizumab 200 mg every 3 weeks or chemotherapy in patients with previously untreated urothelial carcinoma for whom carboplatin rather than cisplatin was selected by the investigator as the better choice of chemotherapy in KEYNOTE-361

Endpoint	Pembrolizumab n=170	Chemotherapy n=196	Pembrolizumab CPS > 10 n=84	Chemotherapy CPS > 10 n=89
Objective response rate
ORR %, (95% CI)	28% (21.1, 35.0)	42% (34.8, 49.1)	30% (20.3, 40.7)	46% (35.4, 57.0)
Complete response	10%	11%	12%	18%
Partial response	18%	31%	18%	28%
Response duration
Median in months (range)	NR (3.2+, 36.1+)	6.3 (1.8+, 33.8+)	NR (4.2, 36.1+)	8.3 (2.1+, 33.8+)
% with duration > 12 months'1"	57%	30%	63%	38%
PFS
Median in months (95% CI)	3.2 (2.2, 5.5)	6.7 (6.2, 8.1)	3.9 (2.2, 6.8)	7.9 (6.1, 9.3)
12-month PFS rate	25%	24%	26%	31%
OS
Median in months (95% CI)	14.6 (10.2, 17.9)	12.3 (10.0, 15.5)	15.6 (8.6, 19.7)	13.5 (9.5, 21.0)
12-month OS rate	54%	51%	57%	54%

Assessed by BICR using RECIST 1.1

' Based on Kaplan-Meier estimation

Number at Risk

Pembrolizumab:

Head and Neck Squamous Cell Carcinoma

KEYNOTE-048: Controlled study of monotherapy and combination therapy in HNSCC patients naïve to 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 for recurrent or metastatic disease and who were considered incurable by local therapies. Patients with nasopharyngeal carcinoma, active autoimmune disease that required systemic therapy within two years of 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 following treatment arms:

• • Pembrolizumab 200 mg every 3 weeks
• • Pembrolizumab 200 mg every 3 weeks, carboplatin AUC 5 mg/mL/min every 3 weeks

or cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1,000 mg/m2/d 4 days continuous every 3 weeks (maximum of 6 cycles of platinum and 5-FU)

• • Cetuximab 400 mg/m2 load then 250 mg/m2 once weekly, carboplatin AUC

5 mg/mL/min every 3 weeks or cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1,000 mg/m2/d 4 days continuous every 3 weeks (maximum of 6 cycles of platinum and 5-FU)

Treatment with pembrolizumab continued until RECIST 1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 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 these 754 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. Disease characteristics 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 patients randomised 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 to pembrolizumab monotherapy compared to standard treatment. Tables 25 and 26 summarise key efficacy 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 for pembrolizumab in combination with chemotherapy and at a median follow-up of 11.5 months for pembrolizumab monotherapy. Kaplan- Meier curves for OS based on the final analysis are shown in Figures 18 and 19.

Table 25: Efficacy results for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1 expression (CPS > 1)

Endpoint	Pembrolizumab + Platinum Chemotherapy + 5-FU n=242	Standard Treatment n=235
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 ratiot (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 ratiot (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-Value1	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

t Based on the stratified Cox proportional hazard model

i Based on stratified log-rank test

§ Response: Best objective response as confirmed complete response or partial response

1 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 18: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in

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

0	5	10	15	20	25	30	35	40	45	50
Number at Risk Pembrolizumab + Chemo: 242	197	144	109	Time in Months 84      70		52	29	5	0	0
Standard:                235	191	122	83	54	35	17	5	1	0	0

Table 26: Efficacy results for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 expression (CPS > 1)

Endpoint	Pembrolizumab n=257	Standard 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-Value1	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%

t t

§

i

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)

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%) and pembrolizumab monotherapy: n=133 (52%) vs. standard treatment: n=122 (48%)] (see Table 27).

Table 27: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as monotherapy by PD-L1 Expression in KEYNOTE-048 (CPS > 20)

Endpoint	Pembrolizumab + Platinum Chemotherapy + 5-FU n=126	Standard Treatment n=110	Pembrolizumab Monotherapy n=133	Standard Treatment * n=122
OS
Number (%) of patients with event	84 (66.7)	98 (89.1)	94 (70.7)	108 (88.5)
Median in months (95% CI)	14.7 (10.3, 19.3)	11.0 (9.2, 13.0)	14.8 (11.5, 20.6)	10.7 (8.8, 12.8)
Hazard ratic/ (95% CI)	0.60 (0.4	15, 0.82)	0.58 (0.44, 0.78)
p-Valuei	0.00044		0.00010
OS rate at 6 months (95% CI)	74.6 (66.0, 81.3)	80.0 (71.2, 86.3)	74.4 (66.1, 81.0)	79.5 (71.2, 85.7)
OS rate at 12 months (95% CI)	57.1 (48.0, 65.2)	46.1 (36.6, 55.1)	56.4 (47.5, 64.3)	44.9 (35.9, 53.4)
OS rate at 24 months (95% CI)	35.4 (27.2, 43.8)	19.4 (12.6, 27.3)	35.3 (27.3, 43.4)	19.1 (12.7, 26.6)

