Melanoma

The approvals from the the Food and Drug Administration (FDA), USA, European Medical Agency (EMA), European Union, Therapeutic Goods Administration (TGA), Australia, for Keytruda (pembrolizumab) for unresectable or metastatic melanoma in previously treated patients were based on several studies (KEYNOTE-006^1,2,3, KEYNOTE-002^1,2, KEYNOTE-001^1,2,3). Patients were treated until disease progression or toxicity.

• KEYNOTE-006 was a multicentre, controlled, Phase III study and involved a total of 834 patients naïve to ipilimumab and who received no or one prior systemic therapy. Patients were randomly assigned to one of 3 groups of similar size and received Keytruda as an intravenous injection (drip) at a dose of 10 mg/kg every 2 or 3 weeks or ipilimumab, another immunotherapy. Subgroups of patients were identified and compared according to their PD-L1 expression (positive or negative).

• KEYNOTE-002 was a multicentre controlled study and involved a total of 540 patients previously treated with ipilimumab and if BRAF V600 mutation-positive, a BRAF or MEK inhibitor. Patients were randomly assigned to one of 3 groups of similar size and received Keytruda at a dose of 2 or 10 mg/kg every 3 weeks or chemotherapy (including dacarbazine, temozolamide, carboplatin, paclitaxel, or carboplatin+paclitaxel). Subgroups of patients were identified and compared according to their PD-L1 expression (positive or negative).

• KEYNOTE-001 open-label study and involved 276 patients who had either been previously treated with ipilimumab (and if BRAF V600 mutation-positive, a BRAF or MEK inhibitor) or who were naïve to treatment with ipilimumab. Patients were randomly assigned to one of 3 groups of similar size and received Keytruda at a dose of 2 or 10 mg/kg every 3 weeks.

Results

The major efficacy outcome measures were progression free survival (PFS), overall survival (OS), overall response rate (ORR), duration of response (DOR).

The median PFS was:

• in KEYNOTE-0061:

• 4.1 months [95% CI: 2.9, 7.2] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• 5.6 months [95% CI: 3.4, 8.2] with Keytruda (pembrolizumab) 10 mg/kg every 2 weeks

• 2.8 months [95% CI: 2.8, 2.9] with Ipilimumab 3 mg/kg every 3 weeks

• in KEYNOTE-0021:

• 2.9 months [95% CI: 2.8, 3.8] with Keytruda (pembrolizumab) 2 mg/kg every 3 weeks

• 3 months [95% CI: 2.8, 5.2] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• 2.8 months [95% CI: 2.6, 2.6] with chemotherapy

The median OS was:

• in KEYNOTE-006:

• Not reached [95% CI: 24 months, NA] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• Not reached [95% CI: 22 months, NA] with Keytruda (pembrolizumab) 10 mg/kg every 2 weeks

• 16 months [95% CI: 14, 22] with Ipilimumab 3 mg/kg every 3 weeks

• in KEYNOTE-002:

• 13.4 months [95% CI: 11.0, 16.4] with Keytruda (pembrolizumab) 2 mg/kg every 3 weeks

• 14.7 months [95% CI: 11.3, 19.5] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• 11.0 months [95% CI: 8.9, 13.8] with chemotherapy

The ORR was:

• in KEYNOTE-006:

• 36% [95% CI: 30, 42] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• 13% complete responses

• 37% [95% CI: 31, 43] with Keytruda (pembrolizumab) 10 mg/kg every 2 weeks

• 12% complete responses

• 13% [95% CI: 10, 18] with Ipilimumab 3 mg/kg every 3 weeks

• 5% complete responses

• PD L1 positive/negative subgroup:

• 40% in PD-L1 positive with Keytruda (pembrolizumab) 10 mg/kg every 2 or 3 weeks vs. 14% with ipilimumab

• 24% in PD-L1 negative with Keytruda (pembrolizumab) 10 mg/kg every 2 or 3 weeks vs. 13% with ipilimumab

• in KEYNOTE-002:

• 22% [95% CI: 16, 29] with Keytruda (pembrolizumab) 2 mg/kg every 3 weeks

• 3% complete responses

• 28% [95% CI: 21, 35] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• 7% complete responses

• 5% [95% CI: 2, 9] with chemotherapy

• 0% complete responses

• PD L1 positive/negative subgroup:

• 25% in PD-L1 positive with Keytruda (pembrolizumab) 2 mg/kg every 2 or 3 weeks vs. 4% with ipilimumab

