The US FDA has accepted for review global healthcare leader Merck's supplemental Biologics License Application (sBLA) for anti-PD-1 therapy, Keytruda (pembrolizumab).

Merck is seeking approval for Keytruda, at the currently approved dose of 2 mg/kg every three weeks, for the first-line treatment of unresectable or metastatic melanoma patients. The FDA granted Priority Review with a PDUFA or target action date of December 19, 2015. Additionally, the FDA has extended the action date for a separate sBLA for Keytruda for the treatment of patients with ipilimumab-refractory advanced melanoma. The new action date is now December 24, 2015.

“Through our clinical programme for Keytruda we have accumulated substantial data on the role of our anti-PD-1 therapy in advanced melanoma. We look forward to the FDA's review of each of these applications, and to delivering on our goal of helping patients with advanced melanoma to achieve long-term disease control and survival,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.

Keytruda is currently 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 tumour 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.

The sBLA submission for first-line use in advanced melanoma was based in part on data from KEYNOTE-006, a phase 3 study which evaluated Keytruda in 834 patients with unresectable or metastatic melanoma with progression of disease. Findings from this study were presented at the 2015 American Associated for Cancer Research (AACR) Annual Meeting and published in the New England Journal of Medicinei.

The sBLA for ipilimumab-refractory advanced melanoma included data from KEYNOTE-002. KEYNOTE-002 is the phase 2 study which demonstrated Keytruda was superior to chemotherapy in helping more patients with ipilimumab-refractory advanced melanoma achieve progression-free survival (PFS). In an effort to provide the FDA with the most robust data for Keytruda in this population, Merck submitted an additional analysis from KEYNOTE-002. The submission constitutes a major amendment which will require additional time for review.

Keytruda is a humanised 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-tumour immune response.

Merck is advancing a broad and fast-growing clinical development programme for Keytruda with more than 100 clinical trials – across more than 30 tumour types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

For the treatment of advanced melanoma, Keytruda was discontinued for adverse reactions in 9 per cent of 411 patients across all doses studied. Adverse reactions, reported in at least two patients, that led to discontinuations of Keytruda were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36 per cent of patients receiving Keytruda. The most frequent serious adverse drug reactions reported in 2 per cent or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. In the US, melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2015, an estimated 73,870 people are expected to be diagnosed and an estimated 9,940 people are expected to die of the disease in the U.S. alone. The five-year survival rates for advanced or metastatic melanoma (stage IV) are estimated to be 15 to 20 per cent.