Endpoint	Pembrolizumab + Platinum Chemotherapy + 5-FU n=126	Standard Treatment * n=110	Pembrolizumab Monotherapy n=133	Standard Treatment * n=122
PFS
Number (%) of patients with event	106 (84.1)	104 (94.5)	115 (86.5)	114 (93.4)
Median in months (95% CI)	5.8 (4.7, 7.6)	5.3 (4.9, 6.3)	3.4 (3.2, 3.8)	5.3 (4.8, 6.3)
Hazard ratiot (95% CI)	0.76 (0.58, 1.01)		0.99 (0.76, 1.29)
p-Valuei	0.02951		0.46791
PFS rate at 6 months (95% CI)	49.4 (40.3, 57.9)	47.2 (37.5, 56.2)	33.0 (25.2, 41.0)	46.6 (37.5, 55.2)
PFS rate at 12 months (95% CI)	23.9 (16.7, 31.7)	14.0 (8.2, 21.3)	23.5 (16.6, 31.1)	15.1 (9.3, 22.2)
PFS rate at 24 months (95% CI)	14.6 (8.9, 21.5)	5.0 (1.9, 10.5)	16.8 (10.9, 23.8)	6.1 (2.7, 11.6)
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 (range)	7.1 (2.1+, 39.0+)	4.2 (1.2+, 31.5+)	22.6 (2.7+, 43.0+)	4.2 (1.2+, 31.5+)

t t

§

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 tumours expressed PD-L1 CPS > 1 to < 20 [pembrolizumab plus chemotherapy: n=116 (45%) vs. standard treatment: n=125 (49%) and pembrolizumab monotherapy: n=124 (48%) vs. standard treatment: n=133 (52%)] (see Table 28).

Table 28: Efficacy results for pembrolizumab plus chemotherapy and pembrolizumab as monotherapy by PD-L1 Expression in KEYNOTE-048 (CPS > 1 to < 20)

Endpoint	Pembrolizumab + Platinum Chemotherapy + 5-FU n=116	Standard Treatment n=125	Pembrolizumab Monotherapy n=124	Standard Treatment * n=133
OS
Number (%) of patients with event	93 (80.2)	115 (92.0)	103 (83.1)	121 (91.0)
Median in months (95% CI)	12.7 (9.4, 15.3)	9.9 (8.6, 11.5)	10.8 (9.0, 12.6)	10.1 (8.7, 12.1)
Hazard ratiot (95% CI)	0.71 (0.54, 0.94)		0.86 (0.66, 1.12)
OS rate at 6 months (95% CI)	76.7 (67.9, 83.4)	77.4 (69.0, 83.8)	67.6 (58.6, 75.1)	78.0 (70.0, 84.2)
OS rate at 12 months (95% CI)	52.6 (43.1, 61.2)	41.1 (32.4, 49.6)	44.0 (35.1, 52.5)	42.4 (33.9, 50.7)
OS rate at 24 months (95% CI)	25.9 (18.3, 34.1)	14.5 (9.0, 21.3)	22.0 (15.1, 29.6)	15.9 (10.3, 22.6)
PFS
Number (%) of patients with event	106 (91.4)	117 (93.6)	113 (91.1)	123 (92.5)
Median in months (95% CI)	4.9 (4.2, 5.3)	4.9 (3.7, 6.0)	2.2 (2.1, 2.9)	4.9 (3.8, 6.0)
Hazard ratiot (95% CI)	0.93 (0.71, 1.21)		1.25 (0.96, 1.61)
PFS rate at 6 months (95% CI)	40.1 (31.0, 49.0)	40.0 (31.2, 48.5)	24.2 (17.1, 32.0)	41.4 (32.8, 49.7)
PFS rate at 12 months (95% CI)	15.1 (9.1, 22.4)	11.3 (6.4, 17.7)	17.5 (11.4, 24.7)	12.1 (7.2, 18.5)
PFS rate at 24 months (95% CI)	8.5 (4.2, 14.7)	5.0 (1.9, 10.1)	8.3 (4.3, 14.1)	6.3 (2.9, 11.5)
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 (range)	5.6 (1.6+, 25.6+)	4.6 (1.4+, 31.4+)	NR (1.5+, 38.9+)	5.0 (1.4+, 38.7+)

* Cetuximab, platinum, and 5-FU

f Based on the stratified Cox proportional hazard model

J Response: Best objective response as confirmed complete response or partial response

KEYNOTE-040: Controlled study in HNSCC patients previously treated with platinum-containing chemotherapy

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 or metastatic HNSCC of the oral cavity, pharynx or larynx in patients who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-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-L1 expression (TPS > 50%), HPV status and ECOG performance status and then randomised (1:1) to receive 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 could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. The study excluded patients with nasopharyngeal carcinoma, active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or who were previously treated with 3 or more systemic regimens for recurrent and/or metastatic HNSCC. Assessment of tumour status was performed at 9 weeks, then every 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 these 129 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 had stage IV disease (stage IV 32%, stage IVa 14%, stage IVb 4%, and stage IVc 44%). Sixteen percent (16%) had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy, 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 months for pembrolizumab compared to 7.1 months for standard treatment. Table 29 summarises the key efficacy measures for the TPS > 50% population. The Kaplan-Meier curve for OS for the TPS > 50% population is shown in Figure 20.