• 10% in PD-L1 negative with Keytruda (pembrolizumab) 2 mg/kg every 2 or 3 weeks vs. 8% with ipilimumab

The DOR was:

• in KEYNOTE-006¹:

• Not reached [95% CI: 24 months, NA] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• Not reached [95% CI: 22 months, NA] with Keytruda (pembrolizumab) 10 mg/kg every 2 weeks

• 16 months [95% CI: 14, 22] with Ipilimumab 3 mg/kg every 3 weeks

• in KEYNOTE-002¹:

• 22.8 months [range: 1.4+, 25.3+] with Keytruda (pembrolizumab) 2 mg/kg every 3 weeks

• Not reached [range: 1.1+, 28.3+] with Keytruda (pembrolizumab) 10 mg/kg every 3 weeks

• 6.8 months [range: 2.8, 11.3] with chemotherapy

• in KEYNOTE-001¹:

• 30.5 months [range: 2.8+, 30.6+] with Keytruda (pembrolizumab) 2 mg/kg every 3 weeks in patients previously treated with ipilimumab

• 27.4 months [range: 1.6+, 31.8+] with Keytruda (pembrolizumab) 2 mg/kg every 3 weeks  in patients naïve to treatment with ipilimumab

Non-small cell lung cancer

1st line approval

The approvals from the Food and Drug Administration (FDA), USA, European Medical Agency (EMA), European Union, Therapeutic Goods Administration (TGA), Australia, of Keytruda (pembrolizumab) for previously untreated metastatic NSCLC were based on one study (KEYNOTE-024^1,2,3). This study involved a total of 305 patients whose tumours had a PD-L1 expression of at least 50%; the study excluded patients with EGFR or ALK mutations. Patients were randomly assigned to one of 2 groups of similar size and received either pembrolizumab at a dose of 200 mg every 3 weeks or investigator’s choice platinum-containing chemotherapy (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 up to a maximum of 24 months¹.

Results

The major efficacy outcome measures were progression free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DOR).

The median PFS was^1,2,3:

• 10.3 months [95% CI: 6.7, N.A.] with Keytruda (pembrolizumab) 200 mg every 3 weeks

• 6.0 months [95% CI: 4.2, 6.2] with chemotherapy

The median OS was^1,2,3:

• Not reached

The ORR was^1,2,3:

• 45% [95% CI: 37, 53] with Keytruda (pembrolizumab) 200 mg every 3 weeks

• 4% complete responses

• 28% [95% CI: 21, 36] with chemotherapy

• 1% complete responses

The median DOR was^1,2,3:

• Not reached [range: 1.9+, 14.5+] with Keytruda (pembrolizumab) 200 mg every 3 weeks

• 6.3 months [range: 2.1+, 12.6+]  with chemotherapy

2nd line approval

The approvals from the Food and Drug Administration (FDA), USA, European Medical Agency (EMA), European Union, Therapeutic Goods Administration (TGA), Australia, of Keytruda (pembrolizumab) for patients previously treated with platinum-containing chemotherapy were based on one study (KEYNOTE-010^1,2,3). This study involved a total of 1033 patients whose tumours had a PD-L1 expression of at least 1%; the study included patients with EGFR or ALK mutations who progressed on medicines specific for these indications. Patients were randomly assigned to one of 3 groups of similar size and received either pembrolizumab at a dose of 2 mg/kg every 3 weeks, pembrolizumab at a dose of 10 mg/kg every 3 weeks or docetaxel at a dose of 75 mg/m2 every 3 weeks. Patients were treated with pembrolizumab until unacceptable toxicity or disease progression¹.

Results

The major efficacy outcome measures were progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DOR).

The median PFS was^1,2,3:

• PD-L1 expression above 1%

• 3.9 months [95% CI: 3.1, 4.1] with Pembrolizumab 2 mg/kg every 3 weeks

• 4.0 months [95% CI: 2.6, 4.3] with Pembrolizumab 10 mg/kg every 3 weeks

• 4.0 months [95% CI: 3.1, 4.2] with docetaxel 75 mg/m2 every 3 weeks

• PD-L1 expression above 50%

• 5.2 months [95% CI: 4.0, 6.5] with Pembrolizumab 2 mg/kg every 3 weeks

• 5.2 months [95% CI: 4.1, 8.1] with Pembrolizumab 10 mg/kg every 3 weeks

• 4.1 months [95% CI: 3.6, 4.3] with docetaxel 75 mg/m2 every 3 weeks

The median OS was^1,2,3:

• PD-L1 expression above 1%

• 10.4 months [95% CI: 9.4, 11.9] with Pembrolizumab 2 mg/kg every 3 weeks

• 12.7 months [95% CI: 10.0, 17.3] with Pembrolizumab 10 mg/kg every 3 weeks

• 8.5 months [95% CI: 7.5, 9.8] with docetaxel 75 mg/m2 every 3 weeks

• PD-L1 expression above 50%

• 14.9 months [95% CI: 10.4, NA] with Pembrolizumab 2 mg/kg every 3 weeks

• 17.3 months [95% CI: 11.8, NA] with Pembrolizumab 10 mg/kg every 3 weeks

• 8.2 months [95% CI: 6.4, 10.7] with docetaxel 75 mg/m2 every 3 weeks

The ORR was^1,2,3:

• PD-L1 expression above 1%

• 18% [95% CI: 14, 23] with Pembrolizumab 2 mg/kg every 3 weeks

• 18% [95% CI: 15, 23]  with Pembrolizumab 10 mg/kg every 3 weeks

• 9% [95% CI: 7, 13] with docetaxel 75 mg/m2 every 3 weeks

• PD-L1 expression above 50%

• 30% [95% CI: 23, 29] with Pembrolizumab 2 mg/kg every 3 weeks

• 29% [95% CI: 22, 37]  with Pembrolizumab 10 mg/kg every 3 weeks

• 8% [95% CI: 4, 13] with docetaxel 75 mg/m2 every 3 weeks

Head and neck cancer

The approvals from the The Food and Drug Administration (FDA), USA, and Therapeutic Goods Administration (TGA), Australia, of Keytruda (pembrolizumab) for recurrent or metastatic head and neck cancer (Head and Neck Squamous Cell Cancer - HNSCC) were based on one study (KEYNOTE-012^2,3).

This study involved a total of 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy². Patients were divided in two groups and received Keytruda 10 mg/kg every 2 weeks (53 patients) or 200 mg every 3 weeks (121 patients) until unacceptable toxicity or disease progression under certain conditions. Patients without disease progression were treated for up to 24 months².  

Results

Among the efficacy outcome measures were the overall response rate (ORR), and duration of response (DOR). These were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks).

The ORR was^1,2,3:

• 16% (95% CI: 11, 22)

• complete response rate: 5%

The DOR among the 28 responding patients was^1,2,3:  

• range: 2.4+ to 27.7+ months

• 23 patients having responses of 6 months or longer

• The median was not reached

Classical Hodgkin Lymphoma

The approvals from the Food and Drug Administration (FDA), USA, European Medical Agency (EMA), European Union, and Therapeutic Goods Administration (TGA), Australia, of Keytruda (pembrolizumab) for relapsed or refractory classical Hodgkin lymphoma (cHL) were based on two multicentre, open-label studies (KEYNOTE-087 and KEYNOTE-013^1,2,3). These studies involved a total of 241 patients with cHL. Both studies included patients regardless of PD-L1 expression.

Results

Among the efficacy outcome measures were the overall response rate (ORR), duration of response (DOR), time to response, progression-free survival (PFS) and overall survival (OS).

The ORR was^1,2,3:

• 69% (95% CI: 62.3, 75.2) in KEYNOTE-087

• Complete remission: 22%

• 58% (95% CI: 39.1, 75.5) in KEYNOTE-013

• Complete remission: 19%

The median DOR was^1,2,3:  

• 11.1 months (range: 0.0+, 11.1) in KEYNOTE-087

• % of patients with duration above 6 months: 76%

• Not reached (range: 0.0+, 26.1+) in KEYNOTE-013

• % of patients with duration above 6 months: 80%

• % of patients with duration above 12 months: 70%

The median time to response was^1,2,3:  

• 2.8 months (range: 2.1, 8.8) in KEYNOTE-087

• 2.8 months (range: 2.4, 8.6) in KEYNOTE-013

The median PFS was^1,2,3:  

• 11.3 months (95% CI: 10.8, not reached) in KEYNOTE-087

• 11.4 months (95% CI: 4.9, 27.8) in KEYNOTE-013

The OS rate was^1,2,3:  

• 99.5% after 6 months in KEYNOTE-087

• 100% after 6 months in KEYNOTE-013

• 97.6% after 12 months in KEYNOTE-087

• 87.1% after 12 months in KEYNOTE-013

Urothelial carcinoma

Cisplatin Ineligible Patients with Urothelial Carcinoma

The Food and Drug Administration (FDA), USA, European Medical Agency (EMA), European Union, and Therapeutic Goods Administration (TGA), Australia, approvals of Keytruda (pembrolizumab) for advanced or metastatic urothelial carcinoma in patients who were not eligible for cisplatin-containing chemotherapy were based on one open-label, single-arm trial (KEYNOTE-052^1,2,3). This study involved a total of 370 patients. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression up to a maximum of 24 months^1,2,3.

