Earlier today, U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda®; Merck, MSD outside the United States and Canada. The drug was previously know as MK-3475) at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy®; BMS/Bristol-Myers Squibb Company) and, if BRAF V600 mutation positive, a BRAF inhibitor.
The approval of this drug, a new treatment for the deadliest form of skin cancer, is based on tumor response rate and durability of response. Although an improvement in survival or disease-related symptoms has not yet been established and a continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials, melanoma patients have been waiting anxiously for this new treatment option, given the promising data that early studies have shown.
... [A] treatment ... that successfully kills melanoma cells and prevents recurrence in every patient has not yet been developed. That is the ultimate goal...
Melanoma is one of the fastest growing cancers in the United States and can strike men and women of all ages, all races and skin types. Over the last 30 year the rates of melanoma have been rising. According to recent data from the American Cancer Society, the disease is about 20 times more common in whites than African Americans. Overal, the lifetime risk is about 2% (1 in 50) for whites, 0.1% (1 in 1,000) for blacks, and 0.5% (1 in 200) for Hispanics. This translates to nearly 77,000 Americans to be diagnosed with the disease in 2014, leading to almost 10,000 deaths. Melanoma is the most common form of cancer for young adults 25- to 29-years-old and the second most common cancer in adolescents and young adults 15- to 29-years-old. 
The majority of melanomas occur on the skin --in fact, melanoma is the most serious type of skin cancer. But melanoma can also occur in the eye, resulting in ocular, or uveal melanoma, in mucous membranes (mucosal melanoma), or even beneath fingernails or toenails.
The approval of pembrolizumab was based on data from a multi-center, open-label, randomized, dose-comparative study cohort of the ongoing KEYNOTE-001 Phase 1b trial in patients with unresectable or metastatic melanoma and progression of disease. Key eligibility criteria included prior treatment with ipilimumab (two or more doses at 3 mg/kg or higher) and a BRAF or MEK inhibitor, if BRAF V600 mutation positive, and disease progression within 24 weeks following the last dose of ipilimumab. 
Patients were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression. The major efficacy outcome measures were confirmed overall response rate as assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response. Tumor response was assessed every 12 weeks. 
Following the recommended 2 mg/kg dose based on data in 89 patients, the overall response rate was 24% (95% CI: 15, 34), with one complete response and 20 partial responses (21/89). At the time of analysis, 86% (18/21) of patients with objective responses had ongoing responses with durations ranging from 1.4+ to 8.5+ months, including eight patients with ongoing responses of 6 months or longer. Fourteen percent (3/21) had progression of disease 2.8, 2.9, and 8.2 months after initial response.
“The accelerated FDA approval of pembrolizumab is a meaningful development for patients with advanced melanoma,” said Omid Hamid, MD, Chief, Translational Research and Immunotherapy and Director of the Melanoma Center at The Angeles Clinic and Research Institute, and a principal investigator for the pembrolizumab melanoma clinical program. “Our new ability to target the PD-1 pathway with pembrolizumab is a very exciting step in the immunotherapy field.”
Hamid was one of the co-authors of an article published in the early, July 15, 2014 online edition of The Lancet. Based on the study results of the KEYNOTE-001 study, the authors conclude that pembrolizumab is an effective treatment in patients for whom there are few effective treatment options available. 
"To see that 24% taking pembrolizumab had their tumors shrink and that most of these patients continued to respond past the 8.5 month study cut off is particularly significant because these studies were conducted in patients who had already failed to respond to other approved therapies," noted Tim Turnham, Executive Director, Melanoma Research Foundation (MRF), the largest independent organization devoted to melanoma.
"The approval of pembrolizumab is a tremendous step forward for the melanoma patient community, as this is the most promising and positive patient response to a melanoma treatment to date," Turnham added.
Pembrolizumab, a humanized monoclonal antibody, is the first melanoma drug approved by the FDA that targets a protein in the human cell called Programmed Death Receptors or PD-1. The drug 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, pembrolizumab releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
This innovative approach to combatting melanoma is highly regarded by researchers, many of whom feel that PD-1 therapies will be the key to successfully treating advanced melanoma and possibly several other cancers.
Other companies in the process of creating their own PD-1 treatments include BMS/Bristol-Myers Squibb and AstraZeneca. Approval of a PD-1 developed by BMS/Bristol-Myers Squibb is expected in the next few months.
A giant leap forward
"With the approval of Merck's PD-1, we are witnessing a giant leap toward a long-term and durable solution to helping people put their melanoma behind them for good. After many years without new treatments, five melanoma treatments have now been approved by the FDA since 2011, indicating major progress in treatments for people diagnosed with this deadly disease. Prior to today's approval, the median survival of a person diagnosed with advanced melanoma was less than a year," Turnham said.
"While today's approval is a critically important milestone, much work remains to be done. Pembrolizumab will not be a treatment option for every person with late stage melanoma and not everyone who takes it will have positive results. While many people who were administered pembrolizumab in clinical trials saw tremendous benefit, a treatment that successfully kills melanoma cells and prevents recurrence in every patient has not yet been developed. That is the ultimate goal," Turnham concluded.
For more information:
 KEYTRUDA® (pembrolizumab) - Highlights of prescribing information [Download]
 KEYTRUDA® (pembrolizumab) Medication Guide [Download]
 American Cancer Society. What are the Key Statistics about Melanoma Skin Cancer. Last accessed September 4, 2014 [Webarticle]
 Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, 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. pii: S0140-6736(14)60958-2. doi: 10.1016/S0140-6736(14)60958-2. [Article][PubMed]
 Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001) - NCT01295827[Study Record Detail]
 Study of MK-3475 (Pembrolizumab) in Participants With Advanced Melanoma (MK-3475-041)- NCT02180061 [Study Record Detail]
 Safety and Tolerability of Pembrolizumab (MK-3475) + Pegylated Interferon Alfa-2b and Pembrolizumab+ Ipilimumab in Participants With Advanced Melanoma or Renal Cell Carcinoma (MK-3475-029/KEYNOTE-29)-NCT02089685 [Study Record Detail]
 Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006) - NCT01866319 [Study Record Detail]
 Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (P08719/KEYNOTE-002) - NCT01704287 [Study Record Detail]
 Program for Pembrolizumab (MK-3475) in Participants With Metastatic Melanoma Who Have Failed Standard of Care Therapy Including Ipilimumab (MK-3475-030) - NCT02083484 [Study Record Detail]
 A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022) NCT02130466 [Study Record Detail]
Photo: KEYTRUDA (Pembrolizumab/MK-3475) 50 mg Lyophilized Vial and Packaging. Photo Courtesy: Merck Sharp & Dohme Corporation/MSD.
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