Table 29: 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 200 mg every 3 weeks n=64	Standard Treatment * n=65
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 ratit? (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-Value1	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 ('%'j of patients with duration > 6 months	9 (66)	2 (50)

t

§ i # s

Methotrexate, docetaxel, or cetuximab

Hazard ratio (pembrolizumab compared to standard treatment) based on the stratified Cox proportional hazard model

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

Based on Kaplan-Meier estimation

t

Number at Risk

Pembrolizumab:      64

Standard Treatment: 65               38            22

Renal cell carcinoma

KEYNOTE-426: Controlled study of combination therapy with axitinib in RCC patients naïve to treatment

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 with autoimmune disease or a medical condition that required immunosuppression. Randomisation was stratified 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 of the following treatment arms:

• • pembrolizumab 200 mg intravenously every 3 weeks in combination with axitinib

5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for

2 consecutive treatment cycles (i.e. 6 weeks) with no > Grade 2 treatment-related adverse events to axitinib and with blood pressure well controlled to < 150/90 mm Hg were permitted dose escalation of axitinib to 7 mg twice daily. Dose escalation of axitinib to 10 mg twice daily was permitted using the same criteria. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage 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 of disease as verified by BICR or confirmed by the investigator, unacceptable toxicity, or for pembrolizumab, a maximum of 24 months. Administration of pembrolizumab and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at baseline, after randomisation at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter. Chemistry and haematology laboratory tests were performed at each cycle.

A total of 861 patients were randomised. The study population characteristics were: median age of 62 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 IMDC risk 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 median follow-up time was 12.8 months (range: 0.1 to 21.5 months). Table 30 summarises key efficacy measures from the pre-specified interim analysis. The Kaplan-Meier curves for OS and PFS based on an additional four months of follow-up are shown in Figures 21 and 22.

Table 30: Efficacy Results in KEYNOTE-426

Endpoint	Pembrolizumab Axitinib n=432	Sunitinib n=429
OS
Number of events (%)	59 (14%)	97 (23%)
Median in months (95% CI)	Not reached (NA, NA)	Not reached (NA, NA)
Hazard ratio (95% CI)	0.53 (0.38, 0.74)
p-Value^	0.00005
PFS i
Number of events (%)	183 (42%)	213 (50%)
Median in months (95% CI)	15.1 (12.6, 17.7)	11.0 (8.7, 12.5)
Hazard ratio* (95% CI)	0.69 (0.56, 0.84)
p-Value^	0.00012
Objective response rate
ORR§ % (95% CI)	59 (54, 64)	36 (31, 40)
Complete response	6%	2%
Partial response	53%	34%
p-Value1	< 0.0001
Response duration
Median in months (range)	Not reached (1.4+, 18.2+)	15.2 (1.1+, 15.4+)
Number (%#) of patients with duration > 6 months	161 (88%)	84 (81%)
Number (%#) of patients with duration > 12 months	58 (71%)	26 (62%)

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

Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region Based on Kaplan-Meier estimation

= not available

t

t

§

1

#

NA

Figure 21: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-426 (intent to treat population)

Number at Risk Pembrolizumab + Axitinib: 432	Time in Months				9	0
	411	392	275	133
Sunitinib:                  4­29	389	346	230	111	6	0

p-Value is nominal. See Table 30 for p-Value for inferential test of OS based on the pre-specified interim analysis, where statistical significance has been reached.

Figure 22: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-426 (intent to treat population)

Number at Risk Pembrolizumab + Axitinib: 432	Time in Months				0	0
	324	247	145	51
Sunitinib:                  4­29	277	175	90	32	0	0

p-Value is nominal. See Table 30 for p-Value for inferential test of PFS based on the pre-specified interim analysis, where statistical significance has been reached.

Subgroup analyses by enrolment were performed in KEYNOTE-426 in patients with PD-L1 CPS > 1 [pembrolizumab/a­xitinib combination: n=243 (56%) vs. sunitinib: n=254 (59%)]; CPS < 1 [pembrolizumab/a­xitinib combination: n=167 (39%) vs. sunitinib: n=158 (37%)], and in patients with IMDC risk categories of favourable [pembrolizumab/a­xitinib combination: n=138 (32%) vs. sunitinib: n=131 (31%)]; intermediate [pembrolizumab/a­xitinib combination: n=238 (55%) vs. sunitinib: n=246 (57%)]; and poor [pembrolizumab/a­xitinib combination: n=56 (13%) vs. sunitinib: n=52 (12%)]. OS and PFS benefits were observed regardless of PD-L1 expression level.

The KEYNOTE-426 study was not powered to evaluate efficacy of individual subgroups. Table 31 summarises the efficacy measures by IMDC risk category from the pre-specified interim analysis.

Table 31: Efficacy Results in KEYNOTE-426 by IMDC Risk Category

Endpoint	Pembrolizumab + Axitinib N = 432	Sunitinib N = 429	Pembrolizumab + Axitinib vs. Sunitinib
OS	12-month OS rate, % (95% CI)		OS HR (95% CI)
Favourable	95.2 (89.6, 97.9)	93.8 (87.4, 97.0)	0.64 (0.24, 1.68)
Intermediate	92.1 (84.7, 96.0)	76.7 (70.6, 81.8)	0.53 (0.35, 0.82)
Poor	70.3 (56.1, 80.7)	45.2 (30.0, 59.3)	0.43 (0.23, 0.81)
PFS	Median (95% CI), months		PFS HR (95% CI)
Favourable	17.7 (15.2, NA)	12.7 (11.5, NA)	0.81 (0.53, 1.24)

Endpoint	Pembrolizumab + Axitinib N = 432	Sunitinib N = 429	Pembrolizumab + Axitinib vs. Sunitinib
Intermediate	14.5 (12.4, 18.0)	9.5 (8.0, 12.5)	0.69 (0.53, 0.90)
Poor	4.9 (2.9, 12.4)	2.9 (2.7, 4.2)	0.58 (0.35, 0.94)
Confirmed ORR	% (95% CI)		ORR difference, % (95% CI)
Favourable	66.7 (58.1, 74.5)	49.6 (40.8, 58.5)	17.0 (5.3, 28.4)
Intermediate	59.2 (52.7, 65.5)	33.7 (27.9, 40.0)	25.5 (16.7, 33.9)
Poor	41.1 (28.1, 55.0)	9.6 (3.2, 21.0)	31.5 (15.7, 46.2)