Results

Among the efficacy outcome measures were the overall response rate (ORR), and duration of response (DOR).

The ORR was^1,2,3:

• 29% (95% CI: 24, 34)

• Complete response: 7%

The median DOR was^1,2,3:  

• Not reached (range: 1.4+, 17.8+)

Previously treated urothelial carcinoma

The Food and Drug Administration (FDA), USA, European Medical Agency (EMA), European Union, and Therapeutic Goods Administration (TGA), Australia, approvals of Keytruda (pembrolizumab) for advanced or metastatic urothelial carcinoma in patients whose disease progressed on or after platinum-containing chemotherapy were based on one randomised, active-controlled trial (KEYNOTE-045^1,2,3). This study involved a total of 542 patients. Patients received KEYTRUDA 200 mg every 3 weeks or chemotherapy (paclitaxel, docetaxel, or vinflunine) until unacceptable toxicity or disease progression up to a maximum of 24 months^1,2,3.

Results

Among the efficacy outcome measures were the overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).

The ORR was^1,2,3:

• 21% (95% CI: 16, 27) with Keytruda (pembrolizumab)

• Complete response: 7%

• 11% (95% CI: 8, 16) with chemotherapy

• Complete response: 3%

The median OS was^1,2,3:  

• 10.3 months (95% CI: 8.0, 11.8) with Keytruda (pembrolizumab)

• %deaths: 57%

• 7.4 months (95% CI 6.1, 8.3 ) with chemotherapy

• %deaths: 66%

The median PFS was^1,2,3:

• 2.1 months (95% CI: 2.0, 2.2) with Keytruda (pembrolizumab)

• 3.3 months (95% CI: 2.3, 3.5) with chemotherapy

MSI-H Cancer

The Food and Drug Administration (FDA), USA, approval of Keytruda (pembrolizumab) for Microsatellite Instability-High Cancer (MSI-H) or mismatch repair deficient (dMMR) solid tumours were based on 5 studies (KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, KEYNOTE-158). These studies involved a total of 149 patients with MSI-H/dMMR solid tumours. Patients received either Keytruda (pembrolizumab) 200 mg every 3 weeks or Keytruda (pembrolizumab) 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression, or up to a maximum of 24 months².

Results

Among the efficacy outcome measures were the overall response rate (ORR), and the duration of response².

The ORR was²:

• 39.6% (95% CI: 31.7, 47.9)

• complete response rate: 7.4%

The median DOR was²:  

• Not reached (range: 1.6+, 22.7+ months)

• 78% of patients had DOR or more than 6 months

Gastric Cancer

The Food and Drug Administration (FDA), USA, approval of Keytruda (pembrolizumab) for gastric cancer were based on one non-randomised, open-label studies (KEYNOTE-059). These studies involved a total of 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression or up to 24 months².

Among the 259 patients, 55% (n = 143) had tumours that expressed PD-L1 with a combined positive score (CPS) of greater than or equal to 1 and microsatellite stable (MSS) tumor status or undetermined MSI or MMR status. The approval was based on the results of this subgroup.

Results

Among the efficacy outcome measures were the overall response rate (ORR), and the duration of response².

The ORR was²:

• among the 143 patients subgroup

• 13.3% (95% CI: 8.2, 20.0)

• complete response rate: 1.4%

The median DOR was²:  

• among the 143 patients subgroup

• Not reached (range: 2.8+, 19.4+  months)

• 26% of patients had DOR or more than 6 months

References

1. Summary of Product Characteristics [EMA]: Keytruda (pembrolizumab) [PDF]
Merck, May 2017.

2. Summary of Product Characteristics [FDA]: Keytruda (pembrolizumab) [PDF]
Merck, Nov 2017.

3. Summary of Product Characteristics [TGA]: Keytruda (pembrolizumab) [PDF]
Merck, EMA, Jan 2018.