Melanoma

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

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage IIB, IIC or III melanoma and who have undergone complete resection (see section 5.1).

Non-small cell lung carcinoma (NSCLC)

KEYTRUDA, in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment, is indicated for the treatment of resectable non-small cell lung carcinoma at high risk of recurrence in adults (for selection criteria, see section 5.1).

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

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

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

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

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

Classical Hodgkin lymphoma (cHL)

KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option.

Urothelial carcinoma

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

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

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

Head and neck squamous cell carcinoma (HNSCC)

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

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

Renal cell carcinoma (RCC)

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

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

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

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

Colorectal cancer (CRC)

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

- first-line treatment of metastatic colorectal cancer;

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

Non-colorectal cancers

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

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

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

Oesophageal carcinoma

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

Triple-negative breast cancer (TNBC)

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

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer in adults whose tumours express PD-L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease (see section 5.1).

Endometrial carcinoma (EC)

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

Cervical cancer

KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD-L1 with a CPS ≥ 1.

Gastric or gastro-oesophageal junction (GEJ) adenocarcinoma

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine and platinum-containing chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1.

KEYTRUDA, in combination with fluoropyrimidine and platinum-containing chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1 (see section 5.1).

Biliary tract carcinoma (BTC)

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

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

PD-L1 testing

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

MSI/MMR testing

If specified in the indication, patient selection for treatment with KEYTRUDA based on MSI-H/dMMR tumour status should be confirmed by a validated test (see sections 4.1 and 5.1).

Posology

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

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

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

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

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

For the neoadjuvant and adjuvant treatment of resectable NSCLC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 4 doses of 200 mg every 3 weeks or 2 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 13 doses of 200 mg every 3 weeks or 7 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.

For the neoadjuvant and adjuvant treatment of TNBC, patients should be treated with neoadjuvant KEYTRUDA in combination with chemotherapy for 8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as monotherapy for 9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity. Patients who experience disease progression that precludes definitive surgery or unacceptable toxicity related to KEYTRUDA as neoadjuvant treatment in combination with chemotherapy should not receive KEYTRUDA monotherapy as adjuvant treatment.

Dose delay or discontinuation (see also section 4.4)

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

Table 1: Recommended treatment modifications for KEYTRUDA

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

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

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

KEYTRUDA in combination with axitinib in RCC

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

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

• If ALT or AST ≥ 3 times ULN but < 10 times ULN without concurrent total bilirubin ≥ 2 times ULN, both KEYTRUDA and axitinib should be withheld until these adverse reactions recover to Grades 0-1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or sequential rechallenge with both medicines after recovery may be considered. If rechallenging with axitinib, dose reduction as per the axitinib SmPC may be considered.

• If ALT or AST ≥ 10 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN, both KEYTRUDA and axitinib should be permanently discontinued and corticosteroid therapy may be considered.

KEYTRUDA in combination with lenvatinib

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

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

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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

Paediatric population

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

Method of administration

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

When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first.

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

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

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

Traceability

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

Assessment of PD-L1 status

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

Immune-mediated adverse reactions

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

For suspected immune-mediated 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-mediated adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered.

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

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

Immune-mediated pneumonitis

Pneumonitis has been reported in patients receiving pembrolizumab (see section 4.8). Patients 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-mediated colitis

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

Immune-mediated 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-mediated 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-mediated 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-mediated 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. Pembrolizumab should be withheld for Grade 2 adrenal insufficiency or hypophysitis until the event is controlled with hormone replacement. Pembrolizumab should be withheld or discontinued for Grades 3 or 4 adrenal insufficiency or symptomatic hypophysitis. Continuation of pembrolizumab may be considered, after corticosteroid taper, if needed (see section 4.2). Pituitary function and hormone levels should be monitored to ensure appropriate hormone replacement.

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

Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Pembrolizumab should be withheld for Grade ≥ 3 until recovery to Grade ≤ 1 hyperthyroidism. Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and are controlled with hormone replacement, if indicated, continuation of pembrolizumab may be considered after corticosteroid taper, if needed. Otherwise treatment should be discontinued (see sections 4.2 and 4.8).

Immune-mediated skin adverse reactions

Immune-mediated severe skin reactions have been reported in patients receiving pembrolizumab (see section 4.8). Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld for Grade 3 skin reactions until recovery to Grade ≤ 1 or permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered (see section 4.2).

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

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

Other immune-mediated adverse reactions

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

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

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

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

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

Transplant-related adverse reactions

Solid organ transplant rejection

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with pembrolizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients.

Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT)

Allogeneic HSCT after treatment with pembrolizumab

Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with cHL undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case (see section 4.8).

