KEYTRUDA Powder for solution for infusion Ref.[7435] Active ingredients: Pembrolizumab

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

Mechanism of action

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

Clinical efficacy and safety

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

Melanoma

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

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

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

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

The primary efficacy outcome measures were progression free survival (PFS; as assessed by Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1) and overall survival (OS). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. Table 3 summarises key efficacy measures in patients naïve to treatment with ipilimumab at the final analysis performed after a minimum of 21 months of follow-up. Kaplan-Meier curves for OS and PFS based on the final analysis are shown in Figures 1 and 2.

Table 3. Efficacy results in KEYNOTE-006:

* Hazard ratio (pembrolizumab compared to ipilimumab) based on the stratified Cox proportional hazard model
^† Based on stratified Log rank test
^‡ Based on patients with a best overall response as confirmed complete or partial response
^§ Based on Kaplan-Meier estimation
NA = not available

Figure 1. Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-006 (intent to treat population):

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

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

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

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

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

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

Table 4. Efficacy results in KEYNOTE-002:

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

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

KEYNOTE-001: Open label study in melanoma patients naïve and previously treated with ipilimumab

The safety and efficacy of pembrolizumab for patients with advanced melanoma were investigated in an uncontrolled, open-label study, KEYNOTE-001. Efficacy was evaluated for 276 patients from two defined cohorts, one which included patients previously treated with ipilimumab (and if BRAF V600 mutation-positive, with a BRAF or MEK inhibitor) and the other which included patients naïve to treatment with ipilimumab. Patients were randomly assigned to receive pembrolizumab at a dose of 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. Patients were treated with pembrolizumab until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Exclusion criteria were similar to those of KEYNOTE-002.

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

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

The primary efficacy outcome measure was ORR as assessed by independent review using RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including complete response, partial response and stable disease), response duration, PFS and OS. Tumour response was assessed at 12-week intervals. Table 5 summarises key efficacy measures in patients previously treated or naïve to treatment with ipilimumab, receiving pembrolizumab at a dose of 2 mg/kg based on a minimum follow-up time of 30 months for all patients.

Table 5. Efficacy results in KEYNOTE-001:

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

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

Sub-population analyses

BRAF mutation status in melanoma

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

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

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

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were BRAF wild type (n=525; 63%), BRAF mutant without prior BRAF treatment (n=163; 20%) and BRAF mutant with prior BRAF treatment (n=139; 17%) as summarised in Table 7.

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

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

PD-L1 status in melanoma

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

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

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

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

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

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

Ocular melanoma

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

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

The efficacy of pembrolizumab was evaluated in KEYNOTE-054, a multicentre, randomized, double- blind, placebo-controlled trial in patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma. A total of 1,019 adult patients were randomized (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. Randomization was stratified by American Joint Committee on Cancer (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 immunohistochemistry assay with the 22C3 anti-PD-L1 antibody; 84% of patients had PD-L1-positive melanoma (PD-L1 expression in ≥ 1% of tumour and tumour-associated immune cells relative to all viable tumour cells). The same scoring system was used for metastatic melanoma (MEL score). T he primary efficacy outcome measures were investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumours, where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. The trial demonstrated a statistically significant improvement in RFS for patients randomized to the pembrolizumab arm compared with placebo at the pre-specified interim analysis. Efficacy results based on an additional seven months of follow-up are summarized in Table 10 and Figure 4.

Table 10. Efficacy results in KEYNOTE-054:

* Based on the stratified Cox proportional hazard model
NR = not reached

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

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

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

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

* Based on the stratified Cox proportional hazard model

NSCLC

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-024, a multicentre, controlled study for the treatment of previously untreated metastatic NSCLC. Patients had PD-L1 expression with a ≥50% tumour proportion score (TPS) based on the PD-L1 IHC 22C3 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. Non-squamous patients could receive pemetrexed maintenance). Patients were treated with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with EGFR or ALK genomic tumour aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks. Patients on chemotherapy who experienced independently-verified progression of disease were able to crossover and receive pembrolizumab.

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

The primary efficacy outcome measure was PFS as assessed by BICR using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by BICR using RECIST 1.1). Table 12 summarizes key efficacy measures for the entire intent to treat (ITT) population. PFS and ORR results are reported from an interim analysis at a median follow-up of 11 months. OS results are reported from the final analysis at a median follow-up of 25 months.