NA = not available

An updated OS analysis was performed when patients had a median follow-up of 16.6 months (range: 0.1 to 26.3 months). At the time of this analysis, the hazard ratio in the overall population (95% CI) was 0.59 (0.45, 0.78) with 84/432 (19.4%) events in the combination arm and 122/429 (28.4%) events in the sunitinib arm. The 12-month OS rate was 89.5% (95% CI 86.2, 92.1) for pembrolizumab in combination with axitinib and 78.8% (95% CI 74.7, 82.4) for sunitinib. The 18-month OS rate was 81.0% (95% CI 76.7, 84.6) for pembrolizumab in combination with axitinib and 70.7% (95% CI 65.8, 75.1) for sunitinib. For the IMDC risk category, the OS hazard ratio for the favourable risk group was 0.94 (95% CI 0.43, 2.07), for the intermediate risk group the OS hazard ratio was 0.52 (95% CI 0.36, 0.75), and for the poor risk group the OS hazard ratio was 0.50 (95% CI 0.29, 0.87).

KEYNOTE-581: Controlled study of combination therapy with lenvatinib in RCC patients naïve to treatment

The efficacy of pembrolizumab in combination with lenvatinib was investigated in KEYNOTE-581, 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 papillary in the first-line setting. Patients were enrolled regardless of PD-L1 tumour expression status. The study excluded patients with active autoimmune disease or a medical condition that required immunosuppression. 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 with lenvatinib 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 the investigator and confirmed by BICR using RECIST 1.1. Administration of pembrolizumab with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Pembrolizumab was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 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 the sunitinib 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% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC risk categories was 33% favourable, 56% intermediate and 10% poor, and by MSKCC prognostic groups was 27% favourable, 64% intermediate and 9% poor. Metastatic disease was present in 99% of the patients and locally advanced disease was present in 1%. Common sites of metastases in patients were lung (69%), lymph node (46%), and bone (26%).

The primary efficacy outcome measure was PFS based on BICR using RECIST 1.1. Key secondary efficacy outcome measures included OS and ORR. The study demonstrated statistically significant improvements in PFS, OS, and ORR in patients randomised to pembrolizumab in combination with lenvatinib compared with sunitinib. The median survival follow-up time was 26.5 months. The median duration of treatment for pembrolizumab plus lenvatinib was 17.0 months. Efficacy results for KEYNOTE-581 are summarised in Table 32 and Figures 23 and 24. PFS results were consistent across pre-specified subgroups, MSKCC prognostic groups and PD-L1 tumour expression status. Efficacy results by MSKCC prognostic group are summarised in Table 33.

Table 32: Efficacy Results in KEYNOTE-581

Endpoint	Pembrolizumab 200 mg every 3 weeks and Lenvatinib n=355	Sunitinib n=357
PFS
Number of patients with event (%)	160 (45%)	205 (57%)
Median in months (95% CI)	23.9 (20.8, 27.7)	9.2 (6.0, 11.0)
Hazard ratio" (95% CI)	0.39 (0.32, 0.49)
p-Value"	< 0.0001
OS
Number of patients with event (%)	80 (23%)	101 (28%)
Median in months (95% CI)	NR (33.6, NR)	NR (NR, NR)
Hazard ratio" (95% CI)	0.66 (0.49, 0.88)
p-Value"	0.0049
Objective response rate
ORR§ (95% CI)	71% (66, 76)	36% (31, 41)
Complete response	16%	4%
Partial response	55%	32%
p-Value1	< 0.0001
Response duration #
Median in months (range)	26 (1.6+, 36.8+)	15 (1.6+, 33.2+)

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

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 plus lenvatinib with sunitinib, (odds ratio: 3.84 [95% CI: 2.81, 5.26], p-Value< 0.0001).

Based on Kaplan-Meier estimates

= not reached

The primary OS analysis was not adjusted to account for subsequent therapies.

Number at Risk

Pembrolizumab + Lenvatinib: : i ï

An updated OS analysis was performed when patients receiving pembrolizumab and lenvatinib or sunitinib had a median survival follow-up of 33.4 months. The hazard ratio was 0.72 (95% CI 0.55, 0.93) with 105/355 (30%) deaths in the combination arm and 122/357 (34%) deaths in the sunitinib arm. This updated OS analysis was not adjusted to account for subsequent therapies.

The KEYNOTE-581 study was not powered to evaluate efficacy of individual subgroups. Table 33 summarises the efficacy measures by MSKCC prognostic group from the pre-specified primary analysis and the updated OS analysis.