Allogeneic HSCT prior to treatment with pembrolizumab

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

Infusion-related reactions

Severe infusion-related reactions, including hypersensitivity and anaphylaxis, have been reported in patients receiving pembrolizumab (see section 4.8). For Grades 3 or 4 infusion reactions, infusion should be stopped and pembrolizumab permanently discontinued (see section 4.2). Patients with Grades 1 or 2 infusion reaction may continue to receive pembrolizumab with close monitoring; premedication with antipyretic and antihistamine may be considered.

Use of pembrolizumab in combination with chemotherapy

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

Disease-specific precautions

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

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

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

The baseline and prognostic disease characteristics of the study population of KEYNOTE-052 included a proportion of patients eligible for a carboplatin-based combination, for whom the benefit has been assessed in a comparative study (KEYNOTE-361). In KEYNOTE-361, a higher number of deaths within 6 months of treatment initiation followed by a long-term survival benefit was observed with pembrolizumab monotherapy compared to chemotherapy (see section 5.1). No specific factor(s) associated with early deaths could be identified. Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with urothelial carcinoma who are considered eligible for carboplatin-based combination chemotherapy. KEYNOTE-052 also included patients eligible for mono-chemotherapy, for whom no randomised data are available. In addition, no safety and efficacy data are available in frailer patients (e.g. ECOG performance status 3) considered not eligible for chemotherapy. In the absence of these data, pembrolizumab should be used with caution in this population after careful consideration of the potential risk-benefit on an individual basis.

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

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

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

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

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

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

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

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

A direct comparison of pembrolizumab when used in combination with lenvatinib 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 lenvatinib) before initiating treatment in patients with advanced or recurrent MSI-H or dMMR endometrial carcinoma.

Use of pembrolizumab for adjuvant treatment of patients with melanoma

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

Use of pembrolizumab in combination with axitinib for first-line treatment of patients with RCC

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

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

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

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

Cholangitis and biliary tract infections are not uncommon in patients with BTC. Cholangitis events were reported in KEYNOTE-966 in both treatment groups (11.2% [n=59] of participants in the pembrolizumab plus chemotherapy arm and 10.3% [n=55] of participants in the placebo plus chemotherapy arm). Patients with biliary stents and drains (n=74) were at increased risk of cholangitis and biliary tract infections in KEYNOTE-966 (39.4% [n=13] of participants in the pembrolizumab plus chemotherapy arm vs. 29.3% [n=12] of participants in the placebo plus chemotherapy arm). Patients with BTC (especially those with biliary stents) should be closely monitored for development of cholangitis or biliary tract infections before initiation of treatment and, regularly, thereafter.

Patients excluded from clinical studies

Patients with the following conditions were excluded from clinical studies: active CNS metastases; ECOG PS ≥ 2 (except for urothelial carcinoma and RCC); HIV infection, hepatitis B or hepatitis C infection (except for BTC); 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-mediated adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks. Patients with active infections were excluded from clinical studies and were required to have their infection treated prior to receiving pembrolizumab. Patients with active infections occurring during treatment with pembrolizumab were managed with appropriate medical therapy. Patients with clinically significant renal (creatinine > 1.5 x ULN) or hepatic (bilirubin > 1.5 x ULN, ALT, AST > 2.5 x ULN in the absence of liver metastases) abnormalities at baseline were excluded from clinical studies, therefore information is limited in patients with severe renal and moderate to severe hepatic impairment.

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

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

Patient 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 card with each prescription.

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-mediated 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.

Women of childbearing potential

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

Pregnancy

There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss (see section 5.3). These results indicate a potential risk, based on its mechanism of action, that administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab.

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

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

Pembrolizumab in monotherapy (see section 4.2)

The safety of pembrolizumab as monotherapy has been evaluated in 7 631 patients across tumour types and across four doses (2 mg/kg bw every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg bw every 2 or 3 weeks) in clinical studies. In this patient population, the median observation time was 8.5 months (range: 1 day to 39 months) and the most frequent adverse reactions with pembrolizumab were fatigue (31%), diarrhoea (22%), and nausea (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-mediated adverse reactions and severe infusion-related reactions (see section 4.4). The incidences of immune-mediated adverse reactions were 37% all Grades and 9% for Grades 3-5 for pembrolizumab monotherapy in the adjuvant setting and 25% all Grades and 6% for Grades 3-5 in the metastatic setting. No new immune-mediated adverse reactions were identified in the adjuvant setting.

Pembrolizumab in combination with chemotherapy (see section 4.2)

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

The safety of pembrolizumab in combination with chemotherapy has been evaluated in 5 183 patients across tumour types receiving 200 mg, 2 mg/kg bw or 10 mg/kg bw pembrolizumab every 3 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were anaemia (52%), nausea (52%), fatigue (35%), diarrhoea (33%), constipation (32%), vomiting (28%), decreased appetite (28%), neutrophil count decreased (27%) and neutropenia (25%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 69% for pembrolizumab combination therapy and 61% for chemotherapy alone, in patients with HNSCC were 85% for pembrolizumab combination therapy and 84% for chemotherapy plus cetuximab, in patients with oesophageal carcinoma were 86% for pembrolizumab combination therapy and 83% for chemotherapy alone, in patients with TNBC were 80% for pembrolizumab combination therapy and 77% for chemotherapy alone, in patients with cervical cancer were 82% for pembrolizumab combination and 75% for chemotherapy, with or without bevacizumab, in patients with gastric cancer were 74% for pembrolizumab combination therapy (chemotherapy with or without trastuzumab) and 68% for chemotherapy with or without trastuzumab, and in patients with biliary tract carcinoma were 85% for pembrolizumab combination therapy and 84% for chemotherapy alone.