Table 12. Efficacy results in KEYNOTE-024:

* Hazard ratio (pembrolizumab compared to chemotherapy) based on the stratified Cox proportional hazard model
^† Based on stratified Log rank test
^‡ Based on patients with a best overall response as confirmed complete or partial response
^§ Based on Kaplan-Meier estimates; includes 43 patients with responses of 6 months or longer
^¶ Based on Kaplan-Meier estimates; includes 16 patients with responses of 6 months or longer
NA = not available

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

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

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

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

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

Patients were randomized (2:1) to receive one of the following regimens:

• Pembrolizumab 200 mg with pemetrexed 500 mg/m² and investigator’s choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by pembrolizumab 200 mg and pemetrexed 500 mg/m² intravenously every 3 weeks (n=410)
• Placebo with pemetrexed 500 mg/m² and investigator’s choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by placebo and pemetrexed 500 mg/m² intravenously every 3 weeks (n=206)

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

Among the 616 patients in KEYNOTE-189, baseline characteristics were: median age of 64 years (49% age 65 or older); 59% male; 94% White and 3% Asian; 43% and 56% ECOG performance status of 0 or 1 respectively; 31% PD-L1 negative (TPS < 1%); and 18% with treated or untreated brain metastases at baseline. A total of 67 patients in the placebo plus chemotherapy arm crossed over to receive monotherapy pembrolizumab at the time of disease progression and 18 additional patients received a checkpoint inhibitor as subsequent therapy.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. The median follow-up time was 10.5 months (range: 0.2 to 20.4 months). Table 13 summarises key efficacy measures. The Kaplan-Meier curves for OS and PFS are shown in Figures 7 and 8.

Table 13. Efficacy results in KEYNOTE-189:

* Based on the stratified Cox proportional hazard model
^† Based on stratified log-rank test
^‡ Based on patients with a best overall response as confirmed complete or partial response
^§ Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status
^¶ Based on Kaplan-Meier estimation
NA = not available

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

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

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

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

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

A total of 57 NSCLC patients aged ≥75 years were enrolled in study KEYNOTE-189 (35 in the pembrolizumab combination and 22 in the control). A HR=2.09 [95% CI 0.84,5.23] in OS and HR=1.73 [95% CI 0.77,3.90] in PFS for pembrolizumab combination vs chemotherapy was reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

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

The efficacy of pembrolizumab in combination with carboplatin and either paclitaxel or nab- paclitaxel was investigated in Study KEYNOTE-407, a randomised, double-blind, multicentre, placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, regardless of tumour PD-L1 expression status, and no prior systemic treatment for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1 expression (TPS <1% [negative] vs. TPS ≥1%), investigator’s choice of paclitaxel or nab- paclitaxel, and geographic region (East Asia vs. non-East Asia).

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

• Pembrolizumab 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m² on Day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m 2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by pembrolizumab 200 mg every 3 weeks. Pembrolizumab was administered prior to chemotherapy on Day 1.
• Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m² on Day 1 of each 21-day cycle for 4 cycles or nab-paclitaxel 100 mg/m² on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

Treatment with pembrolizumab or placebo continued until RECIST 1.1-defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity, or a maximum of 24 months. Administration of pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.

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

Assessment of tumour status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter.

A total of 559 patients were randomised. The study population characteristics were: median age of 65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of 0 (29%) and 1 (71%); and 8% with treated brain metastases at baseline. Thirty-five percent had tumour PD-L1 expression TPS < 1% [negative]; 19% were East Asian; and 60% received paclitaxel.

The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. The median follow-up time was 7.8 months (range: 0.1 to 19.1 months). Table 15 summarises key efficacy measures. The Kaplan-Meier curves for OS and PFS are shown in Figures 9 and 10.

Table 15. Efficacy Results in KEYNOTE-407:

* Based on the stratified Cox proportional hazard model
^† Based on stratified Log rank test
^‡ Based on method by Miettinen and Nurminen
^§ Based on Kaplan-Meier estimation
NA = not available

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

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

An analysis was performed in KEYNOTE-407 in patients who had PD-L1 TPS <1% [pembrolizumab plus chemotherapy arm: n=95 (34%) vs. placebo plus chemotherapy arm: n=99 (35%)], TPS 1% to 49% [pembrolizumab plus chemotherapy arm: n=103 (37%) vs. placebo plus chemotherapy arm: n=104 (37%)] or TPS ≥50% [pembrolizumab plus chemotherapy arm: n=73 (26%) vs. placebo plus chemotherapy arm: n=73 (26%)] (see Table 16).