Table 33: Efficacy Results in KEYNOTE-581 by MSKCC Prognostic Group

	Pembrolizumab + Lenvatinib (N=355)		Sunitinib (N=357)		Pembrolizumab + Lenvatinib vs. Sunitinib
	Number of Patients	Number of Events	Number of Patients	Number of Events
Progression-Free Survival (PFS) by BICR					PFS HR (95% CI)
Favourable	96	39	97	60	0.36 (0.23, 0.54)
Intermediate	227	101	228	126	0.44 (0.34, 0.58)
Poor	32	20	32	19	0.18 (0.08, 0.42)
Overall Survival (OS)					OS HR (95% CI)
Favourable1"	96	11	97	13	0.86 (0.38, 1.92)
Intermediate	227	57	228	73	0.66 (0.47, 0.94)
Poor	32	12	32	15	0.50 (0.23, 1.08)
Updated OS					OS HR (95% CI)
Favourable1	96	17	97	17	1.00 (0.51, 1.96)
Intermediate	227	74	228	87	0.71 (0.52, 0.97)
Poor	32	14	32	18	0.50 (0.25, 1.02)

* Median follow-up: 26.5 months (data cutoff – 28 August 2020)

1 Interpretation of HR is limited by the low number of events (24/193 and 34/193)

* Median follow-up: 33.4 months (data cutoff – 31 March 2021)

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, a multicentre, randomised, double-blind, placebo-controlled study in 994 patients with increased risk of recurrence defined as intermediate-high or high risk, or M1 with no evidence of disease (NED). The intermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Grade without 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 category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins > 4 weeks prior to the time of screening. The study excluded patients with active autoimmune disease or a medical condition that required immunosuppression. Patients with RCC with clear cell component were randomised (1:1) to receive pembrolizumab 200 mg every 3 weeks (n=496) or placebo (n=498) for up to 1 year until disease recurrence 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, then every 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-four percent were N0; 83% had no sarcomatoid features; 86% were pT2 with Grade 4 or sarcomatoid features or pT3; 8% were pT4 or with nodal involvement; and 6% were M1 NED. Baseline characteristics and demographics were generally comparable between the pembrolizumab and placebo arms.

The primary efficacy outcome measure was investigator-assessed disease-free survival (DFS). The key secondary outcome measure was OS. At the pre-specified interim analysis with a median follow-up time of 23.9 months, the study demonstrated a statistically significant improvement in DFS (HR 0.68; 95% CI 0.53, 0.87; p-Value = 0.0010) for patients randomised to the pembrolizumab arm compared with placebo. Updated efficacy results with a median follow-up time of 29.7 months are summarised in Table 34 and Figure 25.

Endpoint	Pembrolizumab 200 mg every 3 weeks n=496	Placebo n=498
DFS
Number (%) of patients with event	114 (23%)	169 (34%)
Median in months (95% CI)	NR	NR
Hazard ratio* (95% CI)	0.63 (0.50, 0.80)
p-Value^	< 0.0001

Based on the stratified Cox proportional hazard model

■■    Nominal p-Value based on stratified log-rank test

NR = not reached

Figure 25: Kaplan-Meier curve for disease-free survival by treatment arm in KEYNOTE-564

At the time of the updated analysis, the DFS hazard ratio (95% CI) was 0.68 (0.52, 0.89) in the subgroup of patients with M0-intermediate-high risk of recurrence, 0.60 (0.33, 1.10) in the subgroup of patients with M0-high risk of recurrence, and 0.28 (0.12, 0.66) in the subgroup of patients with M1 NED. OS results were not yet mature with 23 deaths out of 496 patients in the pembrolizumab arm and 43 deaths out of 498 patients in the placebo arm.

Colorectal cancer

KEYNOTE-177: Controlled study in MSI-H or dMMR CRC patients naïve to treatment in the metastatic setting

The efficacy of pembrolizumab was investigated in KEYNOTE-177, a multicentre, randomised, openlabel, active-controlled study that enrolled patients with previously untreated metastatic MSI-H or dMMR CRC. MSI or MMR (mismatch repair) tumour status was determined locally using polymerase chain reaction (PCR) or IHC, respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients were randomised (1:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator’s cho­ice of the following chemotherapy regimens given intravenously every 2 weeks:

• • mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2,400 mg/m2 over 46–48 hours. Bevacizumab 5 mg/kg bw on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
• • FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2,400 mg/m2 over 46–48 hours. Bevacizumab 5 mg/kg bw on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.

Treatment with pembrolizumab continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with pembrolizumab without disease progression could be treated for up to 24 months. Assessment of tumour status was performed every 9 weeks. Patients randomised to chemotherapy were offered pembrolizumab at the time of disease 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 ECOG performance 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 bevacizumab or 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 a statistically significant improvement in PFS (HR 0.60; 95% CI 0.45, 0.80; p-Value 0.0002) for patients randomised to the pembrolizumab arm compared with chemotherapy at the pre-specified final analysis for PFS. There was no statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis in which 60% of the patients who had been randomized to receive chemotherapy had crossed over to receive subsequent anti-PD-1/PD-L1 therapies including pembrolizumab. Table 35 summarises the key efficacy measures and Figures 26 and 27 show the Kaplan Meier curves for updated PFS and OS based on the final analysis with a median follow-up time of 38.1 months (range: 0.2 to 58.7 months).

Endpoint	Pembrolizumab 200 mg every 3 weeks n=153	Chemotherapy n=154
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 ratio1 (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 rate	13%	4%
Partial response rate	32%	29%
Response duration
Median in months (range)	NR (2.3+, 53.5+)	10.6 (2.8, 48.3+)
% of patients with duration > 24 months1	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

t t

§

1

NR = not reached

Figure 26: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-177 (intent to treat population)

10

100

90

80

70

60

50

40

30

20

Number at Risk Pembrolizumab

Chemotherapy

153

154

96

101

Time in Months

o

w w

<D

T reatme nt arm PFS rate at 24 months PFS rate at 36 months

II » I ■!

Illi.....111 ni ni I il...........  H I li in II......Hi 1111 H.....11­..........1..­.............­.....1111 H I Hl I il 11........11111111111­11111111111111 r 111111 ii 1111.......