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

When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. For additional axitinib safety information for elevated liver enzymes see also section 4.4.

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

Tabulated summary of adverse reactions

Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy or other anti-tumour medicines or reported from post-marketing use of pembrolizumab are listed in Table 2. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Adverse reactions known to occur with pembrolizumab or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.

For additional safety information when pembrolizumab is administered in combination, refer to the SmPC for the respective combination therapy components.

Table 2: Adverse reactions in patients treated with pembrolizumab^†

^† 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:

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

• sarcoidosis (cutaneous sarcoidosis and pulmonary sarcoidosis)

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

• adrenal insufficiency (Addison's disease, adrenocortical insufficiency acute and secondary adrenocortical insufficiency)

• thyroiditis (autoimmune thyroiditis, silent thyroiditis, thyroid disorder, thyroiditis acute and immune-mediated thyroiditis)

• hyperthyroidism (Basedow's disease)

• hypophysitis (hypopituitarism and lymphocytic hypophysitis)

• type 1 diabetes mellitus (diabetic ketoacidosis)

• myasthenic syndrome (myasthenia gravis, including exacerbation)

• encephalitis (autoimmune encephalitis and noninfective encephalitis)

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

• myelitis (including transverse myelitis)

• meningitis aseptic (meningitis and meningitis noninfective)

• uveitis (chorioretinitis, iritis and iridocyclitis)

• myocarditis (autoimmune myocarditis)

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

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

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

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

• gastritis (gastritis erosive and gastritis haemorrhagic)

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

• gastrointestinal ulceration (gastric ulcer and duodenal ulcer)

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

• cholangitis sclerosing (immune-mediated cholangitis)

• pruritus (urticaria, urticaria papular and pruritus genital)

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

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

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

• lichenoid keratosis (lichen planus and lichen sclerosus)

• musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)

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

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

• tenosynovitis (tendonitis, synovitis and tendon pain)

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

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

Pembrolizumab in combination with enfortumab vedotin (see section 4.2)

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

The safety of pembrolizumab in combination with enfortumab vedotin has been evaluated among 564 patients with unresectable or metastatic urothelial carcinoma receiving 200 mg pembrolizumab on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle.

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

Adverse reactions were generally similar to those observed in patients receiving pembrolizumab or enfortumab vedotin as monotherapy. The incidence of rash maculo-papular was 36% all Grades (10% Grades 3-4), which is higher than observed in pembrolizumab monotherapy.

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

Description of selected adverse reactions

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

Immune-mediated adverse reactions (see section 4.4)

Immune-mediated pneumonitis

Pneumonitis occurred in 324 (4.2%) patients, including Grade 2, 3, 4 or 5 cases in 143 (1.9%), 81 (1.1%), 19 (0.2%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.9 months (range: 2 days to 27.2 months). The median duration was 2.0 months (range: 1 day to 51.0+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (3.9%). Pneumonitis led to discontinuation of pembrolizumab in 131 (1.7%) patients. Pneumonitis resolved in 196 patients, 6 with sequelae.

In patients with NSCLC, pneumonitis occurred in 230 (6.1%), including Grade 2, 3, 4 or 5 cases in 103 (2.7%), 63 (1.7%), 17 (0.4%) and 10 (0.3%), respectively. In patients with locally advanced or metastatic NSCLC, pneumonitis occurred in 8.9% with a history of prior thoracic radiation. In patients with cHL, the incidence of pneumonitis (all Grades) ranged from 5.2% to 10.8% for cHL patients in KEYNOTE-087 (n=210) and KEYNOTE-204 (n=148), respectively.

Immune-mediated colitis

Colitis occurred in 158 (2.1%) patients, including Grade 2, 3 or 4 cases in 49 (0.6%), 82 (1.1%) and 6 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 4.3 months (range: 2 days to 24.3 months). The median duration was 1.1 month (range: 1 day to 45.2 months). Colitis led to discontinuation of pembrolizumab in 48 (0.6%) patients. Colitis resolved in 132 patients, 2 with sequelae. In patients with CRC treated with pembrolizumab as monotherapy (n=153), the incidence of colitis was 6.5% (all Grades) with 2.0% Grade 3 and 1.3% Grade 4.