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

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

A total of 65 NSCLC patients aged ≥75 years were enrolled in study KEYNOTE-407 (34 in the pembrolizumab combination and 31 in the control). An HR=0.96 [95% CI 0.37,2.52] in OS, an HR=0.60 [95% CI 0.29,1.21] in PFS, and an ORR of 47% and 42% for pembrolizumab combination vs chemotherapy was reported within this study subgroup. Data about efficacy and safety of pembrolizumab in combination with platinum chemotherapy are limited in this patient population.

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-010, a multicentre, open-label, controlled study for the treatment of advanced NSCLC in patients previously treated with platinum-containing chemotherapy. Patients had PD-L1 expression with a 1% TPS based on the PD-L1 IHC 22C3 pharmDx^TM Kit. Patients with EGFR activation mutation or ALK translocation also had disease progression on approved therapy for these mutations prior to receiving pembrolizumab. Patients were randomised (1:1:1) to receive pembrolizumab at a dose of 2 (n=344) or 10 mg/kg (n=346) every 3 weeks or docetaxel at a dose of 75 mg/m² every 3 weeks (n=343) until disease progression or unacceptable toxicity. The trial excluded patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks. Assessment of tumour status was performed every 9 weeks.

The baseline characteristics for this population included: median age 63 years (42% age 65 or older); 61% male; 72% White and 21% Asian and 34% and 66% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and non-squamous (70%); M1 (91%); stable brain metastases (15%) and the incidence of mutations was EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients received one (69%) or two or more (29%) treatment lines.

The primary efficacy outcome measures were OS and PFS as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were ORR and response duration. Table 17 summarises key efficacy measures for the entire population (TPS ≥1%) and for the patients with TPS 50%, and Figure 11 shows the Kaplan-Meier curve for OS (TPS ≥1%), based on a final analysis with median follow up of 42.6 months.

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

* Hazard ratio (pembrolizumab compared to docetaxel) based on the stratified Cox proportional hazard model
^† Based on stratified Log rank test
^‡ Assessed by blinded independent central review (BICR) using RECIST 1.1
^§ Based on patients with a best overall response as confirmed complete or partial response

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

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

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

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

Classical Hodgkin lymphoma

KEYNOTE-087 and KEYNOTE-013: Open-label studies in patients with relapsed or refractory classical Hodgkin lymphoma (cHL)

The efficacy of pembrolizumab was investigated in KEYNOTE-087 and KEYNOTE-013, two multicentre, open-label studies for the treatment of 241 patients with cHL. These studies enrolled patients who failed ASCT and BV, who were ineligible for ASCT because they were unable to achieve a complete or partial remission to salvage chemotherapy and failed BV, or who failed ASCT and did not receive BV. Five study subjects were ineligible to ASCT due to reasons other than failure to salvage chemotherapy. Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic transplant within the past 5 years (or >5 years but with GVHD), active autoimmune disease or a medical condition that required immunosuppression were ineligible for either trial. Patients received pembrolizumab 200 mg every 3 weeks (n=210; KEYNOTE-087) or 10 mg/kg every 2 weeks (n=31; KEYNOTE-013) until unacceptable toxicity or documented disease progression.

Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or older); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 35% who were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were transplant ineligible; 17% had no prior brentuximab vedotin use; and 36% of patients had prior radiation therapy. Disease subtypes were 80% nodular sclerosis, 11% mixed cellularity, 4% lymphocyte-rich and 2% lymphocyte-depleted.

Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (7% age 65 or older), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5 (range 2 to 15). Eighty-seven percent were refractory to at least one prior therapy, including 39% who were refractory to first line therapy. Seventy-four percent of patients had received Auto-SCT, 26% were transplant ineligible, and 42% of patients had prior radiation therapy. Disease subtypes were 97% nodular sclerosis and 3% mixed cellularity.

