FDA Approves Pembrolizumab for Advanced Melanoma

First PD-1 checkpoint inhibitor to receive agency approval

The USA Food and Drug Administration (FDA) granted on 4 September 2014 accelerated approval to pembrolizumab (Keytruda) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.

Pembrolizumab is the first approved drug that blocks PD-1 cellular pathway.

Pembrolizumab is intended for use following treatment with ipilimumab. For melanoma patients whose tumours express a BRAF V600 gene mutation, pembrolizumab is intended for use after treatment with ipilimumab and a BRAF inhibitor.

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

The five prior FDA approvals for melanoma include: ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

Breakthrough therapy designation

The FDA granted pembrolizumab breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation. Priority review is granted to drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan product designation is given to drugs intended to treat rare diseases.

The FDA action was taken under the agency’s accelerated approval programme, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This programme provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. An improvement in survival or disease-related symptoms has not yet been established.

Clinical efficacy and safety

Pembrolizumab’s efficacy was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with pembrolizumab, either at the recommended dose of 2 mg/kg or at a higher dose of 10 mg/kg.

In the half of the participants who received pembrolizumab at the recommended dose of 2 mg/kg, approximately 24% had their tumours shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumour shrink at the 10 mg/kg dose.

Pembrolizumab’s safety was established in the trial population of 411 participants with advanced melanoma. The most common side effects of pembrolizumab were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia and diarrhoea.

Pembrolizumab also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands and liver, occurred uncommonly.

Keytruda is marketed by Merck & Co., based in Whitehouse Station, New Jersey.