20

40

56

60

42%

11%

n i h I—i-m—I

24 28  32  36

I----HI

Pembrolizumab    48%

Chemotherapy    20%

HR (95% CI) Nominal p-value 0.59 (0.45, 0.79)       0.0001

Figure 27: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-177 (intent to treat population)

Oesophageal carcinoma

KEYNOTE-590: Controlled study of combination therapy in oesophageal carcinoma patients naïve to treatment

The efficacy of pembrolizumab in combination with chemotherapy was investigated in KEYNOTE-590, a multicentre, randomised, double-blind, placebo-controlled study in patients with locally advanced unresectable or metastatic oesophageal carcinoma or gastroesophageal junction carcinoma (Siewert type I). Patients with active autoimmune disease, a medical condition that required immunosuppression, or known HER-2 positive GEJ adenocarcinoma patients were ineligible for the study. Randomisation was 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 with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and 5-FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for 5-FU administration.
• • Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and 5-FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for 5-FU administration.

Treatment with pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression or a maximum of 24 months. Patients randomised to pembrolizumab were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. 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 these 383 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 cell carcinoma, 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 a statistically significant improvement in OS and PFS for all pre-specified study populations. In all patients randomised to pembrolizumab in combination with chemotherapy, compared to chemotherapy the OS HR was 0.73 (95% CI 0.62–0.86) and the PFS HR was 0.65 (95% CI 0.55–0.76). Secondary efficacy outcome measures were ORR and duration of response, according to RECIST 1.1 as assessed by the investigator. Table 36 summarises key efficacy measures from the pre-specified analysis in patients whose tumours expressed PD-L1 with a CPS > 10 in KEYNOTE-590 performed at a median follow-up time of 13.5 months (range: 0.5 to 32.7 months). The Kaplan-Meier curve for OS and PFS are shown in Figures 28 and 29.

Table 36: Efficacy Results for pembrolizumab plus chemotherapy in KEYNOTE-590 with

PD-L1 expression (CPS > 10)

Endpoint	Pembrolizumab Cisplatin Chemotherapy 5-FU n=186	Standard Treatment n=197
OS
Number (%) of patients with event	124 (66.7%)	165 (83.8%)
Median in months1 (95% CI)	13.5 (11.1, 15.6)	9.4 (8.0, 10.7)
Hazard ratio1 (95% CI)	0.62 (0.49, 0.78)
p-Value§	< 0.0001
PFS 1
Number (%) of patients with event	140 (75.3)	174 (88.3)
Median in months1 (95% CI)	7.5 (6.2, 8.2)	5.5 (4.3, 6.0)
Hazard ratio1 (95% CI)	0.51 (0.41, 0.65)
p-Value§	< 0.0001
Objective response rate 1
Objective response rate§ (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 1, '’
Median in months (range)	10.4 (1.9, 28.9+)	5.6 (1.5+, 25.0+)
% with duration > 6 months1	80.2%	47.7%
% with duration > 12 months1	43.7%	23.2%
% with duration > 18 months1	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) and tumour histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1)

Assessed by investigator using RECIST 1.1

One-sided p-Value for testing. H0: difference in % = 0 versus H1: difference in % > 0

Best objective response as confirmed complete response or partial response.

t t

§

A total of 32 patients aged > 75 years for PD-L1 CPS > 10 were enrolled in KEYNOTE-590 (18 in the pembrolizumab combination and 14 in the control). Data about efficacy of pembrolizumab in combination with chemotherapy are too limited in this patient population.

0

3

6

9

12

15     18     21 Time in Months

24

27

30

33

Number at Risk

Pembrolizumab+SOC	186	175	151	125	100	79	66	40	23	10	4	0
SOC	197	174	142	102	73	55	42	28	13	6	1	0

• Figure 29: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-590 with PD-L1 expression (CPS > 10)

100

90

80

70

60

50

40

30

20

10

0

109     56      48      36      29      17      12      2       1 0

85      26      14      12      7       5       2       1       0 0

Triple-negative breast cancer

KEYNOTE-355: Controlled study of combination therapy in TNBC patients previously untreated  for metastatic disease

The efficacy of pembrolizumab in combination with paclitaxel, nab-paclitaxel, or gemcitabine and carboplatin 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 the advanced setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by chemotherapy treatment (paclitaxel or nab-paclitaxel vs. gemcitabine and carboplatin), tumour PD-L1 expression (CPS > 1 vs. CPS < 1), and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Patients were randomised (2:1) to one of the following treatment arms via intravenous infusion:

• • Pembrolizumab 200 mg 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 28 days, or gemcitabine 1,000 mg/m2 and carboplatin AUC 2 mg/mL/min on 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 28 days, or gemcitabine 1,000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 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 of pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Assessment of tumour status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter.

Among the 847 patients randomised in KEYNOTE-355, 636 (75%) had tumours that expressed PD-L1 with 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-L1 expression 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%) and 1 (39%); 67% were post-menopausal status; 3% had a history of brain metastases; and 20% had disease-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 BICR using RECIST 1.1. The study demonstrated a statistically significant improvement in PFS at its pre-specified interim analysis (HR 0.65; 95% CI 0.49, 0.86; p-Value 0.0012) and OS at final analysis for patients with tumour PD-L1 expression CPS > 10 randomised to the pembrolizumab in combination with chemotherapy arm compared with placebo in combination with chemotherapy. Table 37 summarises key efficacy measures and Figures 30 and 31 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 to 53.1 months) for patients with tumour PD-L1 expression CPS > 10.

