This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

KEYTRUDA® 50 mg powder for concentrate for solution for infusion.

2. Qualitative and quantitative composition

One vial of powder contains 50 mg of pembrolizumab.

After reconstitution, 1 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

Powder for concentrate for solution for infusion.

White to off-white lyophilised powder.

4. Clinical particulars
4.1 Therapeutic indications

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).

KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) 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 NSCLC 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 NSCLC in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC 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.

KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV.

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).

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 (HNSCC) 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 HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy (see section 5.1).

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

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 for patients with NSCLC, urothelial carcinoma, or HNSCC

Testing for PD-L1 tumour expression using a validated test is recommended for patients with NSCLC. In patients with NSCLC whose tumours have high PD-L1 expression, the risk of adverse reactions with combination therapy relative to pembrolizumab monotherapy should be considered and the benefit/risk ratio of the combined therapy evaluated on an individual basis (see sections 4.1, 4.4, 4.8 and 5.1).

Patients with HNSCC or previously untreated urothelial carcinoma should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).

Posology

The recommended dose of KEYTRUDA as monotherapy 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 part of combination therapy is 200 mg every 3 weeks administered as an intravenous infusion over 30 minutes.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity. 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, 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)

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

Adrenal insufficiency

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 endocrinopathy that improved to Grade 2 or lower and is controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued.

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)

Grades 3 or 4 myocarditis

Grades 3 or 4 encephalitis

Grades 3 or 4 Guillain-Barré syndrome

Grade 4 or recurrent Grade 3

Withhold until adverse reactions recover to Grades 0-1*

Permanently discontinue

 

 

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 Summary of Product Characteristics (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.

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 section 5.1). Data from patients ≥ 65 years are too limited to draw conclusions on cHL population (see section 5.1). Data from pembrolizumab monotherapy in patients with resected Stage III melanoma, from pembrolizumab in combination with axitinib in patients with advanced RCC, from chemotherapy combination in patients with metastatic NSCLC, and from pembrolizumab (with or without chemotherapy) in patients receiving first-line treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited (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).

Ocular melanoma

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

Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 2

Patients with ECOG performance status score ≥ 2 were excluded from the clinical trials of melanoma, NSCLC, cHL, and HNSCC (see sections 4.4 and 5.1).

Paediatric population

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

Method of administration

KEYTRUDA must be administered by intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection.

For use in combination, see the SmPC for the concomitant therapies. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first.

For instructions on reconstitution and 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

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 remains at 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 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. (See 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, and pembrolizumab should be withheld for adrenal insufficiency or symptomatic hypophysitis until the event is controlled with hormone replacement. 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 Grade 3 hyperglycaemia 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. For patients with Grade 3 or Grade 4 hyperthyroidism that improved to Grade 2 or lower, continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see sections 4.2 and 4.8). Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

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 or permanently discontinued, 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 signs or symptoms of 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 anticancer agents.

Other immune-related adverse reactions

The following additional clinically significant, immune-related adverse reactions have been reported in clinical trials or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis and encephalitis (see sections 4.2 and 4.8).

Based on the severity of the adverse reaction, pembrolizumab should be withheld and corticosteroids administered.

Pembrolizumab may be restarted within 12 weeks after last dose of KEYTRUDA if the adverse reaction remains at 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 (see sections 4.2 and 4.8).

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid 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 classical Hodgkin lymphoma 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 severe infusion reactions, infusion should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with mild or moderate infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with antipyretic and antihistamine may be considered.

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 cancer, 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 cancer 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 is being assessed in a comparative study, and 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 non-small cell lung cancer whose tumours express PD-L1.

Efficacy and safety data from patients ≥ 75 years are limited. For patients ≥ 75 years, pembrolizumab combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis (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 head and neck squamous cell carcinoma 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).

Patients excluded from clinical trials

Patients with the following conditions were excluded from clinical trials: active CNS metastases; ECOG PS ≥ 2 (except for urothelial carcinoma and RCC); HIV, 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 trials 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 trials, therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

For subjects with relapsed or refractory classical Hodgkin lymphoma, clinical data for the use of pembrolizumab in patients ineligible to ASCT due to reasons other than failure to salvage chemotherapy are limited (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 signaling 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 may have a minor influence on the ability to drive and use machines. Fatigue has 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 safety of pembrolizumab as monotherapy has been evaluated in 5,884 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or HNSCC across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks) in clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the median observation time was 7.3 months (range: 1 day to 31 months) and the most frequent adverse reactions with pembrolizumab were fatigue (32%), nausea (20%), and diarrhoea (20%). 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 safety of pembrolizumab in combination with chemotherapy has been evaluated in 1,067 patients with NSCLC or HNSCC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, in clinical studies. The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the most frequent adverse reactions were anaemia (50%), nausea (50%), fatigue (37%), constipation (35%), diarrhoea (30%), neutropaenia (30%), decreased appetite (28%) and vomiting (25%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone and in patients with HNSCC were 85% for pembrolizumab combination therapy and 84% for chemotherapy plus cetuximab.

The safety of pembrolizumab in combination with axitinib has been evaluated in a clinical study of 429 patients with advanced RCC receiving 200 mg pembrolizumab every 3 weeks and 5 mg axitinib twice daily. In this patient population, the most frequent adverse reactions were diarrhoea (54%), hypertension (45%), fatigue (38%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysaesthesia syndrome (28%), nausea (28%), ALT increased (27%), AST increased (26%), dysphonia (25%), cough (21%), and constipation (21%). Incidences of Grades 3-5 adverse reactions were 76% for pembrolizumab combination therapy and 71% for sunitinib alone.