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

Table 18. Efficacy results in KEYNOTE-087 and KEYNOTE-013:

^a Median follow-up time of 10.1 months
^b Median follow-up time of 28.7 months
^c Assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria by PET CT scans
^d Based on patients (n=145) with a response by independent review
^e Based on patients (n=18) with a response by independent review
^f Based on Kaplan-Meier estimation; includes 31 patients with responses of 6 months or longer
^g Based on Kaplan-Meier estimation; includes 9 patients with responses of 6 months or longer
^h Based on Kaplan-Meier estimation; includes 7 patients with responses of 12 months or longer

Safety and efficacy in elderly patients

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

Urothelial Carcinoma

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

The safety and efficacy of pembrolizumab were evaluated in KEYNOTE-045, a multicentre, randomised (1:1), controlled study for the treatment of locally advanced or metastatic urothelial carcinoma in patients with disease progression on or after platinum-containing chemotherapy. Patients must have received first line platinum-containing regimen for locally advanced/metastatic disease or as neoadjuvant/adjuvant treatment, with recurrence/progression ≤12 months following completion of therapy. Patients were randomised (1:1) to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m² (n=84), docetaxel 75 mg/m² (n=84), or vinflunine 320 mg/m² (n=87). Patients were treated with pembrolizumab until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with autoimmune disease, a medical condition that required immunosuppression and patients with more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer. Patients with an ECOG performance status of 2 had to have a hemoglobin ≥10 g/dL, could not have liver metastases, and must have received the last dose of their last prior chemotherapy regimen ≥3 months prior to enrollment. Assessment of tumour status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among the 542 randomised patients in KEYNOTE-045, baseline characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 56% ECOG performance status of 1 and 1% ECOG performance status of 2; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumour in the lower tract and 14% had a primary tumour in the upper tract. Fifteen percent of patients had disease progression following prior platinum- containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% was treated with other platinum-based regimens.

The primary efficacy outcomes were OS and PFS as assessed by BICR using RECIST v1.1. Secondary outcome measures were ORR (as assessed by BICR using RECIST v1.1) and duration of response. Table 19 summarises the key efficacy measures for the ITT population at the final analysis. The Kaplan-Meier curve based on the final analysis for OS is shown in Figure 12. The study demonstrated statistically significant improvements in OS and ORR for patients randomised to pembrolizumab as compared to chemotherapy. There was no statistically significant difference between pembrolizumab and chemotherapy with respect to PFS.

Table 19. Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial carcinoma previously treated with chemotherapy in KEYNOTE-045:

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

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

An analysis was performed in KEYNOTE-045 in patients who had PD-L1 CPS <10 [pembrolizumab: n=186 (69%) vs. chemotherapy: n=176 (65%)] or ≥10 [pembrolizumab: n=74 (27%) vs. chemotherapy: n=90 (33%)] in both pembrolizumab- and chemotherapy-treated arms (see Table 20).

Table 20. OS by PD-L1 Expression:

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

Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time to deterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated with pembrolizumab compared to investigator’s choice chemotherapy (HR 0.70; 95% CI 0.55-0.90). Over 15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL, while those treated with investigator’s choice chemotherapy had a decline in global health status/QoL. These results should be interpreted in the context of the open-label study design and therefore taken cautiously.

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-052, a multicentre, open- label study for the treatment of locally advanced or metastatic urothelial carcinoma in patients who were not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. The study excluded patients with autoimmune disease or a medical condition that required immunosuppression. Assessment of tumour status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy baseline characteristics were: median age 74 years (82% age 65 or older); 77% male; and 89% White and 7% Asian. Eighty-eight percent had M1 disease and 12% had M0 disease. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: baseline creatinine clearance of <60 mL/min (50%), ECOG performance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of <60 mL/min (9%), and other (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had a primary tumour in the lower tract, and 19% of patients had a primary tumour in the upper tract.

The primary efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Secondary efficacy outcome measures were duration of response, PFS, and OS. Table 21 summarises the key efficacy measures for the study population at the final analysis based on a median follow-up time of 11.4 months (range: 0.1, 41.2 months) for all patients.

Table 21. Response to pembrolizumab 200 mg every 3 weeks in patients with urothelial carcinoma ineligible for cisplatin-containing chemotherapy in KEYNOTE-052:

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

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

Table 22. ORR and OS by PD-L1 Expression:

* BICR using RECIST 1.1

KEYNOTE-361 is an ongoing Phase III, randomised, controlled, open-label clinical trial of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy as first-line treatment in subjects with advanced or metastatic urothelial carcinoma. Preliminary data from an early review showed a reduced survival with pembrolizumab monotherapy in patients whose tumours express PD-L1 with a CPS <10 compared with standard chemotherapy.