Table 37: Efficacy Results in KEYNOTE-355 patients with CPS > 10

Endpoint	Pembrolizumab with chemotherapy n=220	Placebo with chemotherapy * n=103
PFS '
Number (%) of patients with event	144 (65%)	81 (79%)
Hazard ratio-1– (95% CI)	0.66 (0.50, 0.88)
p-Value§	0.0018
Median in months (95% CI)	9.7 (7.6, 11.3)	1         5.6 (5.3, 7.5)
OS
Number (%) of patients with event	155 (70%)	84 (82%)
Hazard ratio1 (95% CI)	0.73 (0.55, 0.95)
p-Value1	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, 60)	41% (31, 51)
Complete response	17%	14%
Partial response	36%	27%
Response duration' 1'
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

• t Assessed by BICR using RECIST 1.1

* Based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by chemotherapy on study (taxane vs. gemcitabine and carboplatin) and prior treatment with same class of chemotherapy in the neoadjuvant setting (yes vs. no)

§ Nominal p-Value based on log-rank test stratified by chemotherapy on study (taxane vs. gemcitabine and carboplatin) and prior treatment with same class of chemotherapy in the neoadjuvant setting (yes vs. no). At the pre-specified interim analysis of PFS (median follow-up time of 19.2 months), statistically significant superiority 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 and carboplatin) and prior treatment with same class of chemotherapy in the neoadjuvant setting (yes vs. no). OS results 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 30: Kaplan-Meier curve for progression-free survival by treatment arm in

KEYNOTE-355 patients with PD-L1 expression (CPS > 10)

100

15

52

15

12

63

18

18 21 24 27 30 33

Time in Months

36

27

6

39

19 4

42

13

4

45

6

3

48

51

54

9

173

80

122

41

95

30

44 42 38 36 34

12 11 11 10 8

32 8

Number at Risk

Pembrolizumab + Chemotherapy

Placebo + Chemotherapy

220

103

0.66 (0.50, 0.88) 0.0018

90

80

70

60

50

40

30

41 S III  II I—H—I

-I--

20

10

–4

niTiTnTr|Tmii­iiii|iiiiiiif­npTmTiTTT]nim­rTTijTTTnmrTpTrmi­ii|iiuiiiiiip­Tn,rTTniprrii­iiiii|iiiiiin­TT[TnTiTnn|ii­iiiiiiii|iiHi­iiiii|tiiiiii­iii|iiiiiMiii|i­iiiiiiiii|iii­iiiiiii

39% 23%

T reatment arm ----Pembrolizumab + Chemotherapy ---Placebo + Chemotherapy

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

Figure 31: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-355 patients with PD-L1 expression (CPS > 10)

KEYNOTE-775: Controlled study of combination therapy in advanced EC patients previously treated with systemic chemotherapy

The efficacy of pembrolizumab in combination with lenvatinib was investigated in KEYNOTE-775, a randomised, multicentre, open-label, active-controlled study conducted in patients with advanced EC who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Participants may have received up to 2 platinum-containing therapies in total, as long as one was given in the neoadjuvant or adjuvant treatment setting. The study excluded patients with endometrial sarcoma, carcinosarcoma, pre-existing Grade > 3 fistula, uncontrolled BP (> 150/90 mmHg), significant cardiovascular impairment or event within previous 12 months, or patients who had active autoimmune disease or a medical condition that required 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 were randomised (1:1) to one of the following treatment arms:

• • pembrolizumab 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily.
• • investigator’s cho­ice consisting of either doxorubicin 60 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly, 3 weeks on/1 week off.

Treatment with pembrolizumab and lenvatinib continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for pembrolizumab, a maximum of 24 months.

Administration of study treatment was permitted beyond RECIST-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated. A total of 121/411 (29%) of the pembrolizumab and lenvatinib-treated patients received continued study therapy beyond RECIST-defined disease progression. The median duration of the post-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 with lenvatinib (n=411) or investigator’s cho­ice of doxorubicin (n=306) or paclitaxel (n=110). The baseline characteristics 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 pMMR tumour status and 16% with dMMR tumour status. The histologic subtypes were endometrioid carcinoma (60%), serous (26%), clear cell carcinoma (6%), mixed (5%), and other (3%). All 827 of these patients received prior systemic therapy for EC: 69% had one, 28% had two, and 3% had three or 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. The median follow-up time was 11.4 months (range: 0.3 to 26.9 months). Efficacy results by MMR subgroups were consistent with overall study results. Efficacy measures are summarised in Table 38 and Kaplan-Meier curves for OS and PFS are shown in Figures 32 and 33, respectively.

Table 38: Efficacy results in KEYNOTE-775

Endpoint	Pembrolizumab 200 mg every 3 weeks Lenvatinib n=411	Chemotherapy n=416
OS
Number (%) of patients with event	188 (46%)	245 (59%)
Median in months (95% CI)	18.3 (15.2, 20.5)	11.4 (10.5, 12.9)
Hazard ratio" (95% CI)	0.62 (0.51, 0.75)
p-Value"	< 0.0001
PFS
Number (%) of patients with event	281 (68%)	286 (69%)
Median in months (95% CI)	7.2 (5.7, 7.6)	3.8 (3.6, 4.2)
Hazard ratio" (95% CI)	0.56 (0.4	17, 0.66)
p-Value^	< 0.0001
Objective response rate
ORR§ (95% CI)	32% (27, 37)	15% (11, 18)
Complete response %	7%	3%
Partial response %	25%	12%
p-Value1	< 0.0001
Response duration
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

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 performance status, geographic region, and history of pelvic radiation

Based on Kaplan-Meier estimation

t t

§

1

Figure 32: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-775 (intent to treat population)