Immune-mediated hepatitis

Hepatitis occurred in 80 (1.0%) patients, including Grade 2, 3 or 4 cases in 12 (0.2%), 55 (0.7%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 3.5 months (range: 8 days to 26.3 months). The median duration was 1.3 months (range: 1 day to 29.0+ months). Hepatitis led to discontinuation of pembrolizumab in 37 (0.5%) patients. Hepatitis resolved in 60 patients.

Immune-mediated nephritis

Nephritis occurred in 37 (0.5%) patients, including Grade 2, 3 or 4 cases in 11 (0.1%), 19 (0.2%) and 2 (< 0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 4.2 months (range: 12 days to 21.4 months). The median duration was 3.3 months (range: 6 days to 28.2+ months). Nephritis led to discontinuation of pembrolizumab in 17 (0.2%) patients. Nephritis resolved in 25 patients, 5 with sequelae. In patients with non-squamous 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-mediated endocrinopathies

Adrenal insufficiency occurred in 74 (1.0%) patients, including Grade 2, 3 or 4 cases in 34 (0.4%), 31 (0.4%) and 4 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of adrenal insufficiency was 5.4 months (range: 1 day to 23.7 months). The median duration was not reached (range: 3 days to 40.1+ months). Adrenal insufficiency led to discontinuation of pembrolizumab in 13 (0.2%) patients. Adrenal insufficiency resolved in 28 patients, 11 with sequelae.

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

Hyperthyroidism occurred in 394 (5.2%) patients, including Grade 2 or 3 cases in 108 (1.4%) and 9 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range: 1 day to 23.2 months). The median duration was 1.6 months (range: 4 days to 43.1+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 4 (0.1%) patients. Hyperthyroidism resolved in 326 (82.7%) patients, 11 with sequelae. In patients with melanoma, NSCLC and RCC treated with pembrolizumab monotherapy in the adjuvant setting (n=2 060), the incidence of hyperthyroidism was 11.0%, the majority of which were Grade 1 or 2.

Hypothyroidism occurred in 939 (12.3%) patients, including Grade 2 or 3 cases in 687 (9.0%) and 8 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.4 months (range: 1 day to 25.9 months). The median duration was not reached (range: 2 days to 63.0+ months). Hypothyroidism led to discontinuation of pembrolizumab in 6 (0.1%) patients. Hypothyroidism resolved in 216 (23.0%) patients, 16 with sequelae. In patients with cHL (n=389) the incidence of hypothyroidism was 17%, all of which were Grade 1 or 2. In patients with HNSCC treated with pembrolizumab as monotherapy (n=909), the incidence of hypothyroidism was 16.1% (all Grades) with 0.3% Grade 3. In patients with HNSCC treated with pembrolizumab in combination with platinum and 5-FU chemotherapy (n=276), the incidence of hypothyroidism was 15.2%, all of which were Grade 1 or 2. In patients treated with pembrolizumab in combination with axitinib or lenvatinib (n=1 456), the incidence of hypothyroidism was 46.2% (all Grades) with 0.8% Grade 3 or 4. In patients with melanoma, NSCLC and RCC treated with pembrolizumab monotherapy in the adjuvant setting (n=2 060), the incidence of hypothyroidism was 18.5%, the majority of which were Grade 1 or 2.

Immune-mediated skin adverse reactions

Immune-mediated severe skin reactions occurred in 130 (1.7%) patients, including Grade 2, 3, 4 or 5 cases in 11 (0.1%), 103 (1.3%), 1 (< 0.1%) and 1 (< 0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 2.8 months (range: 2 days to 25.5 months). The median duration was 1.9 months (range: 1 day to 47.1+ months). Severe skin reactions led to discontinuation of pembrolizumab in 18 (0.2%) patients. Severe skin reactions resolved in 95 patients, 2 with sequelae.

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

Complications of allogeneic HSCT in cHL

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

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

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

Elevated liver enzymes when pembrolizumab is combined with axitinib in RCC

In a clinical study of previously untreated patients with RCC receiving pembrolizumab in combination with axitinib, a higher than expected incidence of Grades 3 and 4 ALT increased (20%) and AST increased (13%) were observed. The median time to onset of ALT increased was 2.3 months (range: 7 days to 19.8 months). In patients with ALT ≥ 3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. Of the patients who recovered, 92 (84%) were rechallenged with either pembrolizumab (3%) or axitinib (31%) monotherapy or with both (50%). Of these patients, 55% had no recurrence of ALT > 3 times ULN, and of those patients with recurrence of ALT > 3 times ULN, all recovered. There were no Grade 5 hepatic events.

Laboratory abnormalities

In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 9.4% for lymphocytes decreased, 7.4% for sodium decreased, 5.8% for haemoglobin decreased, 5.3% for phosphate decreased, 5.3% for glucose increased, 3.3% for ALT increased, 3.1% for AST increased, 2.6% for alkaline phosphatase increased, 2.3% for potassium decreased, 2.1% for potassium increased, 1.9% for neutrophils decreased, 1.8% for platelets decreased, 1.8% for calcium increased, 1.7% for bilirubin increased, 1.5% for calcium decreased, 1.4% for albumin decreased, 1.3% for creatinine increased, 1.2% for glucose decreased, 0.8% for leucocytes decreased, 0.7% for magnesium increased, 0.5% for sodium increased, 0.4% for haemoglobin increased, and 0.2% for magnesium decreased.