Tabulated list 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. Adverse reactions known to occur with pembrolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. 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.

Table 2: Adverse reactions in patients treated with pembrolizumab*

Monotherapy

Combination with chemotherapy

Combination with axitinib

Infections and infestations

Common

pneumonia

pneumonia

pneumonia

Blood and lymphatic system disorders

Very common

anaemia

anaemia, neutropaenia, thrombocytopaenia

Common

thrombocytopaenia, lymphopaenia

febrile neutropaenia, leukopaenia, lymphopaenia

anaemia, neutropaenia, leukopaenia, thrombocytopaenia

Uncommon

neutropaenia, leukopaenia, eosinophilia

lymphopaenia, eosinophilia

Rare

immune thrombocytopenic purpura, haemolytic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis

eosinophilia

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

hyperthyroidism, hypothyroidismb

Common

hyperthyroidism

hypothyroidism, hyperthyroidism

hypophysitisd, thyroiditise, adrenal insufficiencyc

Uncommon

adrenal insufficiencyc, hypophysitisd, thyroiditise

hypophysitisd, thyroiditise, adrenal insufficiencyc

Metabolism and nutrition disorders

Very common

decreased appetite

hypokalaemia, decreased appetite

decreased appetite

Common

hyponatraemia, hypokalaemia, hypocalcaemia

hyponatraemia, hypocalcaemia

hypokalaemia, hyponatraemia, hypocalcaemia

Uncommon

type 1 diabetes mellitusf

type 1 diabetes mellitus

type 1 diabetes mellitusf

Psychiatric disorders

Common

insomnia

insomnia

insomnia

Nervous system disorders

Very common

headache

dizziness, headache, neuropathy peripheral, dysgeusia

headache, dysgeusia

Common

dizziness, neuropathy peripheral, lethargy, dysgeusia

lethargy

dizziness, lethargy, neuropathy peripheral

Uncommon

epilepsy

epilepsy

myasthenic syndromeh

Rare

Guillain-Barré syndromeg, myasthenic syndromeh, meningitis (aseptic)i, encephalitis

Eye disorders

Common

dry eye

dry eye

dry eye

Uncommon

uveitisj

uveitisj

Rare

Vogt-Koyanagi-Harada syndrome

Cardiac disorders

Common

cardiac arrhythmia(including atrial fibrillation)

cardiac arrhythmia(including atrial fibrillation)

cardiac arrhythmia(including atrial fibrillation)

Uncommon

pericardial effusion, pericarditis

pericardial effusion

myocarditisk

Rare

myocarditisk

myocarditisk, pericarditis

Vascular disorders

Very common

hypertension

Common

hypertension

hypertension

Respiratory, thoracic and mediastinal disorders

Very common

dyspnoea, cough

dyspnoea, cough

dyspnoea, cough, dysphonia

Common

pneumonitisl

pneumonitisl

pneumonitisl

Gastrointestinal disorders

Very common

diarrhoea, abdominal painm, nausea, vomiting, constipation

diarrhoea, nausea, vomiting, constipation, abdominal painm

diarrhoea, abdominal painm, nausea, vomiting, constipation

Common

colitisn, dry mouth

colitisn, dry mouth

colitisn, dry mouth

Uncommon

pancreatitiso

pancreatitiso

pancreatitiso

Rare

small intestinal perforation

Hepatobiliary disorders

Common

hepatitisp

Uncommon

hepatitisp

hepatitisp

Skin and subcutaneous tissue disorders

Very common

rashq, pruritusr

rashq, alopecia, pruritusr

palmar-plantar erythrodysaesthesia syndrome, rashq, pruritusr

Common

severe skin reactionss, erythema, dry skin, vitiligot, eczema, alopecia, dermatitis acneiform

severe skin reactionss, erythema, dry skin

severe skin reactionss, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema

Uncommon

lichenoid keratosisu, psoriasis, dermatitis, papule, hair colour changes

psoriasis, dermatitis acneiform, dermatitis, vitiligot, eczema

hair colour changes, lichenoid keratosis, papule, psoriasis, vitiligot

Rare

toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema nodosum

hair colour changes, lichenoid keratosis, papule

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal painv, arthralgia

musculoskeletal painv, arthralgia

musculoskeletal painv, arthralgia, pain in extremity

Common

pain in extremity, myositisw, arthritisx

myositisw, pain in extremity, arthritisx

myositisw, arthritisx, tenosynovitisy

Uncommon

tenosynovitisy

tenosynovitisy

Renal and urinary disorders

Common

nephritisz, acute kidney injury

acute kidney injury, nephritisz

Uncommon

nephritisz

General disorders and administration site conditions

Very common

fatigue, asthenia, oedemaaa, pyrexia

fatigue, asthenia, pyrexia, oedemaaa

fatigue, asthenia, pyrexia

Common

influenza like illness, chills

chills, influenza-like illness

oedemaaa, influenza like illness, chills

Investigations

Very common

blood creatinine increased

alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased

Common

aspartate aminotransferase increased, alanine aminotransferase increased, hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased, blood creatinine increased

hypercalcaemia, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased

blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased

Uncommon

amylase increased

blood bilirubin increased, 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 and cytokine release syndrome)

b. hypothyroidism (myxoedema)

c. adrenal insufficiency (Addison's disease, adrenocortical insufficiency acute, secondary adrenocortical insufficiency)

