Richard Pazdur, MD

The FDA has approved pembrolizumab (Keytruda) as a treatment for patients with advanced or unresectable melanoma following progression on prior therapies. This decision makes pembrolizumab the first PD-1 inhibitor to gain approval in the United States.

The accelerated approval was based on response rates demonstrated in clinical trial data from 173 patients with melanoma in the KEYNOTE-001 study. At the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate (ORR) was 24%, with a response duration lasting from 1.4 to 8.5 months.

The treatment was approved under the FDA's priority review program and follows a breakthrough therapy designation. The scheduled approval date for the first-in-class agent was October 28, 2014. Merck, the company marketing pembrolizumab, announced that it plans to make the drug available by mid-September.

“Keytruda is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release. “Many of these treatments have different mechanisms of action and bring new options to patients with melanoma.”

The approval was based on a portion of patients enrolled in the phase Ib KEYNOTE-001 study that examined pembrolizumab in 276 patients with ipilimumab-naÃ¯ve (n = 102) and refractory (n = 173) melanoma. In the study, patients received treatment with pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks. The primary endpoint was ORR, with secondary outcome measures focused on investigator-assessed immune-related response criteria (irRC).

For patients who were refractory to ipilimumab, 89 received the 2-mg/kg dose and 84 were treated with 10-mg/kg pembrolizumab. Overall, 13% tested positive for a BRAF mutation in the 2-mg/kg arm and 23% were positive in the 10-mg/kg arm. Additionally, 57% of patients had M1c disease in the 2 mg/kg arm. Prior treatment with a BRAF inhibitor was allowed in the study.

According to phase Ib results from the KEYNOTE-001 study that were presented at the 2014 ASCO Annual Meeting, for patients treated with the 2 mg/kg dose, the ORR was 26% by RECIST criteria, with a disease control rate of 51%.

By irRC criteria, the ORR was 27% with 2-mg/kg pembrolizumab and 32% with the larger dose. The estimated progression-free survival rate at 24 weeks was 44% with the 2 mg/kg dose and 37% with 10 mg/kg pembrolizumab.

In an update analysis of the data submitted to the FDA, the ORR in the 2 mg/kg arm was indicated as 24%, with 1 CR and 20 PRs. When this analysis was conducted in May 2014, 86% of patients continued to response to therapy.

The median overall survival (OS) for patients treated with the 2 mg/kg dose had not yet been reached at the May data cuttoff. However, in the 10 mg/kg arm, the median OS was 18 months. The 12-month OS rate was 58% with 2-mg/kg pembrolizumab and 63% with the 10-mg/kg dose.

“Pembrolizumab is the first PD-1 drug to be approved by the FDA, and it is a clearly effective drug that will prolong survival for many patients with metastatic melanoma," Jeffrey S. Weber, MD, PhD, the director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, said in a statement. "This approval is a real advance, and a major milestone in the treatment of the disease."

The safety profile for pembrolizumab was established based on data from 411 patients enrolled in various studies. The most common side effects were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea, according to the FDA.

Across the 411 patients, pembrolizumab was discontinued as a result of adverse reactions in 9% of patients. At the 2-mg/kg dose, the discontinuation rate was 6%. Immune-mediated adverse reactions included pneumonitis (2.9%), colitis (1%), hepatitis (0.5%), hypophysitis (0.5%), nephritis (0.7%), hyperthyroidism (1.2%), and hypothyroidism (8.3%).

“The accelerated FDA approval of Keytruda is a meaningful development for patients with advanced melanoma,” Omid Hamid, MD, the director of the Melanoma Center at The Angeles Clinic and Research Institute, said in a press release. “Our new ability to target the PD-1 pathway with Keytruda is a very exciting step in the immunotherapy field.”

Pembrolizumab is a highly selective humanized monoclonal IgG4 antibody directed against the PD-1 receptor on the cell surface. The drug blocks the PD-1 receptor, preventing binding and activation of PD-L1 and PD-L2. This mechanism causes the activation of T-cell mediated immune responses against tumor cells.

Multiple clinical trials are currently underway exploring pembrolizumab across a variety of tumor types, including a phase II and III study investigating the agent for advanced melanoma. At this point, over 30 studies are exploring the drug.