In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 39.9% for neutrophils decreased, 25.5% for lymphocytes decreased, 23.3% for leucocytes decreased, 20.8% for haemoglobin decreased, 13.7% for platelets decreased, 10.4% for sodium decreased, 7.7% for potassium decreased, 7.3% for phosphate decreased, 5.7% for ALT increased, 5.5% for glucose increased, 5.3% for AST increased, 3.6% for bilirubin increased, 3.5% for calcium decreased, 3.4% for potassium increased, 3.1% for creatinine increased, 2.8% for alkaline phosphatase increased, 2.6% for albumin decreased, 1.7% for calcium increased, 1.0% for glucose decreased, 0.5% for sodium increased and 0.1% for haemoglobin increased.

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

Immunogenicity

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

Paediatric population

The safety of pembrolizumab as monotherapy has been evaluated in 161 paediatric patients aged 9 months to 17 years with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg bw every 3 weeks in the Phase I/II study KEYNOTE-051. The cHL population (n=22) included patients 11 to 17 years of age. The safety profile in paediatric patients was generally similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (33%), vomiting (30%), headache (26%), abdominal pain (22%), anaemia (21%), cough (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grades 1 or 2 severity. Seventy-six (47.2%) patients had 1 or more Grades 3 to 5 adverse reactions of which 5 (3.1%) patients had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. Long-term safety data of pembrolizumab in adolescents with Stage IIB, IIC and III melanoma treated in the adjuvant setting are currently unavailable.

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.

There is no information on overdose with pembrolizumab.

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

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

Mechanism of action

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

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

Clinical efficacy and safety

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

Melanoma

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-006, a multicentre, open-label, controlled, Phase III study for the treatment of advanced melanoma in patients who were naï ve to ipilimumab. Patients were randomised (1:1:1) to receive pembrolizumab 10 mg/kg bw every 2 (n=279) or 3 weeks (n=277) or ipilimumab 3 mg/kg bw every 3 weeks (n=278). Patients with BRAF V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.

Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter.

Of the 834 patients, 60% were male, 44% were ≥ 65 years (median age was 62 years [range: 18-89]) and 98% were white. Sixty-five percent of patients had M1c stage, 9% had a history of brain metastases, 66% had no and 34% had one prior therapy. Thirty-one percent had an ECOG Performance Status of 1, 69% had ECOG Performance Status of 0 and 32% had elevated LDH. BRAF mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours, 139 (46%) were previously treated with a BRAF inhibitor.

The primary efficacy outcome measures were progression-free survival (PFS; as assessed by Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcome measures were objective response rate (ORR) and response duration. Table 3 summarises key efficacy measures in patients naï ve 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

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 study in melanoma patients previously treated with ipilimumab

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

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

Of the 540 patients, 61% were male, 43% were ≥ 65 years (median age was 62 years [range: 15-89]) and 98% were white. Eighty-two percent had M1c stage, 73% had at least two and 32% of patients had three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG Performance Status of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour.

The primary efficacy outcome measures were PFS as assessed by IRO using RECIST version 1.1 and OS. Secondary efficacy outcome measures were ORR and response duration. Table 4 summarises key efficacy measures at the final analysis in patients previously treated with ipilimumab, and the Kaplan-Meier curve for PFS is shown in Figure 3. Both pembrolizumab arms were superior to chemotherapy for PFS, and there was no difference between pembrolizumab doses. There was no statistically significant difference between pembrolizumab and chemotherapy in the final OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised to the chemotherapy arm, 55% crossed over and subsequently received treatment with pembrolizumab.

Table 4: Efficacy results in KEYNOTE-002

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 naï ve 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 naï ve to treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 2 mg/kg bw every 3 weeks or 10 mg/kg bw every 3 weeks. Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Exclusion criteria were similar to those of KEYNOTE-002.

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

Of the 51 patients receiving 2 mg/kg bw of pembrolizumab who were naï ve 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 naï ve to treatment with ipilimumab, receiving pembrolizumab at a dose of 2 mg/kg bw based on a minimum follow-up time of 30 months for all patients.

Table 5: Efficacy results in KEYNOTE-001

^* 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 naï ve to treatment with ipilimumab

^¶ Based on Kaplan-Meier estimation

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

Sub-population analyses

BRAF mutation status in melanoma

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

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

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

PD-L1 status in melanoma

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

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

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were PD-L1 positive (n=671; 80%) vs. PD-L1 negative (n=150; 18%). Among patients who were evaluable for PD-L1 expression (98%), 82% were PD-L1 positive and 18% were PD-L1 negative. Table 9 summarises efficacy results by PD-L1 expression.

