Pembrolizumab, Another Adjuvant Option for Resected Stage III Melanoma

In recent years, immunotherapy and targeted therapy (for BRAF positive) have emerged as potential adjuvant therapy options for patients with high-risk stage III melanoma following resection. The first of these agents approved for high-risk resected melanoma was the CTLA-4 inhibitor ipilimumab. This was based on improved survival rates compared to placebo, though at the expense of significant toxicity. In 2017, the PD-1 inhibitor nivolumab showed a significant relapse-free survival (RFS) advantage and favorable toxicity compared to ipilimumab and was approved for both BRAF wild type and BRAF mutant stage IIIB, IIIC, and IV melanoma. An alternative option approved for BRAF mutant stage III melanoma is the combination of BRAF and MEK inhibitors dabrafenib and trametinib, which demonstrated outcomes similar to nivolumab in patients with BRAF mutation.

The PD-1 inhibitor pembrolizumab is currently approved for treatment of patients with metastatic melanoma based on prolongation of progression-free survival (PFS) and overall survival (OS) compared to ipilimumab, irrespective to PD-L1 expression and BRAF mutation status. In the randomized phase III Keynote-054/ EORTC 1325-MG trial, high-risk patients with completely resected stage III melanoma (N = 1019) received pembrolizumab (200 mg) or placebo every 3 weeks for up to 1 year.

The co-primary endpoints of this trial were RFS in the intent-to-treat (ITT) population and in PD-L1 positive patients. At a median follow-up of 15 months, pembrolizumab significantly improved RFS compared to placebo in the ITT population, with a 1-year RFS rate of 75.4% versus 61.0% (HR 0.57, P<.001). RFS rates at 18 months were 71.4% and 53.2% in the pembrolizumab and placebo groups, respectively. Similar improvements were seen in patients with PD-L1 expression, with 1-year RFS rates of 77.1%, compared to 62.6% with placebo (HR 0.54, P<.001). Importantly, pembrolizumab was more effective than placebo in patients with PD-L1 negative tumors.

Treatment-related adverse events (AEs) occurred in 77.8% of patients receiving pembrolizumab and 66.1% of patients receiving placebo. Grade 3 or higher treatment-related AEs occurred in 14.7% of patients receiving pembrolizumab and 3.4% of patients receiving placebo. Immune-related AEs occurred in 37.3% of patients in the pembrolizumab group and 9.0% of patients in the placebo group. The most common immune-related AEs of any grade occurring in the pembrolizumab group were hypothyroidism (14.3%), hyperthyroidism (10.2%), pneumonitis (3.3%), and sarcoidosis (1.4%). The incidence of grade 3 or 4 immune-mediated AEs was low (7.1%). One patient receiving pembrolizumab died due to treatment-related myositis.

The investigators concluded that pembrolizumab is associated with significant improvements in RFS with manageable toxicity in high-risk patients with stage III melanoma, regardless of PD-L1 expression status. Continued analysis of this trial, including OS endpoints, is ongoing. Efficacy and safety data from this trial appear similar to those observed with nivolumab in the CheckMate-238 trial, and it is expected that pembrolizumab will soon become another treatment option for adjuvant therapy after resection of high risk melanoma

N Engl J Med. 2018 April 15 [Epub ahead of print].

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