Considerations for adjuvant immunotherapy in stage II melanoma: KEYNOTE-716 and beyond

Abstract

The utility of adjuvant programmed cell death protein 1 (PD-1) inhibition in cutaneous melanoma patients was first established by KEYNOTE-054 and Checkmate-238, where both nivolumab and pembrolizumab improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected high-risk stage III disease (1,2). Stage II disease, however, remains a significant cause of melanoma morbidity and mortality. The incidence of stage II disease is double that of stage III disease. About 7% of all newly diagnosed melanoma is stage IIB or IIC, which refer to tumors that are thick and/or ulcerated but remain lymph node negative (T3bN0-T4bN0) (3). The 10-year melanoma-specific survival (MSS) for patients with stage IIB-IIC tumors ranges from 75-83%. The 5-year MSS for patients with T4b tumors is 82%, which is similar to the 5-year MSS for patients with N1 (and thus stage III) disease (4). The risk of recurrence is high in patients with stage IIB-IIC disease; 2-year recurrence risk was 20-30% in a large prospective trial (5), and 10-year RFS was 33-49% for patients with stage IIC disease and 56% in stage IIB in a large German cohort (6), highlighting a need for effective preventative therapies. KEYNOTE-716 is a practice-changing trial that sought to expand the application of adjuvant immune checkpoint inhibition to the stage II setting. It is a multicenter, double-blind placebo-controlled phase III randomized control trial that studied the benefit of one year of adjuvant pembrolizumab for completely resected stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma (7,8). The trial included 976 patients who were randomly assigned to pembrolizumab or placebo every 3 weeks for 17 cycles until disease recurrence or unacceptable toxicity. In part 2 of the study, eligible patients with disease recurrence could either be rechallenged with or crossover to receive pembrolizumab. The primary endpoint of the study was RFS, and the secondary endpoints included DMFS and overall survival (OS). The third interim analysis took place after a median follow-up of 27.4 months, at which time median RFS was 37.2 months for the pembrolizumab arm and not reached for the placebo arm (8). The risk of recurrence was significantly lower with pembrolizumab (HR 0.64, 95% CI: 0.50-0.84), confirming the benefit with pembrolizumab that was observed at the first and second interim analyses. The RFS benefit with pembrolizumab was consistent across T stage subgroups (T3b, T4a, T4b), though for the T4b subgroup the HR for recurrence was 0.76 with a 95% CI of 0.51-1.13. Twenty-four-month RFS was 81% in the pembrolizumab arm and 73% for the placebo arm. In an updated analysis, median DMFS was not reached in either group but was significantly improved in the pembrolizumab arm (HR 0.64, 95% CI: 0.47-0.88, P=0.0029) (7). Twenty-four-month DMFS was 88% for the pembrolizumab group and 82% for the placebo group. Subgroup analysis for DMFS demonstrated a mostly consistent benefit with pembrolizumab with HR <1 across all subgroups, but the Editorial Commentary Comment on: Long GV, Luke JJ, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 2022;23:1378-88.