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

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-716: Placebo-controlled study for the adjuvant treatment of patients with resected Stage IIB or IIC melanoma

The efficacy of pembrolizumab was evaluated in KEYNOTE-716, a multicentre, randomised, double-blind, placebo-controlled study in patients with resected Stage IIB or IIC melanoma. A total of 976 patients were randomised (1:1) to receive pembrolizumab 200 mg every three weeks (or the paediatric [12 to 17 years old] dose of 2 mg/kg intravenously [up to a maximum of 200 mg] every three weeks) (n=487) or placebo (n=489), for up to one year or until disease recurrence or unacceptable toxicity. Randomisation was stratified by American Joint Committee on Cancer (AJCC) 8^th edition T stage. 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 were ineligible. Patients underwent imaging every six months from randomisation through the 4^th year, and then once in year 5 from randomisation or until recurrence, whichever came first.

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

The primary efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population, 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 occurred first. The secondary outcome measures were distant metastasis-free survival (DMFS) and OS in the whole population. OS was not formally assessed at the time of this analysis. The study initially demonstrated a statistically significant improvement in RFS (HR 0.65; 95% CI 0.46, 0.92; p-Value = 0.00658) for patients randomised to the pembrolizumab arm compared with placebo at its pre-specified interim analysis. Results reported from the pre-specified final analysis for RFS at a median follow-up of 20.5 months are summarised in Table 10. Updated RFS results at a median follow-up of 38.5 months were consistent with the final analysis for RFS for patients randomised to the pembrolizumab arm compared with placebo (HR 0.62; 95% CI 0.49, 0.79) (see Figure 4). The study demonstrated a statistically significant improvement in DMFS (HR 0.64; 95% CI 0.47, 0.88; p-Value = 0.00292) for patients randomised to the pembrolizumab arm compared with placebo at its pre-specified interim analysis at a median follow-up of 26.9 months. Results reported from the pre-specified final analysis for DMFS at a median follow-up time of 38.5 months are summarised in Table 10 and Figure 5.

Table 10: Efficacy results in KEYNOTE-716

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

Figure 5: Kaplan-Meier curve for distant metastasis-free survival by treatment arm in KEYNOTE-716 (intent to treat population)

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

The efficacy of pembrolizumab was evaluated in KEYNOTE-054, a multicentre, randomised, double-blind, placebo-controlled study in patients with completely resected stage IIIA (> 1 mm 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 AJCC 7^th edition stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥ 4 positive lymph nodes) and geographic region (North America, European countries, Australia and other countries as designated). Patients must have undergone lymph node dissection, and if indicated, radiotherapy within 13 weeks prior to starting treatment. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Patients who received prior therapy for melanoma other than surgery or interferon for thick primary melanomas without evidence of lymph node involvement were ineligible. Patients underwent imaging every 12 weeks after the first dose of pembrolizumab for the first two years, then every 6 months from year 3 to 5, and then annually.

Among the 1 019 patients, the baseline characteristics were: median age of 54 years (25% age 65 or older); 62% male; and ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% had stage IIIB; 18% had stage IIIC (1-3 positive lymph nodes) and 20% had stage IIIC (≥ 4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type. PD-L1 expression was tested retrospectively by IHC assay with the 22C3 anti-PD-L1 antibody; 84% of patients had PD-L1-positive melanoma (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cells relative to all viable tumour cells). The same scoring system was used for metastatic melanoma (MEL score).

The primary efficacy outcome measures were investigator-assessed 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 occurred first. The secondary outcome measures were DMFS and OS in the whole population and in the population with PD-L1 positive tumours. OS was not formally assessed at the time of these analyses. The study initially demonstrated a statistically significant improvement in RFS (HR 0.57; 98.4% CI 0.43, 0.74; p-Value < 0.0001) for patients randomised to the pembrolizumab arm compared with placebo at its pre-specified interim analysis. Updated efficacy results with a median follow-up time of 45.5 months are summarised in Table 11 and Figures 6 and 7.

Table 11: Efficacy results in KEYNOTE-054

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

Figure 7: Kaplan-Meier curve for distant metastasis-free survival by treatment arm in KEYNOTE-054 (intent to treat population)

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

NSCLC

KEYNOTE-671: Controlled study for the neoadjuvant and adjuvant treatment of patients with resectable NSCLC

The efficacy of pembrolizumab in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as monotherapy as adjuvant treatment was investigated in KEYNOTE-671, a multicentre, randomised, double-blind, placebo-controlled study. Key eligibility criteria were previously untreated and resectable patients with NSCLC who are at high risk (Stage II, IIIA, or IIIB (N2) by AJCC 8^th edition) of recurrence, regardless of tumour PD-L1 expression based on the PD-L1 IHC 22C3 pharmDx^TM Kit. Testing for genomic tumour aberrations or oncogenic drivers was not mandatory for enrolment.

