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The U.S. Food and Drug Administration has granted accelerated approval to Keytruda (pembrolizumab, formerly known as MK-3475) for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs. Keytruda is the first approved drug that blocks the PD-1 pathway, which prevents the body's immune system from attacking melanoma cells.

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"This drug is a game changer, a very significant advance in the treatment of melanoma," said Antoni Ribas, MD, PhD, principal investigator for the Phase I study of the drug and Professor of Medicine in the Division of Hematology-Oncology at UCLA's David Geffen School of Medicine. "For patients who have not responded to prior therapies, this drug now provides a very real chance to shrink their tumors and the hope of a lasting response to treatment."


Keytruda, which is marketed by Merck & Co., is intended for use following treatment with ipilimumab immunotherapy. For patients whose tumors express the BRAF V600 mutation, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor.


The FDA granted Keytruda the Breakthrough Therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies, the agency said. The drug also received priority review and orphan drug status. Priority review is granted to drugs that have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the orphan drug designation is given to drugs intended to treat rare diseases.


Keytruda was approved as part of the agency's accelerated approval program, 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 program 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.


"Keytruda is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research," Richard Pazdur, MD, Director of the FDA's Office of Hematology and Oncology Products, said in a news release. "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 (OT, 4/25/11), peginterferon alfa-2b (OT, 4/25/11), vemurafenib (OT, 9/10/11), dabrafenib (OT, 6/25/13), and trametinib (OT, 6/25/13).


The efficacy for Keytruda was established in a clinical trial of 173 patients with advanced melanoma whose disease had progressed after prior treatment. All participants received Keytruda, either at the recommended dose of 2 mg/kg or a higher dose of 10 mg/kg. Of the lower-dose patients, approximately 24 percent had their tumors shrink, lasting 1.4 to 8.5 months and continuing got longer in most patients. Similar results were seen for the patients receiving the higher dose.


The safety for Keytruda was established in a trial of 411 patients with advanced melanoma. The most common side effects reported were: fatigue, cough, nausea, pruritus, rash, decreased appetite, arthralgia, and diarrhea.


The FDA noted that the drug does have the potential for severe immune-mediated side effects, although they occurred uncommonly in the trial involving the lung, colon, hormone-producing glands, and liver.


Phase II and III clinical studies of Keytruda in advanced melanoma are ongoing, which are designed to provide further confirmatory evidence for this indication.