Updated Results Confirm Benefits of Adjuvant Pembrolizumab for Advanced Melanoma Are Sustained

Adjuvant treatment with pembrolizumab (Keytruda) extended distant metastasis-free survival (DMFS) compared with placebo following complete resection of high-risk, stage III melanoma, according to updated, long-term follow-up from the EORTC 1325/KEYNOTE-054 clinical trial. Long-term follow-up also confirmed a sustained benefit of pembrolizumab on the end point of recurrence-free survival (RFS), the study’s primary end point.

Compared with placebo, pembrolizumab also decreased the incidence of distant metastasis as a first recurrence and locoregional-only recurrence.

The updated analyses were presented at the virtual ESMO 2020 Congress by Alexander M.M. Eggermont, MD, PhD, Chief Scientific Officer, Pediatric Oncology, Princess Máxima Center, Utrecht, Netherlands.

DMFS was a secondary end point of the double-blind, phase 3 EORTC 1325/KEYNOTE-054 trial. The primary analysis showed that pembrolizumab improved RFS (hazard ratio [HR], 0.57; P ˂.0001) compared with placebo at a median follow-up of 1.25 years, and led to approval of pembrolizumab as adjuvant treatment for patients with high-risk, stage III melanoma by the US Food and Drug Administration and the European Medicines Agency.

EORTC 1325/KEYNOTE-054 included 1019 patients who underwent complete resection of cutaneous melanoma metastatic to the lymph nodes and were randomized to either pembrolizumab (200 mg) or placebo every 3 weeks for approximately 1 year (18 doses).

In this latest update of results, the researchers found that after a median 3.5-year follow-up (418 DMFS events), pembrolizumab significantly increased DMFS compared with placebo—65.3% versus 49.4% (HR, 0.60; P <.0001). A similar advantage to pembrolizumab on DMFS was observed in the 853 patients with PD-L1–positive tumors (HR, 0.61; P <.0001). The improvement in DMFS with pembrolizumab was similar when assessed by the American Joint Committee on Cancer (AJCC)-7 stage. Pembrolizumab was superior to placebo on DMFS in patients with AJCC-7 stage IIIA disease (80.8% vs 70.8%; HR, 0.63; P = .169), stage IIIB disease (68.1% vs 51.0%; HR, 0.58; P <.001), and stage IIIC disease (55.8% vs 39.2%; HR, 0.61; P <.001).

The favorable effect of pembrolizumab on DMFS was evident in patients with PD-L1–negative tumors, with a DMFS of 58.0% in the pembrolizumab group versus 40.2% in the placebo group (HR, 0.49; P = .008), as well as in those with PD-L1–positive tumors (66.7% vs 51.6%; HR, 0.61; P <.001). In the 440 patients with BRAF-mutated disease, DMFS was 63.7% with pembrolizumab versus 43.4% with placebo (HR, 0.53; P ˂.001). In those with BRAF wild-type disease, DMFS rates were 62.1% versus 51.4%, respectively (HR, 0.73; P = .035).

An updated RFS analysis showed that at a median of 3.5 years, RFS rates were 59.8% in the pembrolizumab arm and 41.4% in the placebo arm (HR, 0.59; P <.001) in the intent-to-treat population. Pembrolizumab compared with placebo decreased the 3.5-year incidence of distant metastasis as first recurrence (24.9% vs 39.5%; HR, 0.57; P <.0001) and the rate of locoregional-only recurrence (14.0% vs 18.9%; HR, 0.73, P = .05).

In comparison with placebo, pembrolizumab demonstrated significant improvement in DMFS, a sustained RFS benefit, and decreased incidence of recurrence over 3.5 years.

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