d. hypophysitis (hypopituitarism)

e. thyroiditis (autoimmune thyroiditis and thyroid disorder)

f. type 1 diabetes mellitus (diabetic ketoacidosis)

g. Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)

h. myasthenic syndrome (myasthenia gravis, including exacerbation)

i. meningitis aseptic (meningitis, meningitis non-infective)

j. uveitis (iritis and iridocyclitis)

k. myocarditis (autoimmune myocarditis)

l. pneumonitis (interstitial lung disease)

m. abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)

n. colitis (colitis microscopic, enterocolitis, enterocolitis haemorrhagic, and autoimmune colitis)

o. pancreatitis (autoimmune pancreatitis and pancreatitis acute)

p. hepatitis (autoimmune hepatitis, immune-mediated hepatitis and drug induced liver injury)

q. rash (rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)

r. pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital)

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

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

u. lichenoid keratosis (lichen planus and lichen sclerosus)

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

w. myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis)

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

y. tenosynovitis (tendonitis, synovitis and tendon pain)

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

aa. 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 every 3 weeks, 10 mg/kg 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 253 (4.3%) patients, including Grade 2, 3, 4 or 5 cases in 106 (1.8%), 69 (1.2%), 13 (0.2%) and 9 (0.2%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.3 months (range 2 days to 26.8 months). The median duration was 1.9 months (range 1 day to 25.3+ 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 (3.4%). Pneumonitis led to discontinuation of pembrolizumab in 98 (1.7%) patients. Pneumonitis resolved in 138 patients, 2 with sequelae.

In patients with NSCLC, pneumonitis occurred in 107 (4.9%), including Grade 2, 3, 4 or 5 cases in 39 (1.8%), 30 (1.4%), 10 (0.5%) and 9 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.1% with a history of prior thoracic radiation.

Immune-related colitis

Colitis occurred in 107 (1.8%) patients, including Grade 2, 3 or 4 cases in 31 (0.5%), 62 (1.1%) and 3 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 4.3 months (range 7 days to 24.3 months). The median duration was 0.9 months (range 1 day to 8.7+ months). Colitis led to discontinuation of pembrolizumab in 29 (0.5%) patients. Colitis resolved in 84 patients, 2 with sequelae.

Immune-related hepatitis

Hepatitis occurred in 50 (0.8%) patients, including Grade 2, 3 or 4 cases in 8 (0.1%), 31 (0.5%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 3.6 months (range 8 days to 21.4 months). The median duration was 1.1 months (range 1 day to 20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 19 (0.3%) patients. Hepatitis resolved in 36 patients.

Immune-related nephritis

Nephritis occurred in 22 (0.4%) patients, including Grade 2, 3 or 4 cases in 5 (0.1%), 14 (0.2%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 5.0 months (range 12 days to 21.4 months). The median duration was 2.6 months (range 6 days to 12.0 months). Nephritis led to discontinuation of pembrolizumab in 10 (0.2%) patients. Nephritis resolved in 13 patients, 3 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 46 (0.8%) patients, including Grade 2, 3 or 4 cases in 19 (0.3%), 20 (0.3%) and 3 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of adrenal insufficiency was 5.4 months (range 1 day to 17.7 months). The median duration was not reached (range 3 days to 26.2+ months). Adrenal insufficiency led to discontinuation of pembrolizumab in 4 (0.1%) patients. Adrenal insufficiency resolved in 16 patients, 4 with sequelae.

Hypophysitis occurred in 36 (0.6%) patients, including Grade 2, 3 or 4 cases in 13 (0.2%), 19 (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 18.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 8 (0.1%) patients. Hypophysitis resolved in 17 patients, 8 with sequelae.

Hyperthyroidism occurred in 244 (4.1%) patients, including Grade 2 or 3 cases in 64 (1.1%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 22.5 months). The median duration was 1.8 months (range 4 days to 29.2+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (0.1%) patients. Hyperthyroidism resolved in 191 (78.3%) patients, 5 with sequelae.

Hypothyroidism occurred in 645 (11.0%) patients, including Grade 2 or 3 cases in 475 (8.1%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 1 day to 19.6 months). The median duration was not reached (range 2 days to 32.6+ months). Two patients (< 0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 153 (23.7%) patients, 10 with sequelae. In patients with cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3. 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.

Immune-related skin adverse reactions

Immune-related severe skin reactions occurred in 89 (1.5%) patients, including Grade 2, 3 or 5 cases in 10 (0.2%), 65 (1.1%) 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 19.4 months). The median duration was 1.6 months (range 1 day to 27.3+ months). Severe skin reactions led to discontinuation of pembrolizumab in 9 (0.2%) patients. Severe skin reactions resolved in 64 patients.

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 classical Hodgkin lymphoma

Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed severe hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a median follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).

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: 10.9% for lymphocytes decreased, 8.2% for sodium decreased, 6.3% for haemoglobin decreased, 5.2% for phosphate decreased, 4.8% for glucose increased, 2.8% for AST increased, 2.7% for alkaline phosphatase increased, 2.7% for ALT increased, 2.2% for potassium decreased, 1.8% for calcium increased, 1.8% for neutrophils decreased, 1.8% for potassium increased, 1.7% for bilirubin increased, 1.7% for platelets decreased, 1.6% for albumin decreased, 1.5% for calcium decreased, 1.3% for creatinine increased, 0.8% for leucocytes decreased, 0.7% for magnesium increased, 0.6% for glucose decreased, 0.2% for magnesium decreased, and 0.2% for sodium increased.

