Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial

Abstract

PURPOSE We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)–positive tumors. RESULTS Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1–positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

BRAF Gene and Melanoma: Back to the Future

“…Analogously, pembrolizumab for high-risk stage III melanoma resulted in significantly longer RFS than placebo, with no new toxic effects reported and no differences according to the BRAF status. The 3-year RFS rate was 63.7% for pembrolizumab versus 44.1% for placebo with a HR of 0.56 (95% CI, 0.47 to 0.68) [ 83 ] ( Table 3 ). The combination of nivolumab and ipilimumab has also been investigated in the adjuvant setting.…”

Recent advancements in melanoma management

“…In addition, the toxicity profile of nivolumab was favourable compared to ipilimumab. Further data to support adjuvant PD‐1 inhibitor treatment were seen in the Keynote‐054 trial, which showed an RFS benefit of adjuvant pembrolizumab for up to 1 year compared with placebo in patients with resected Stage III melanoma 46,47 . The OS results are eagerly awaited.…”

Hyperprogression fortgeschrittener Melanomerkrankung unter Pembrolizumab adjuvant

“…Im klinischen Alltag sind diese Konzepte, insbesondere in Akutsituationen, oft schwer voneinander zu differenzieren. Pembolizumab‐assoziierte Grad 3–5 irAE wurden mit einer Häufigkeit von 31,6 % berichtet [1]. Die Autoimmunhepatitis tritt im Median 1,3 Monate mit einem dokumentierten Mindestzeitraum von acht Tagen nach Administration auf.…”