	0	3	6	9	12	15	18	21	24	27
Number at Risk Pembrolizumab + Lenvatinib: – ■ '		333	337	282	Time in Months 198     136		81	40	7	0
Chemotherapy:	416	373	300	228	138	80	40	11	3	0

Figure 33: Kaplan-Meier curve for progression free-survival by treatment arm in KEYNOTE-775 (intent to treat population)

+

Chemotherapy:

Number at Risk Pembrolizumab

Treatment arm

Pembrolizumab + Lenvatinib

Chemotherapy

HR (95% CI) p-value

0.56 (0.47, 0.66) <0.0001

For pMMR patients (n=697), the OS HR was 0.68 (95% CI: 0.56, 0.84), p=0.0001, one-sided; with median OS of 17.4 months for pembrolizumab and lenvatinib versus 12.0 months for chemotherapy. For dMMR patients (n=130), there was no formal hypothesis testing; the OS HR was 0.37 (95% CI: 0.22, 0.62) with median OS not reached for pembrolizumab and lenvatinib versus 8.6 months for chemotherapy.

Elderly population

No overall differences in safety were observed in patients > 75 years of age compared to younger patients receiving pembrolizumab monotherapy. Based on limited safety data from patients > 75 years of age, when administrated in combination with chemotherapy, pembrolizumab showed less tolerability 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.

Paediatric population

In KEYNOTE-051, 161 paediatric patients (62 children aged 9 months to less than 12 years and 99 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 bw every 3 weeks. All patients received pembrolizumab for a median of 4 doses (range 1–35 doses), with 138 patients (85.7%) receiving pembrolizumab for 2 doses or more. Participants were enrolled across 28 tumour types by primary diagnosis. The most common tumour types by histology were Hodgkin lymphoma (13.7%), glioblastoma multiforme (9.3%), neuroblastoma (6.2%), osteosarcoma (6.2%) and melanoma (5.6%). Of the 161 patients, 137 were enrolled with solid tumours, 22 with Hodgkin lymphoma, 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. In the Hodgkin lymphoma population (n=22), in patients aged 11 years to 17 years, the baseline characteristics were median age 15 years; 64% male; 68% White; 77% had a Lansky/Karnofsky scale 90–100 and 23% had scale 70–80. Eighty-six percent had two or more prior lines of therapy and 91% had Stage 3 or higher. In these paediatric patients with cHL, the ORR assessed by BICR according to the 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.

The European Medicines Agency has deferred the obligation to submit the results of studies with pembrolizumab in one or more subsets of the paediatric population in treatment of Hodgkin lymphoma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of pembrolizumab was studied in 2,993 patients with metastatic or unresectable melanoma, NSCLC, or carcinoma who received doses in the range of 1 to 10 mg/kg bw every 2 weeks, 2 to 10 mg/kg bw every 3 weeks, or 200 mg every 3 weeks.

Absorption

Pembrolizumab is administered via the intravenous route and therefore is immediately and completely bioavailable.

Distribution

Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady-state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.

Biotransformation

Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its clearance.

Elimination

Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) after achieving 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.

Linearity/non-linearity

Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area under the plasma concentration 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 an every 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 and 29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve at steady-state over 3 weeks (AUCo—3weeks) was 794 mcg^day/mL at a dose of 2 mg/kg bw every 3 weeks and 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 observed median Cmin at steady-state was up to 40% higher than that in other tumour types treated with the same dosage; however, the range of trough concentrations is similar. There are no notable differences in median Cmax between cHL and other tumour types. Based on available safety data in cHL and other tumour types, these differences are not clinically meaningful.

Special populations

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range 15–94 years), gender, race, mild or moderate renal impairment, mild hepatic impairment and tumour burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of exposure. Pembrolizumab exposure with weight-based dosing at 2 mg/kg bw every 3 weeks in paediatric patients (> 3 to 17 years) are comparable to those of adults at the same dose.

Renal impairment

The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Pembrolizumab has not been studied in patients with severe renal impairment.

Hepatic impairment

The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild hepatic impairment (as defined using the US National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment (see section 4.2).

5.3 Preclinical safety data

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 the 1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free period. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was > 200 mg/kg bw, which produced exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 mg/kg bw, respectively. The exposure multiple between 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 pathway is 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 and to result in an increase in foetal loss.

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, many animals in these studies were not sexually mature.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Polysorbate 80 (E433)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

2 years.

After preparation of infusion

From a microbiological point of view, the product, once diluted, should be used immediately. The diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 2°C to 8°C. This 96-hour hold may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior to use.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

4 mL of concentrate in a 10 mL Type I clear glass vial, with a coated grey chlorobutyl or bromobutyl stopper and an aluminium seal with a dark blue coloured flip-off cap, containing 100 mg pembrolizumab.

Each carton contains one vial.

6.6 Special precautions for disposal and other handling

Preparation and administration of the infusion

• • 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 and discolouration 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 an intravenous bag containing sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Each vial contains an excess fill of 0.25 mL (total content per vial 4.25 mL) to ensure the recovery of 4 mL of concentrate. Mix diluted solution by gentle inversion.
• • From a microbiological point of view, the product, once diluted, should be used immediately. The diluted solution must not be frozen. If not used immediately, chemical and physical in-use stability of KEYTRUDA has been demonstrated for 96 hours at 2°C to 8°C. This 96-hour hold may include up to 6 hours at room temperature (at or below 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to come to room temperature prior 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 jam 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.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.

Waarderweg 39 2031 BN Haarlem The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1024/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 July 2015

Date of latest renewal: 24 March 2020