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: 26.7% for neutrophils decreased, 23.9% for lymphocytes decreased, 19.1% for haemoglobin decreased, 17.9% for leucocytes decreased, 12.2% for platelets decreased, 10.2% for sodium decreased, 8.9% for phosphate decreased, 7.4% for glucose increased, 6.5% for potassium decreased, 3.3 for creatinine increased, 3.1% for ALT increased, 3.1% for AST increased, 3.1% for calcium decreased, 3.0% for potassium increased, 2.9% for albumin decreased, 2.3% for calcium increased, 1.2% for alkaline phosphatase increased, 0.8% for glucose decreased, 0.7% for bilirubin increased, and 0.3% for sodium increased.

In patients treated with pembrolizumab in combination with axitinib, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 20.1% for ALT increased, 13.2% for AST increased, 10.8% for lymphocytes decreased, 8.9% for glucose increased, 7.8% for sodium decreased, 6.4% for phosphate decreased, 6.2% for potassium increased, 4.3% for creatinine increased, 3.6% for potassium decreased, 2.1% for bilirubin increased, 2.1% for haemoglobin decreased, 1.7% for alkaline phosphatase increased, 1.5% for prothrombin INR increased, 1.4% for leukocytes decreased, 1.4% for platelets decreased, 1.2% for activated partial thromboplastin time prolonged, 1.2% for neutrophils decreased, 1.2% for sodium increased, 0.7% for calcium decreased, 0.7% for calcium increased, 0.5% for albumin decreased, and 0.2% for glucose decreased.

Immunogenicity

In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg 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 154 paediatric patients with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg every 3 weeks in the Phase I/II study KEYNOTE-051. The safety profile in these 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 (31%), vomiting (26%), headache (22%), abdominal pain (21%), anaemia (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. Sixty-nine (44.8%) patients had 1 or more Grades 3 to 5 adverse reactions of which 6 (3.9%) 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC18

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.

Clinical efficacy and safety

Pembrolizumab doses of 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks were evaluated in melanoma or previously treated NSCLC clinical trials. 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 every 3 weeks, and 400 mg every 6 weeks as monotherapy (see section 4.2).

Melanoma

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, 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 every 2 (n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg 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 overall 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 every 3 weeks

n=277

Pembrolizumab

10 mg/kg every 2 weeks

n=279

Ipilimumab

3 mg/kg 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 overall 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

Based on stratified Log rank test

Based on patients with a best overall 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)

Figure 2: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-006 (intent to treat population)

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-002, a multicentre, 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 (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 or 10 mg/kg 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 every 3 weeks

n=180

Pembrolizumab

10 mg/kg 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

0.0106

---

Median in months (95% CI)

13.4 (11.0, 16.4)

14.7 (11.3, 19.5)

11.0 (8.9, 13.8)

Best overall 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%

79%

0%

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

Based on stratified Log rank test

Not statistically significant after adjustment for multiplicity

§ Based on patients with a best overall response as confirmed complete or partial response from the final analysis

Based on Kaplan-Meier estimation

Figure 3: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-002 (intent to treat population)

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 every 3 weeks or 10 mg/kg 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 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 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 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 every 3 weeks in patients previously treated with ipilimumab

n=89

Pembrolizumab 2 mg/kg every 3 weeks in patients naïve to treatment with ipilimumab

n=51

Best Overall Response* by IRO

ORR %, (95% CI)

26% (17, 36)

35% (22, 50)

Complete response

7%

12%

Partial response

19%

24%

Disease Control Rate %

48%

49%

Response Duration§

Median in months (range)

30.5 (2.8+, 30.6+)

27.4 (1.6+, 31.8+)

% ongoing at 24 months

75%

71%

PFS

Median in months (95% CI)

4.9 (2.8, 8.3)

4.7 (2.8, 13.8)

PFS rate at 12 months

34%

38%

OS

Median in months (95% CI)

18.9 (11, not available)

28.0 (14, not available)

OS rate at 24 months

44%

56%

* Includes patients without measurable disease at baseline by independent radiology

IRO = Integrated radiology and oncologist assessment using RECIST 1.1

Based on best response of stable disease or better

§ Based on patients with a confirmed response by independent review, starting from the date the response was first recorded; n=23 for patients previously treated with ipilimumab; n=18 for patients naïve to treatment with ipilimumab

Based on Kaplan-Meier estimation

Results for patients previously treated with ipilimumab (n=84) and naïve to treatment with ipilimumab (n=52) who received 10 mg/kg of pembrolizumab every 3 weeks were similar to those seen in patients who received 2 mg/kg 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 2mg/kg every 3 weeks (n=136)

Chemotherapy

(n=137)

Pembrolizumab 2mg/kg every 3 weeks (n=44)

Chemotherapy

(n=42)

PFS Hazard ratio* (95% CI)

0.50 (0.39, 0.66)

---

0.79 (0.50, 1.25)

---

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 10mg/kg every 2 or 3 weeks (pooled)

Ipilimumab (n=170)

Pembrolizumab 10mg/kg every 2 or 3 weeks (pooled)

Ipilimumab (n=55)

Pembrolizumab 10mg/kg 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 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 every 3 weeks

Chemotherapy

Pembrolizumab

2 mg/kg every 3 weeks

Chemotherapy

PD-L1 positive

PD-L1 negative

PFS Hazard ratio*

(95% CI)

0.55 (0.40, 0.76)

---

0.81 (0.50, 1.31)

---

OS Hazard ratio*

(95% CI)

0.90 (0.63, 1.28)

---

1.18 (0.70, 1.99)

---

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 summarizes efficacy results by PD-L1 expression.

