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 V600^E/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.

Trial registration: ClinicalTrials.gov NCT02362594.

FIG 1.

CONSORT diagram. Safety population indicates patients who started the allocated treatment. ITT, intention to treat; PD-L1, programmed cell death-ligand 1; PPT, per-protocol treatment.

FIG 2.

Recurrence-free survival (RFS) by treatment group. (A) In the overall population and according to programmed cell death-ligand 1 (PD-L1) tumor status. (B) PD-L1 positive. (C) PD-L1 negative. EV/No., events/number of patients; HR, hazard ratio.

FIG 3.

Forest plot of recurrence-free survival. AJCC, American Joint Committee on Cancer (seventh edition; AJCC-7; AJCC (eighth edition; AJCC-8), HR, hazard ratio; PD-L1, programmed cell death-ligand 1; WT, wild type.

FIG 4.

Recurrence-free survival by treatment group according to the American Joint Committee on Cancer Cancer Staging Manual (seventh edition; AJCC-7). (A) Stage IIIA. (B) Stage IIIB. (C) Stage IIIC. EV/No., events/number of patients; HR, hazard ratio.

FIG 5.

Recurrence-free survival by treatment group according to American Joint Committee on Cancer Cancer Staging Manual (eighth edition; AJCC-8). (A) Stage IIIA. (B) Stage IIIB. (C) Stage IIIC. (D) Stage IIID. EV/No., events/number of patients; HR, hazard ratio.

FIG 6.

Recurrence-free survival by treatment group. (A) BRAF-V600^E/K mutated melanoma. (B) BRAF wild-type melanoma. EV/No., events/number of patients; HR, hazard ratio.