Europe Approves Pembrolizumab for Advanced Melanoma

Nick Mulcahy


July 22, 2015

The European Commission has approved the immunotherapy pembrolizumab (Keytruda, Merck) for the treatment of unresectable or metastatic melanoma for both previously treated and untreated patients.

Pembrolizumab can now be marketed in all 28 European member states at the approved dose of 2 mg/kg every 3 weeks.

The drug is already approved for use in the United States, but only for previously treated patients with advanced unresectable or metastatic (advanced) melanoma. Nevertheless, the Centers for Medicare and Medicaid covers pembrolizumab use in the first-line setting, despite its current lack of approval from the US Food and Drug Administration for this indication.

Pembrolizumab is the second programmed cell death inhibitor for melanoma approved in Europe. It joins nivolumab (Opdivo, Bristol-Myers Squibb), which was approved last month for first-line use in melanoma. Both of these immunotherapies are now regarded as an advance over the original immune checkpoint inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb).

Clinical Trial Data

The new approval is based on data from three clinical studies conducted in more than 1500 first-line and previously treated patients with advanced melanoma.

In the 834-patient phase 3 KEYNOTE-006 trial, pembrolizumab significantly prolonged progression-free survival and overall survival. In addition, there was less high-grade toxicity with pembrolizumab than with ipilimumab, which has been the standard of care for advanced melanoma.

Specifically, the estimated 6-month progression-free survival rates for the newer drug were nearly twice as good as for the older drug; rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab. The hazard ratio for disease progression with the pembrolizumab regimens, compared with ipilimumab, was 0.58 (P < .001).

The estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively. The hazard ratio for death with pembrolizumab every 2 weeks was 0.63 (P = .0005) and with pembrolizumab every 3 weeks was 0.69 (P = .0036).

The response rates were nearly three times greater for pembrolizumab: the rate was 33.7% for the 2-week regimen and 32.9% for the 3-week regimen, compared with 11.9% for ipilimumab (P < .001 for both comparisons).

The study results were first presented earlier this year at the of the American Association of Cancer Research Annual Meeting, and were simultaneously published in the New England Journal of Medicine, as reported by Medscape Medical News.

At the meeting, a pembrolizumab investigator urged regulators around the world to green-light the new immunotherapy because of its superiority over ipilimumab.

"I hope the drug regulatory agencies around the world act fast on approving pembrolizumab for front-line therapy for metastatic melanoma," said Antoni Ribas, MD, PhD, from the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

The safety analysis supporting the European approval of pembrolizumab was based on 1012 advanced melanoma patients across three doses (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in two other studies (KEYNOTE-001 and KEYNOTE-002) combined.

The most common adverse reactions (>10%) with pembrolizumab were diarrhea (15%), nausea (12%), pruritus (25%), rash (25%), arthralgia (13%), and fatigue (33%). The majority of adverse reactions reported were grade 1 or 2.

The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.


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