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

Endpoint

Pembrolizumab 10 mg/kg every 2 or 3 weeks (pooled)

Ipilimumab

Pembrolizumab 10 mg/kg 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 trial 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 trial 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 immunohistochemistry 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 trial demonstrated a statistically significant improvement in RFS for patients randomised to the pembrolizumab arm compared with placebo at the pre-specified interim analysis. Efficacy results based on an additional seven months of follow-up are summarized in Table 10 and Figure 4.

Table 10: Efficacy results in KEYNOTE-054

Endpoint

KEYTRUDA

200 mg every 3 weeks

n=514

Placebo

 

n=505

Number (%) of patients with event

158 (31%)

246 (49%)

Median in months (95% CI)

NR

21.7 (17.1, NR)

Hazard ratio* (98% CI)

0.56 (0.44, 0.72)

p-Value (stratified log-rank)

< 0.0001

RFS at 6 months

RFS rate

82%

73%

RFS at 12 months

RFS rate

76%

61%

RFS at 18 months

RFS rate

72%

54%

* Based on the stratified Cox proportional hazard model

NR = not reached

KEYNOTE-054 enrolled patients per AJCC 7th edition and a subgroup analysis of RFS per AJCC 8th edition was performed after the RFS study results were reported. A statistically significant improvement in RFS for patients randomised to the pembrolizumab arm compared with placebo was demonstrated in the overall population across resected stage III melanoma per AJCC 7th edition. Stage IIIA melanoma according to the AJCC 8th edition identifies a patient population with a better prognosis compared to stage IIIA according to AJCC 7th edition. Per the AJCC 8th edition classification, a total of 82 subjects were classified as stage IIIA; 42 in the pembrolizumab arm and 40 in the placebo arm; with a total of 13 RFS events; 6 in the pembrolizumab arm and 7 in the placebo arm. There is limited data on subjects with stage IIIA according to AJCC 8th edition at the time of this RFS analysis.

Figure 4: Kaplan-Meier curve for recurrence-free survival by treatment arm in KEYNOTE-054 (intent to treat population)

While the analysis in patients with PD-L1 positive tumours was a co-primary endpoint, pre-defined subgroup analyses were performed in patients whose tumours were PD-L1 negative, BRAF mutation positive or negative. Table 11 summarises efficacy results by PD-L1 expression and BRAF mutation status.

Table 11: Efficacy results by PD-L1 expression and BRAF mutation status in KEYNOTE-054

Endpoint

Pembrolizumab

200 mg every 3 weeks

Placebo

Pembrolizumab

200 mg every 3 weeks

Placebo

PD-L1 positive

PD-L1 negative

n=428

n=425

n=59

n=57

RFS Hazard ratio* (95% CI)

0.54 (0.42, 0.69)

---

0.47 (0.26, 0.85)

---

RFS rate at 6 months

84%

75%

81%

64%

BRAF mutation positive

BRAF mutation negative

n=245

n=262

n=233

n=214

RFS Hazard ratio* (95% CI)

0.49 (0.36, 0.67)

---

0.64 (0.47, 0.87)

---

RFS rate at 6 months

83%

73%

80%

72%

*Based on the stratified Cox proportional hazard model

NSCLC

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had PD-L1 expression with a ≥ 50% tumour proportion score (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. Non-squamous patients 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 BICR using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by BICR using RECIST 1.1). Table 12 summarizes 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 12: 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-Value

< 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 (0.47, 0.86)

p-Value

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

Median in months (range)

Not reached

(1.9+, 14.5+)

6.3

(2.1+, 12.6+)

% with duration ≥ 6 months

88%§

59%

* 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 overall response as confirmed complete or partial response

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

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

NA = not available

Figure 5: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-024 (intent to treat population)

Figure 6: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-024 (intent to treat population)

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-189: Controlled trial of combination therapy in non-squamous NSCLC patients naïve to treatment

The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was investigated in a multicentre, randomised, active-controlled, double-blind trial, 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. A total of 67 patients in the placebo plus chemotherapy arm crossed over to receive monotherapy pembrolizumab at the time of disease progression and 18 additional patients received a checkpoint inhibitor as subsequent therapy.

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 10.5 months (range: 0.2 to 20.4 months). Table 13 summarises key efficacy measures. The Kaplan-Meier curves for OS and PFS are shown in Figures 7 and 8.

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

127 (31%)

108 (52%)

Hazard ratio* (95% CI)

0.49 (0.38, 0.64)

p-Value

< 0.00001

Median in months (95% CI)

Not reached

(NA, NA)

11.3

(8.7, 15.1)

PFS

Number (%) of patients with event

244 (60%)

166 (81%)

Hazard ratio* (95% CI)

0.52 (0.43, 0.64)

p-Value

< 0.00001

Median in months (95% CI)

8.8 (7.6, 9.2)

4.9 (4.7, 5.5)

Objective Response Rate

ORR % (95% CI)

48% (43, 53)

19% (14, 25)

Complete response %

0.5%

0.5%

Partial response %

47%

18%

p-Value§

< 0.0001

Response duration

Median in months (range)

11.2

(1.1+, 18.0+)

7.8

(2.1+, 16.4+)

% with duration ≥ 6 months

81%

63%

% with duration ≥ 9 months

60%

44%

* Based on the stratified Cox proportional hazard model

Based on stratified log-rank test

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

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

Based on Kaplan-Meier estimation

NA = not available

Figure 7: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-189 (intent to treat population)

