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Since 2011, several agents have been approved to treat varying types of melanoma. The most recent approval came this month, when FDA granted accelerated approval to pembrolizumab (Keytruda, Merck) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.

Pembrolizumab is a relatively new name in melanoma care; it only began clinical trials three and a half years ago. The speedy approval is attributed to the fact that FDA granted it “breakthrough therapy designation,” because, according to the agency, “the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapy.” This effectively put the agent on an accelerated path to approval.


Pembrolizumab works by blocking a cellular pathway known as PD-1, which restricts the body's immune system from attacking melanoma cells. For melanoma patients whose tumors express the BRAF V600 gene mutation, Keytruda is intended for use after treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.

Positive findings published in The Lancet in July were key in the approval decision. In the study, 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment were treated with pembrolizumab, either at the recommended dose of 2mg/kg or at a higher dose of 10mg/kg every three weeks for eight months. Over eight months, overall response rate was 26 percent at both doses. Moreover, in the half of participants who received pembrolizumab at the recommended dose of 2mg/ kg, approximately 24 percent had their tumors shrink. The most common side effects were fatigue, pruritus, and rash. Grade 3 fatigue, reported in three percent of patients in the 2mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. Investigators concluded that pembrolizumab would be an effective treatment in patients for whom there are few options.


This approval caps a roughly three-year period that has seen an explosion of new therapies. Moreover, it will be beneficial to have an agent that specifically targets the PD-1 pathway, a pathway not manipulated by other immunomodulatory immunotherapy currently approved to treat melanoma. At this time, it is difficult to project the impact of a drug such as this. Once it becomes available, the hope is that it will prolong life expectancy of patients with melanoma. Organizations such as the Society for Immunotherapy of Cancer (SITC) have already expressed intentions to re-work treatment guidelines to accommodate pembrolizumab. Other groups will likely follow suit, as pembrolizumab becomes the standard follow-up to treatment with other agents.

While the addition of new agents has no doubt revitalized the treatment landscape, it also signals a call for continued progress into the etiology and treatment of what has become one of the deadliest carcinomas in the world. With much still to learn about melanoma, the most effective means of curbing the rising rates of melanoma is primary prevention, starting with UV avoidance and education.

Jonathan Wolfe, MD is a Clinical Associate Professor of Dermatology at the University of Pennsylvania in Philadelphia, PA.

  1. Robert C, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Jul 14.
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