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

If indicated, patients received adjuvant radiation therapy prior to adjuvant pembrolizumab or placebo. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by stage (II vs. III), tumour PD-L1 expression (TPS ≥ 50% or < 50%), histology (squamous vs. non- squamous), and geographic region (East Asia vs. non-East Asia).

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

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

• Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m² and either pemetrexed 500 mg/m² on Day 1 or gemcitabine 1 000 mg/m² on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Following surgery, placebo was administered every 3 weeks for up to 13 cycles.

All study medications were administered via intravenous infusion. Treatment with pembrolizumab or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumour status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase, and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumour status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter.

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

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

A total of 797 patients in KEYNOTE-671 were randomised: 397 patients to the pembrolizumab arm and 400 to the placebo arm. Baseline characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older; 71% male; 61% White, 31% Asian, and 2% Black. Sixty-three percent and 37% had ECOG performance of 0 or 1, respectively; 30% had Stage II and 70% had Stage III disease; 33% had TPS ≥ 50% and 67% had TPS < 50%; 43% had tumours with squamous histology and 57% had tumours with non-squamous histology; 31% were from the East Asian region. Four percent of patients had EGFR mutations and in 66% EGFR mutation status was unknown. Three percent of patients had ALK translocations and in 68% ALK translocation status was unknown.

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

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

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

Table 12: Efficacy results in KEYNOTE-671

Figure 8: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-671 (intent to treat population)

Figure 9: Kaplan-Meier curve for event-free survival by treatment arm in KEYNOTE-671 (intent to treat population)

A post-hoc exploratory subgroup analysis was performed in KEYNOTE-671 in patients who had PD-L1 TPS ≥ 50% (pembrolizumab arm [n=132; 33%] vs. placebo arm [n=134; 34%]); TPS = 1 - 49% (pembrolizumab arm [n=127; 32%] vs. placebo arm [n=115; 29%]) and TPS < 1% (pembrolizumab arm [n=138; 35%] vs. placebo arm [n=151; 38%]). The EFS HR was, 0.48 (95% CI: 0.33, 0.71) in patients with a TPS ≥ 50%, 0.52 (95% CI: 0.36, 0.73) in patients with a TPS = 1 - 49% and 0.75 (95% CI: 0.56, 1.01) in patients with a TPS < 1%. The OS HR was 0.55 (95% CI: 0.33, 0.92) in patients with a TPS ≥ 50%, 0.69 (95% CI: 0.44, 1.07) in patients with a TPS = 1 - 49% and 0.91 (95% CI: 0.63, 1.32) in patients with a TPS < 1%.

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

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

The following selection criteria define patients with high risk of recurrence who are included in the therapeutic indication and are reflective of the patient population with stage IB [T2a ≥ 4 cm], II or IIIA according to the 7th edition staging system: Tumour size ≥ 4 cm; or tumours of any size that are either accompanied by N1 or N2 status; or tumours that are invasive of thoracic structures (directly invade the parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina); or tumours that involve the main bronchus < 2 cm distal to the carina but without involvement of the carina; or tumours that are associated with atelectasis or obstructive pneumonitis of the entire lung; or tumours with separate nodule(s) in the same lobe or different ipsilateral lobe as the primary. The study did not include patients who had N2 status with tumours also invading the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, or with separate tumour nodule(s) in a different ipsilateral lobe.

Patients may or may not have received adjuvant chemotherapy as recommended by their physician. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 4 cycles of adjuvant chemotherapy were ineligible. Randomisation was stratified by stage (IB vs. II vs. IIIA), adjuvant chemotherapy (no adjuvant chemotherapy vs. adjuvant chemotherapy), PD-L1 status (TPS < 1% [negative] vs. TPS 1-49% vs. TPS ≥ 50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomised (1:1) to receive pembrolizumab 200 mg (n=590) or placebo (n=587) intravenously every 3 weeks.

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

Of 1 177 patients randomised, 1 010 (86%) received adjuvant platinum-based chemotherapy following complete resection. Among these 1 010 patients in KEYNOTE-091, baseline characteristics were: median age of 64 years (range: 35 to 84), 49% age 65 or older; 68% male; and 77% White, 18% Asian, 86% current or former smokers. Sixty-one percent and 39% had ECOG performance of 0 or 1, respectively. Twelve percent had stage IB (T2a ≥ 4 cm), 57% had stage II, and 31% had stage IIIA disease. Thirty-nine percent had tumour PD-L1 expression TPS < 1% [negative], 33% had TPS 1-49%, 28% had TPS ≥ 50%. Seven percent had known EGFR mutations, thirty-eight percent without EGFR mutations and in fifty-six percent EGFR mutation status was unknown. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World.