Figure 8: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-189 (intent to treat population)

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)

0.59 (0.38, 0.92)

0.55 (0.34, 0.90)

0.42 (0.26, 0.68)

PFS Hazard ratio*

(95% CI)

0.75 (0.53, 1.05)

0.55 (0.37, 0.81)

0.36 (0.25, 0.52)

ORR %

32%

14%

48%

21%

61%

23%

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

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=2.09 [95% CI 0.84,5.23] in OS and HR=1.73 [95% CI 0.77,3.90] in PFS for pembrolizumab combination vs chemotherapy was reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

KEYNOTE-407: Controlled trial 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 blinded independent central review (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. The median follow-up time was 7.8 months (range: 0.1 to 19.1 months). Table 15 summarises key efficacy measures. The Kaplan-Meier curves for OS and PFS are shown in Figures 9 and 10.

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 (%)

85 (31%)

120 (43%)

Median in months (95% CI)

15.9 (13.2, NA)

11.3 (9.5, 14.8)

Hazard ratio* (95% CI)

0.64 (0.49, 0.85)

p-Value

0.0008

PFS

Number of events (%)

152 (55%)

197 (70%)

Median in months (95% CI)

6.4 (6.2, 8.3)

4.8 (4.3, 5.7)

Hazard ratio* (95% CI)

0.56 (0.45, 0.70)

p-Value

< 0.0001

Overall Response Rate

Overall response rate (95% CI)

58% (52, 64)

38% (33, 44)

Complete response %

1.4%

2.1%

Partial response %

57%

36%

p-Value

< 0.0001

Duration of Response

Median duration of response in months (range)

7.7 (1.1+, 14.7+)

4.8 (1.3+, 15.8+)

% with duration ≥ 6 months§

62%

40%

* 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

NA = not available

Figure 9: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

Figure 10: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-407

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)

0.61 (0.38, 0.98)

0.57 (0.36, 0.90)

0.64 (0.37, 1.10)

PFS Hazard ratio*

(95% CI)

0.68 (0.47, 0.98)

0.56 (0.39, 0.80)

0.37 (0.24, 0.58)

ORR %

63%

40%

50%

41%

60%

33%

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

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=0.96 [95% CI 0.37,2.52] in OS, an HR=0.60 [95% CI 0.29,1.21] in PFS, and an ORR of 47% and 42% for pembrolizumab combination vs chemotherapy was reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

KEYNOTE-010: Controlled trial 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 (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 trial 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%); M1 (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 blinded independent central review (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 11 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 every 3 weeks in previously treated patients with NSCLC in KEYNOTE-010

Endpoint

Pembrolizumab 2 mg/kg every 3 weeks

Pembrolizumab 10 mg/kg every 3 weeks

Docetaxel 75 mg/m2 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-Value

0.00128

< 0.001

---

Median in months (95% CI)

10.4 (9.5, 11.9)

13.2 (11.2, 16.7)

8.4 (7.6, 9.5)

PFS

Number (%) of patients with event

305 (89%)

292 (84%)

314 (92%)

Hazard ratio* (95% CI)

0.88 (0.75, 1.04)

0.75 (0.63, 0.89)

---

p-Value

0.065

< 0.001

---

Median in months (95% CI)

3.9 (3.1, 4.1)

4.0 (2.7, 4.5)

4.1 (3.8, 4.5)

Overall 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-Value

< 0.001

< 0.001

---

Median in months (95% CI)

15.8 (10.8, 22.5)

18.7 (12.1, 25.3)

8.2 (6.4, 9.8)

PFS

Number (%) of patients with event

107 (77%)

115 (76%)

138 (91%)

Hazard ratio* (95% CI)

0.59 (0.45, 0.77)

0.53 (0.41, 0.70)

---

p-Value

< 0.001

< 0.001

---

Median in months (95% CI)

5.3 (4.1, 7.9)

5.2 (4.1, 8.1)

4.2 (3.8, 4.7)

Overall 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%

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

Based on stratified Log rank test

Assessed by blinded independent central review (BICR) using RECIST 1.1

§ Based on patients with a best overall response as confirmed complete or partial response

Figure 11: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-010 (patients with PD-L1 expression tumour proportion score ≥ 1%, intent to treat population)

Efficacy results were similar for the 2 mg/kg and 10 mg/kg 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-087 and KEYNOTE-013: Open-label studies in patients with relapsed or refractory classical Hodgkin lymphoma (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 trial. Patients received pembrolizumab 200 mg every 3 weeks (n=210; KEYNOTE-087) or 10 mg/kg 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 35% who were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were transplant ineligible; 17% had no prior brentuximab vedotin use; and 36% of patients had prior radiation therapy. Disease subtypes were 80% 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 Auto-SCT, 26% were transplant ineligible, and 45% of patients had prior radiation therapy. Disease subtypes were 97% nodular sclerosis and 3% mixed cellularity.

The major efficacy outcome measures (ORR and CRR) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were duration of response, PFS and OS. Response was assessed in KN087 and KN013 every 12 and 8 weeks, respectively, with the first planned post-baseline assessment at week 12. Efficacy results are summarized in Table 18.

