The European Commission has approved Merck's anti-PD-1 therapy, Keytruda (pembrolizumab) for the treatment of advanced (unresectable or metastatic) melanoma in adults.

The European Commission approval of Keytruda is based on data from three clinical studies conducted in more than 1,500 first-line and previously-treated patients with advanced melanoma.

Keytruda received European Commission regulatory approval based on phase 3 data which showed it is the first and only anti-PD-1 therapy to provide a statistically superior survival benefit as a monotherapy compared to ipilimumab, the current standard of care for advanced melanoma. Today’s approval allows marketing of Keytruda in all 28 EU member states at the approved dose of 2 mg/kg every three weeks.

“The European approval supports our goal of accelerating immuno-oncology research for the benefit of patients around the world,” said Dr. Roger M. Perlmutter, president, Merck research laboratories. “We believe that the broad data set supporting this approval helps illustrate the significant potential of Keytruda to treat advanced melanoma, a devastating disease.”

“Merck has long-believed that innovation and access must go hand-in-hand, which is why we work to bring forward new innovations, and ensure access to those innovations,” said Deepak Khanna, senior vice president and regional president, Europe, MSD Oncology.

“Merck is committed to working collaboratively with governments and other stakeholders to ensure that Keytruda will be made available to advanced melanoma patients in Europe as rapidly as possible.”

The European Commission’s approval is based on data from three studies -- KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006. These studies evaluated the efficacy and safety of Keytruda in advanced melanoma patients – across treatment lines, prognostic factors, tumor characteristics, and BRAF mutational status – and established 2 mg/kg every three weeks as the approved dose.

KEYNOTE-001, the largest phase 1b study to date of an anti-PD-1 antibody, is a single arm, open label study of Keytruda (2 mg/kg every three weeks or 10 mg/kg every two or three weeks) that included patients with advanced melanoma who were previously-treated with ipilimumab (and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor) and patients who were ipilimumab-naïve. In two cohorts of advanced melanoma patients comparing doses of Keytruda, of the 140 patients receiving the approved 2 mg/kg every three week dose, the overall response rate (ORR) (primary endpoint) for Keytruda was 33 percent in ipilimumab-naïve patients (95 per cent CI, 21, 48) (n=51) and 25 per cent in patients previously-treated with ipilimumab (95 per cent CI, 16, 35) (n=89). The secondary endpoints were overall survival (OS), progression-free survival (PFS), and duration of response per RECIST v1.1. Results were similar across dosing schedules.

KEYNOTE-002 is a phase 2, multi-center, randomized study of Keytruda (2 mg/kg every three weeks or 10 mg/kg every three weeks) compared to investigator-choice chemotherapy in 540 patients with advanced melanoma who were previously-treated with ipilimumab and, if BRAF V600 mutation positive, a BRAF or MEK inhibitor. The primary endpoints were PFS and OS. Both Keytruda doses evaluated were superior compared to chemotherapy for PFS at both six-months and nine-months, with PFS rates of 34 and 24 percent, respectively, for the 2 mg/kg dose (95 per cent CI, 0.57 [0.45, 0.73]) (n=180) and 38 and 29 per cent for the 10 mg/kg dose (95 per cent CI, 0.50 [0.39, 0.64]) (n=181), compared to 16 and 8 percent for investigator-choice chemotherapy (n=179). OS data were not mature at the time of the analysis. The secondary endpoints were ORR and duration of response per RECIST v1.1.

KEYNOTE-006 is a phase 3, multi-center, randomized, study of Keytruda (10 mg/kg every two or three weeks) compared to ipilimumab in 834 patients with advanced melanoma. In the planned interim analysis of the co-primary endpoints, KEYTRUDA demonstrated superior PFS and OS compared to ipilimumab. The estimated 6-month and 9-month PFS rates for KEYTRUDA were 47 and 40 percent, respectively, for the 2-week group (95 per cent CI, 0.58 [0.46, 0.72], p<0.00001) (n=279) and 46 and 42 percent for the 3-week group (95 per cent CI, 0.58 [0.47, 0.72], p<0.00001) (n=277), compared to 27 and 16 percent for ipilimumab (n=278). One-year OS for KEYTRUDA was 74 percent (2-week group) (95 per cent CI, 0.63 [0.47, 0.83], p = 0.00052) and 68 percent (3-week group) (95 per cent CI, 0.69 [0.52, 0.90], p = 0.00358), compared to 58 percent for ipilimumab. The risk of death was reduced by 31 percent for patients treated with KEYTRUDA in the 3-week group (hazard ratio 0.69) and 37 per cent in the 2-week group (hazard ratio 0.63). The secondary endpoints were ORR and duration of response per RECIST v1.1.

The safety analysis supporting the European approval of Keytruda was based on 1,012 advanced melanoma patients across three doses (2 mg/kg every three weeks or 10 mg/kg every two or three weeks) in studies KEYNOTE-001 and KEYNOTE-002 combined. The most common adverse reactions (>10 per cent) with Keytruda were diarrhea (15 per cent), nausea (12 per cent), pruritus (25 per cent), rash (25 per cent), arthralgia (13 per cent) and fatigue (33 per cent). The majority of adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.

Melanoma, the most serious form of skin cancer, is characterised by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades. In Europe, approximately 100,000 new cases were estimated to be diagnosed in 2012, which is almost half of the global incidence of melanoma. The five-year survival rates for advanced or metastatic melanoma (Stage IV) are estimated to be 15 to 20 per cent in the United States and 5 to 22 per cent in Europe.

Keytruda (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

With the European Commission decision, Keytruda is now approved in more than 35 countries for the treatment of advanced melanoma. Merck is advancing a broad and fast-growing clinical development programme for Keytruda with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

Keytruda is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.