The first immunomodulator that acts as a programmed death (PD) inhibitor has been approved by the US Food and Drug Administration (FDA). Pembrolizumab (Keytruda, Merck & Co), previously known as MK-3475, has been approved for use in patients with advanced or unresectable melanoma who are no longer responding to other drugs.
Pembrolizumab has beaten a number of other similar drugs to the American market, including nivolumab (Bristol-Myers Squibb/Ono), which was recently approved in Japan for use in melanoma, and also MPDL-3280A (Roche/Genentech/Chugai) and MED14736 (AstraZeneca/MedImmune).
It has been approved nearly 2 months earlier than had been expected. Pembrolizumab was granted priority review by the FDA with an action date of October 28; it was also given breakthrough therapy and orphan drug designation. The drug is also awaiting approval in Europe.
The drug was granted an accelerated approval, which is based on clinical data showing an effect on a surrogate end point reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials, the FDA noted. An improvement in survival or disease-related symptoms has not yet been established.
Pembrolizumab is intended for use following treatment with ipilimumab (Yervoy, Bristol-Myers Squibb). It can also be used in patients whose tumors express BRAF V600, after treatment with both ipilimumab and a BRAF inhibitor.
Such patients currently have few therapeutic options. The company demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies, the FDA noted.
Results showing efficacy in 173 melanoma patients with ipilimumab-refractory disease were published online July 15 in the Lancet.
All the patients in this trial received pembrolizumab, either at the recommended dose of 2 mg/kg or the higher dose of 10 mg/kg.
At both doses, about 24% of patients showed tumor shrinkage, and this effect lasted at least 1.4 to 8.5 months, and continued beyond this period in most patients, the FDA noted.
Safety was established in a trial population of 411 patients with advanced melanoma, the agency noted. The most common adverse effects of pembrolizumab were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. The product also has the potential for severe immune-mediated adverse effects, and severe immune-mediated adverse effects involving healthy organs, including the lung, colon, hormone-producing glands, and liver, have occurred uncommonly, the FDA noted.
When the results with pembrolizumab were published earlier this year in the Lancet, an accompanying editorial said they "add to the burgeoning literature on the potential of PD-1 blockade to improve outcomes in patients with metastatic melanoma."
"Treatment of melanoma has never been this promising," the editorialists added.
One of the lead investigators of the PD-1 clinical trial, Jeffrey S. Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Center in Tampa, Florida, commented in a statement: "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. This approval is a real advance, and a major milestone in the treatment of the disease."
This new class of drugs, the PD inhibitors, is also being investigated in many other cancer types, generating particular excitement in lung cancer. In fact, they are predicted to be "game-changers" in the treatment of cancer, and have been hailed as a success for a fourth modality — immunotherapy — joining chemotherapy, radiotherapy, and surgery as tools for tackling the disease.
But already there is concern that these drugs will be hugely expensive. According to a report in the Wall Street Journal, pembrolizumab will be priced at around $150,000 in the United States, while in Japan where nivolumab was recently launched, the cost of the drug is around $143,000 per year.
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Cite this: FDA Okays First PD Inhibitor: Pembrolizumab for Melanoma - Medscape - Sep 04, 2014.