Table 18: 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 every 2 weeks

n=31

Objective response ratec

ORR % (95% CI)

69% (62.3, 75.2)

58% (39.1, 75.5)

Complete Remission

22%

19%

Partial Remission

47%

39%

Response durationc

Median in months (range)

11.1 (0.0+, 11.1)d

Not reached (0.0+, 45.6+)e

% with duration ≥ 6-months

76%f

80%g

% with duration ≥ 12-months

---

70%h

Time to response

Median in months (range)

2.8 (2.1, 8.8)d

2.8 (2.4, 8.6)e

PFSc

Number (%) of patients with event

70 (33%)

19 (61%)

Median in months (95% CI)

11.3 (10.8, Not reached)

11.4 (4.9, 27.8)

6-month PFS rate

72%

66%

9-month PFS rate

62%

---

12-month PFS rate

---

48%

OS

Number (%) of patients with event

4 (2%)

6 (19%)

6-month OS rate

99.5%

100%

12-month OS rate

97.6%

87.1%

a Median follow-up time of 10.1 months

b Median follow-up time of 52.8 months

c Assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria by PET CT scans

d Based on patients (n=145) 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 31 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 7 patients with responses of 12 months or longer

Safety and efficacy in elderly patients

Overall, 20 cHL patients ≥ 65 years were treated with pembrolizumab in studies KEYNOTE-087 and KEYNOTE-013. Data from these patients are too limited to draw any conclusion on safety or efficacy in this population.

Urothelial Carcinoma

KEYNOTE-045: Controlled trial in urothelial carcinoma patients who have received prior platinum-containing chemotherapy

The safety and efficacy of pembrolizumab were evaluated in KEYNOTE-045, a multicentre, 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 KEYTRUDA 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 cancer. Patients with an ECOG performance status of 2 had to have a hemoglobin ≥ 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 enrollment. 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 19 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 12. 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 19: 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‡,¶

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 overall response as confirmed complete or partial response

# Based on Kaplan-Meier estimation

Figure 12: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-045 (intent to treat population)

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 20).

Table 20: OS by PD-L1 Expression

PD-L1 Expression

Pembrolizumab

Chemotherapy

OS by PD-L1 Expression

Number of Events (number of patients)*

Hazard Ratio (95% CI)

CPS < 10

140 (186)

144 (176)

0.75 (0.59, 0.95)

CPS ≥ 10

53 (74)

72 (90)

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 trial 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 21 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 21: 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

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 22).

Table 22: 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 an ongoing Phase III, randomised, controlled, open-label clinical trial of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy as first-line treatment in subjects with advanced or metastatic urothelial carcinoma. Preliminary data from an early review showed a reduced survival with pembrolizumab monotherapy in patients whose tumours express PD-L1 with a CPS < 10 compared with standard chemotherapy.

Based on a recommendation by an external Data Monitoring Committee, the accrual in the pembrolizumab monotherapy arm was stopped for patients whose tumours express PD-L1 with a CPS < 10. The pembrolizumab monotherapy arm remains open only to patients whose tumours express PD-L1 with a CPS ≥ 10. Subjects whose tumours express PD-L1 CPS < 10 already enrolled into the pembrolizumab monotherapy arm can continue treatment. Randomisation to the chemotherapy and the chemotherapy-pembrolizumab arms remains open.

Head and Neck Squamous Cell Carcinoma

KEYNOTE-048: Controlled trial 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, randomized, 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. Randomization was stratified by tumour PD-L1 expression (TPS ≥ 50% or < 50%), HPV status (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:

• KEYTRUDA 200 mg every 3 weeks

• KEYTRUDA 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 trial 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 23 and 24 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 13 and 14.

Table 23: 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 ratio (95% CI)

0.65 (0.53, 0.80)

p-Value

0.00002

PFS

Number (%) of patients with event

212 (88%)

221 (94%)

Median in months (95% CI)

5.1 (4.7, 6.2)

5.0 (4.8, 6.0)

Hazard ratio (95% CI)

0.84 (0.69, 1.02)

p-Value

0.03697

ORR

Objective response rate§ (95% CI)

36% (30.3, 42.8)

36% (29.6, 42.2)

Complete response

7%

3%

Partial response

30%

33%

p-Value

0.4586

Duration of Response

Median in months (range)

6.7 (1.6+, 39.0+)

4.3 (1.2+, 31.5+)

% with duration ≥6 months

54%

34%

* Cetuximab, platinum, and 5-FU

Based on the stratified Cox proportional hazard model

Based on stratified log-rank test

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

Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive vs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 13: Kaplan-Meier curve for overall survival for pembrolizumab plus chemotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

Table 24: 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

ORR

Objective response rate§ (95% CI)

19.1% (14.5, 24.4)

35% (29.1, 41.1)

Complete response

5%

3%

Partial response

14%

32%

p-Value

1.0000

Duration of Response

Median in months (range)

23.4 (1.5+, 43.0+)

4.5 (1.2+, 38.7+)

% with duration ≥6 months

81%

36%

* Cetuximab, platinum, and 5-FU

Based on the stratified Cox proportional hazard model

Based on stratified log-rank test

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

Based on Miettinen and Nurminen method stratified by ECOG (0 vs. 1), HPV status (positive vs. negative) and PD-L1 status (strongly positive vs. not strongly positive)

Figure 14: Kaplan-Meier curve for overall survival for pembrolizumab as monotherapy in KEYNOTE-048 with PD-L1 expression (CPS ≥ 1)

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 25).

Table 25: 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 ratio† (95% CI)

0.60 (0.45, 0.82)

0.58 (0.44, 0.78)

p-Value‡

0.00044

0.00010

OS rate at 6 months (95% 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)

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 ratio (95% CI)

0.76 (0.58, 1.01)

0.99 (0.76, 1.29)

p-Value

0.02951

0.46791

PFS rate at 6 months (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)

ORR

Objective response rate§ (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)

Duration of Response

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+)

* 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 26).