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

Head and Neck Squamous Cell Carcinoma

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

The safety and efficacy of pembrolizumab were investigated in KEYNOTE-040, a multicentre, open- label, randomised, controlled study for the treatment of recurrent or metastatic HNSCC in patients who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy, and were not amenable to local therapy with curative intent. Patients were stratified by PD-L1 expression (TPS ≥50%), HPV status and ECOG performance status and then randomised (1:1) to receive either pembrolizumab 200 mg every 3 weeks (n=247) or one of three standard treatments (n=248): methotrexate 40 mg/m² once weekly (n=64), docetaxel 75 mg/m² once every 3 weeks (n=99), or cetuximab 400 mg/m² loading dose and then 250 mg/m² once weekly (n=71). Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. The study excluded patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or who were previously treated with 3 or more systemic regimens for recurrent and/or metastatic HNSCC. Assessment of tumour status was performed at 9 weeks, then every 6 weeks through week 52, followed by every 9 weeks through 24 months.

Among the 495 patients in KEYNOTE-040, 129 (26%) had tumours that expressed PD-L1 with a TPS ≥50% based on the PD-L1 IHC 22C3 pharmDx^TM Kit. The baseline characteristics of these 129 patients included: median age 62 years (40% age 65 or older); 81% male; 78% White, 11% Asian, and 2% Black; 23% and 77% with an ECOG performance status 0 or 1, respectively; and 19% with HPV positive tumours. Sixty-seven percent (67%) of patients had M1 disease and the majority had Stage IV disease (Stage IV 32%, Stage IVa 14%, Stage IVb 4%, and Stage IVc 44%). Sixteen percent (16%) had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy, and 84% had received 1-2 prior systemic regimens for metastatic disease.

The primary efficacy outcome was OS in the ITT population. The initial analysis resulted in a HR for OS of 0.82 (95% CI: 0.67, 1.01) with a one-sided p-value of 0.0316. The median OS was 8.4 months for pembrolizumab compared to 7.1 months for standard treatment. Table 23 summarises the key efficacy measures for the TPS ≥50% population. The Kaplan-Meier curve for OS for the TPS ≥50% population is shown in Figure 13.

Table 23. Efficacy of pembrolizumab 200 mg every 3 weeks in HNSCC patients with TPS ≥50% who were previously treated with platinum chemotherapy in KEYNOTE-040:

* Methotrexate, docetaxel, or cetuximab
^† Hazard ratio (pembrolizumab compared to standard treatment) based on the stratified Cox proportional hazard model
^‡ One-sided p-Value based on log-rank test
^§ Assessed by BICR using RECIST 1.1
^¶ Based on method by Miettinen and Nurminen
^# Based on patients with a best overall response as confirmed complete or partial response
^Þ Based on Kaplan-Meier estimation

Figure 13. Kaplan-Meier curve for overall survival by treatment arm in KEYNOTE-040 patients with PD-L1 expression (TPS ≥50%):

Paediatric population

In KEYNOTE-051, 154 paediatric patients (60 children aged 6 months to less than 12 years and 94 adolescents aged 12 years to 18 years) with advanced melanoma or PD-L1 positive advanced, relapsed, or refractory solid tumours or lymphoma were administered pembrolizumab 2 mg/kg every 3 weeks. All patients received pembrolizumab for a median of 3 doses (range 1-35 doses), with 130 patients (84.4%) receiving pembrolizumab for 2 doses or more. Participants were enrolled across 28 tumour types by primary diagnosis. The most common tumour types by histology were Hodgkin lymphoma (11.7%), glioblastoma multiforme (9.1%), neuroblastoma (6.5%), osteosarcoma (6.5%) and melanoma (5.2%). Of the 154 patients, 134 were enrolled with solid tumours, 18 with Hodgkin lymphoma, and 2 with other lymphomas. In patients with solid tumours and other lymphomas, the ORR was 5.9%, no patient had a complete response and 8 patients (5.9%) had a partial response. In the Hodgkin lymphoma population, the ORR was 50.0%, 2 patients (11.1%) had a complete response and 7 patients (38.9%) had a partial response.

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