Merck, a global healthcare leader, known as MSD outside the United States and Canada, announced results from the randomized, pivotal phase 3 study, Keynote-006, in the treatment of unresectable advanced melanoma. In the study, Keytruda (pembrolizumab) was statistically superior to ipilimumab for progression-free survival (PFS), overall survival (OS), and overall response rate (ORR).

On March 24, 2015, Merck announced that Keynote-00 would be stopped early based on these data (link). The results were presented at the American Association for Cancer Research (AACR) annual meeting by Dr. Antoni Ribas of Jonsson Comprehensive Cancer Center, University of California, Los Angeles (abstract # CT101), included in the AACR press program, and were also published in the New England Journal of Medicine.

“Improving survival is the ultimate objective in treating patients with cancer. In this important study in advanced melanoma, Keytruda was statistically superior to ipilimumab for progression-free survival and overall survival, and also demonstrated a lower frequency of severe adverse events,” said Dr. Caroline Robert, head of dermatology at Gustave Roussy, Villejuif and Paris-Sud University Cancer Campus, Grand Paris and lead author of the New England Journal of Medicine publication.

In mid-2015, Merck plans to submit a supplemental Biologics License Application (sBLA) for Keytruda based on Keynote-006 for the first-line treatment of advanced melanoma. Merck recently submitted data from Keynote-002 in ipilimumab-refractory advanced melanoma as part of a supplemental application.

Keytruda was the first anti-PD-1 therapy approved in the United States and is currently indicated in the United States for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

“Our goal with the Keytruda development program is to help improve long-term disease control and survival for people suffering from a wide range of cancers,” said Dr. Roger Perlmutter, president, Merck Research Laboratories.

“The Keynote-006 study compared two immunotherapies that target distinct immune checkpoint pathways, PD-1 and CTLA-4. In this study, our anti-PD-1 antibody, Keytruda, improved overall survival by more than 30 percent compared to ipilimumab, an anti-CTLA-4 antibody, in the treatment of advanced melanoma. We look forward to filing these data with the FDA and health authorities around the world.”

Keynote-006 is a global, open-label, randomized, pivotal, phase 3 study of 834 patients from 16 countries with unresectable stage III or IV advanced melanoma with no more than one prior systemic therapy.

Patients received Keytruda 10 mg/kg every two weeks (n=279), Keytruda 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278). The primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response, and safety.

Tumor response was assessed at week 12, then every six weeks thereafter by independent central review per RECIST 1.1. This first presentation of data from Keynote-006 is based on interim analyses conducted for PFS with a data cut-off of September 3, 2014 (median follow-up, 7.9 months) and for OS with a data cut off of March 3, 2015 (median follow-up, 13.8 months).

Data showed Keytruda was statistically superior to Ipilimumab for PFS, OS and ORR.

The median PFS for Keytruda was 5.5 months (2-week group) and 4.1 months (3-week group) compared to 2.8 months for ipilimumab (HR 0.58, P<0.00001 for the KEYTRUDA groups vs. ipilimumab, 95% CI, 0.46-0.72 for 2-week group and 0.47-0.72 for 3-week group, respectively).

The estimated 6-month PFS rates for Keytruda and ipilimumab arms were 47.3 per cent, 46.4 percent and 26.5 percent, respectively. One-year OS for Keytruda was 74.1 per cent (2-week group) and 68.4 percent (3-week group) compared to 58.2 per cent for ipilimumab (HR 0.63 [95% CI, 0.47-0.83, P=0.00052] for the 2-week group and HR 0.69 [95% CI, 0.52-0.90, P=0.00358] for the 3-week group). At the time of analysis, median overall survival was not reached in any treatment group.

ORR for Keytruda was 33.7 per cent (2-week group) and 32.9 percent (3-week group) compared to 11.9 percent for ipilimumab (P=0.00013 for 2-week group; P=0.00002 for 3-week group); complete response rates were 5.0 per cent, 6.1 percent, and 1.4 percent, respectively. Responses were ongoing in 89.4 per cent (2-week group) and 96.7 per cent (3-week group) of Keytruda-treated patients and in 87.9 per cent of ipilimumab-treated patients. Median duration of response was not reached for Keytruda 3-week group (42+ to 246+) and ipilimumab (33+ to 239+).

The efficacy and safety profiles were similar between the two Keytruda schedules evaluated in the study. Two previous studies, Keynote-001 and Keynote-002, demonstrated that the efficacy and safety were similar among the Keytruda doses and schedules evaluated; 10 mg/kg every two weeks, 10 mg/kg every three weeks, and 2 mg/kg every three weeks (the currently approved dose in the US).

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.

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.

Merck is advancing a broad and fast-growing clinical development program for Keytruda with more than 85 clinical trials  across more than 30 tumor types and over 14,000 patients  both as a monotherapy and in combination with other therapies.