Table 26: 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 ratio† (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 ratio (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)

ORR

Objective response rate(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)

Duration of Response

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

† Based on the stratified Cox proportional hazard model

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

KEYNOTE-040: Controlled trial 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 27 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 15.

Table 27: 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 ratio (95% CI)

0.58 (0.39, 0.86)

p-Value

0.003

Median in months (95% CI)

3.5 (2.1, 6.3)

2.1 (2.0, 2.4)

Rate (%) at 6 months (95% CI)

40.1 (28.1, 51.9)

17.1 (8.8, 27.7)

Overall response rate§

ORR% (95% CI)

26.6 (16.3, 39.1)

9.2 (3.5, 19.0)

p-Value

0.0009

Complete response

5%

2%

Partial response

22%

8%

Stable disease

23%

23%

Response duration§,#

Median in months (range)

Not reached (2.7, 13.8+)

6.9 (4.2, 18.8)

Number (%Þ) of patients with duration ≥ 6 months

9 (66)

2 (50)

* 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 overall response as confirmed complete or partial response

Þ Based on Kaplan-Meier estimation

Figure 15: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-040 patients with PD-L1 expression (TPS ≥ 50%)

Renal cell carcinoma

KEYNOTE-426: Controlled trial of combination therapy 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 trial 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 trial 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 28 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 16 and 17.

Table 28: 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

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

Overall response rate

ORR§% (95% CI)

59 (54, 64)

36 (31, 40)

Complete response

6%

2%

Partial response

53%

34%

p-Value

< 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 overall 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

NA = not available

Figure 16: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-426 (intent to treat population)*

*p-Value is nominal. See Table 28 for p-Value for inferential test of OS based on the pre-specified interim analysis, where statistical significance has been reached.

Figure 17: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-426 (intent to treat population)*

*p-Value is nominal. See Table 28 for p-Value for inferential test of PFS based on the pre-specified interim analysis, where statistical significance has been reached.

Subgroup analyses by enrollment 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 trial was not powered to evaluate efficacy of individual subgroups. Table 29 summarises the efficacy measures by IMDC risk category from the pre-specified interim analysis.

Table 29: 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)

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).

Paediatric population

In KEYNOTE-051, 154 paediatric patients (60 children aged 6 months to less than 12 years and 94 adolescents aged 12 years to 18 years) with advanced melanoma or PD-L1 positive advanced, relapsed, or refractory solid tumours or lymphoma were administered pembrolizumab 2 mg/kg every 3 weeks. All patients received pembrolizumab for a median of 3 doses (range 1-35 doses), with 130 patients (84.4%) 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 (11.7%), glioblastoma multiforme (9.1%), neuroblastoma (6.5%), osteosarcoma (6.5%) and melanoma (5.2%). Of the 154 patients, 134 were enrolled with solid tumours, 18 with Hodgkin lymphoma, and 2 with other lymphomas. In patients with solid tumours and other lymphomas, the ORR was 5.9%, no patient had a complete response and 8 patients (5.9%) had a partial response. In the Hodgkin lymphoma population, the ORR was 50.0%, 2 patients (11.1%) had a complete response and 7 patients (38.9%) 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 every 2 weeks, 2 to 10 mg/kg 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 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 (AUC0-3weeks) was 794 mcg∙day/mL at a dose of 2 mg/kg 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 concentrations with weight-based dosing at 2 mg/kg every 3 weeks in paediatric patients (2 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 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, which produced exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 mg/kg, 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 signaling 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 particulars
6.1 List of excipients

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Polysorbate 80

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

3 years.

After reconstitution

From a microbiological point of view, the reconstituted or diluted solution should be used immediately. The reconstituted or 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 total hold from reconstitution 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).

For storage conditions after reconstitution or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

15 mL Type I glass vial, with a grey bromobutyl stopper and an aluminium seal with an avocado coloured flip-off cap, containing 50 mg pembrolizumab.

Each carton contains one vial.

6.6 Special precautions for disposal and other handling

Preparation and administration

• Prior to reconstitution, the vial of lyophilised powder can be out of refrigeration (temperatures at or below 25°C) for up to 24 hours.

• Aseptically add 2.3 mL of water for injections to yield a 25 mg/mL (pH 5.2-5.8) solution of KEYTRUDA. Each vial contains an excess fill of 10 mg (0.4 mL) to ensure the recovery of 50 mg of KEYTRUDA per vial. After reconstitution, 1 mL of concentrate contains 25 mg of pembrolizumab.

• To avoid foaming, deliver the water along the walls of the vial and not directly on the lyophilised powder.

• Slowly swirl the vial to allow reconstitution of the lyophilised powder. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.

• Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration. Reconstituted KEYTRUDA 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 2 mL (50 mg) of KEYTRUDA 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. Mix diluted solution by gentle inversion.

• From a microbiological point of view, the reconstituted or diluted solution should be used immediately. The reconstituted or 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 total hold from reconstitution 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 µm in-line or add-on filter.

• Do not co-administer other medicinal products through the same infusion line.

• KEYTRUDA is for single use only. Discard any unused portion left in the vial.

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

7. Marketing authorisation holder

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

8. Marketing authorisation number(s)

EU/1/15/1024/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 17 July 2015

10. Date of revision of the text

14 November 2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

© Merck Sharp & Dohme Limited 2019. All rights reserved.

SPC.KTD.50mg.19.UK.7014 II065 II080