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

The study demonstrated a statistically significant improvement in DFS in the overall population (HR = 0.76 [95% CI: 0.63, 0.91; p = 0.0014]) at a pre-specified interim analysis with a median follow-up time of 32.4 months (range: 0.6 to 68 months) for patients randomised to the pembrolizumab arm compared to patients randomised to the placebo arm. Table 13 and Figure 10 summarise efficacy results in patients who received adjuvant chemotherapy at the final analysis for DFS performed at a median follow-up time of 46.7 months (range: 0.6 to 84.2). At the time of this analysis, OS results were not mature with only 58% of pre-specified OS events in the overall population. An exploratory analysis of OS suggested a trend in favour of pembrolizumab compared to placebo with a HR of 0.79 (95% CI: 0.62, 1.01) in patients who received adjuvant chemotherapy.

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

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

KEYNOTE-024: Controlled study of NSCLC patients naï ve to treatment

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, open-label, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had PD-L1 expression with a ≥ 50% TPS based on the PD-L1 IHC 22C3 pharmDx^TM Kit. Patients were randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=154) or investigator's choice platinum-containing chemotherapy (n=151; including pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin. Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Patients were treated with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy who experienced independently-verified progression of disease were able to crossover and receive pembrolizumab.

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

The primary efficacy outcome measure was PFS as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by BICR using RECIST 1.1). Table 14 summarises key efficacy measures for the entire intent to treat (ITT) population. PFS and ORR results are reported from an interim analysis at a median follow-up of 11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

Table 14: Efficacy results in KEYNOTE-024

Figure 11: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-024 (intent to treat population)

Figure 12: 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-042: Controlled study of NSCLC patients naï ve to treatment

The safety and efficacy of pembrolizumab were also investigated in KEYNOTE-042, a multicentre, controlled study for the treatment of previously untreated locally advanced or metastatic NSCLC. The study design was similar to that of KEYNOTE-024, except that patients had PD-L1 expression with a ≥ 1% TPS based on the PD-L1 IHC 22C3 pharmDx^TM Kit. Patients were randomised (1:1) to receive pembrolizumab at a dose of 200 mg every 3 weeks (n=637) or investigator's choice platinum-containing chemotherapy (n=637; including pemetrexed+carboplatin or paclitaxel+carboplatin. Patients with non-squamous NSCLC could receive pemetrexed maintenance.). Assessment of tumour status was performed every 9 weeks for the first 45 weeks, and every 12 weeks thereafter.

Among the 1 274 patients in KEYNOTE-042, 599 (47%) had tumours that expressed PD-L1 with TPS ≥ 50% based on the PD-L1 IHC 22C3 pharmDx^TM Kit. The baseline characteristics of these 599 patients included: median age 63 years (45% age 65 or older); 69% male; 63% White and 32% Asian; 17% Hispanic or Latino; and ECOG performance status 0 and 1 in 31% and 69%, respectively. Disease characteristics were squamous (37%) and non-squamous (63%); stage IIIA (0.8%); stage IIIB (9%); stage IV (90%); and treated brain metastases (6%).

The primary efficacy outcome measure was OS. Secondary efficacy outcome measures were PFS and ORR (as assessed by BICR using RECIST 1.1). The study demonstrated a statistically significant improvement in OS for patients whose tumours expressed PD-L1 TPS ≥ 1% randomised to pembrolizumab monotherapy compared to chemotherapy (HR 0.82; 95% CI 0.71, 0.93 at the final analysis) and in patients whose tumours expressed PD-L1 TPS ≥ 50% randomised to pembrolizumab monotherapy compared to chemotherapy. Table 15 summarises key efficacy measures for the TPS ≥ 50% population at the final analysis performed at a median follow-up of 15.4 months. The Kaplan-Meier curve for OS for the TPS ≥ 50% population based on the final analysis is shown in Figure 13.

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

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

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

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

The efficacy of pembrolizumab in combination with pemetrexed and platinum chemotherapy was investigated in a multicentre, randomised, active-controlled, double-blind study, KEYNOTE-189. Key eligibility criteria were metastatic non-squamous NSCLC, no prior systemic treatment for metastatic NSCLC, and no EGFR or ALK genomic tumour aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomised (2:1) to receive one of the following regimens:

• Pembrolizumab 200 mg with pemetrexed 500 mg/m² and investigator's choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by pembrolizumab 200 mg and pemetrexed 500 mg/m² intravenously every 3 weeks (n=410)

• Placebo with pemetrexed 500 mg/m² and investigator's choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by placebo and pemetrexed 500 mg/m² intravenously every 3 weeks (n=206)

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

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

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. Table 16 summarises key efficacy measures and Figures 14 and 15 show the Kaplan-Meier curves for OS and PFS based on the final analysis with a median follow-up of 18.8 months.

Table 16: Efficacy results in KEYNOTE-189

Figure 14: Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-189 (intent to treat population)

Figure 15: Kaplan-Meier curve for progression-free survival by treatment arm in KEYNOTE-189 (intent to treat population)