Rare Disease Report: FDA Expands Keytruda Indication for Advanced Melanoma

The FDA has approved an expanded indication for Keytruda (pembrolizumab), an anti-PD-1 (programmed death receptor-1) therapy, to include it as first-line therapy for patients with unresectable or metastatic melanoma, regardless of BRAF status.

The approved dose is 2 mg/kg every 3 weeks.

The FDA also approved a labeling change for Keytruda to include its use in patients with ipilimumab-refractory advanced melanoma.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes.

Expanded Indication

Approval of the expanded indication was based on the Phase 3 “KEYNOTE-006” trial in which patients with unresectable or metastatic melanoma experienced superior overall survival (OS) when given pembroluzimab compared to those treated with ipilimumab.

Efficacy and Safety
The KEYNOTE-066 was a multicenter, controlled, Phase 3 study in which 834 patients with unresectable or metastatic melanoma with progression of disease; no prior therapy with ipilimumab; and prior therapy with at most one other systemic treatment were randomized to receive pembroluzimab [10 mg/kg every 2 (n=279) or 3 weeks (n=277)] until disease progression or unacceptable toxicity, or ipilimumab [3 mg/kg every 3 weeks for 4 doses (n=278) unless discontinued earlier for disease progression or unacceptable toxicity. The primary efficacy outcome measures were OS and progression-free survival (PFS).

At the end of the study, pembroluzimab 10 mg/kg every 2 or 3 weeks showed superior OS compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; P < .001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; P = .004], respectively). Median PFS was 5.5 months (95% CI: 3.4, 6.9), 4.1 months (95% CI: 2.9, 6.9), and 2.8 months (95% CI: 2.8, 2.9) with pembroluzimab 10 mg/kg every 2 weeks, pembroluzimab 10 mg/kg every 3 weeks, and ipilimumab, respectively. For PFS, both schedules for pembroluzimab 10 mg/kg every two or three weeks resulted in superior outcomes compared to ipilimumab (hazard ratio: 0.58 [95% CI: 0.46, 0.72; P <.001] and hazard ratio: 0.58 [95% CI: 0.47, 0.72; P< .001], respectively). Eighty percent of patients had PD-L1 positive melanoma, 18 percent had PD-L1 negative melanoma, and 2 percent had unknown PD-L1 status (positive: greater than or equal to 1 percent of tumor cells using an Investigational Use Only assay). BRAF mutations were reported in 36 percent of patients, of which 46 percent were previously treated with a BRAF-inhibitor. Patients with BRAF V600E mutated melanoma were not required to have received prior BRAF inhibitor therapy.

In a press release, Dr. Roger M. Perlmutter, president, Merck Research Laboratories said, “Today’s news is another exciting milestone for Keytruda and for patients with this disease. Data supporting the approval emerged from a large and diverse patient population, including patients with very advanced disease and patients whose tumors carried BRAF mutations, thus demonstrating both the breadth of our clinical development program for Keytruda, and the potential of Keytruda to extend the lives of those afflicted with this grievous malignancy.”

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