Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: 5-year results of the EORTC 1325-MG/Keynote-054 double-blinded phase III trial

We conducted the randomized phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. At 3.5-year (yr) median follow-up, pembrolizumab improved recurrence-free survival (RFS) (hazard ratio [HR] 0.59; 95% CI 0.49-0.70, P<0.0001) and distant metastasis-free survival (DMFS) (HR 0.60, 95% CI 0.49-0.73, P<0.0001) as compared to placebo (Eggermont, TLO 2020). Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis >1 mm), IIIB or IIIC (without in-transit metastasis). Between Aug-2015 until Nov-2016, 1019 pts were randomized to pembrolizumab 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity. The co-primary endpoints were RFS in the intention-to-treat (ITT) overall population and in pts with PD-L1-positive tumors. DMFS was a secondary and progression/recurrence-free survival 2 (PRFS2, time from randomization until the 2nd disease recurrence, a progression of the 1st recurrence, or death) an exploratory endpoint. Overall, 15%/46%/39% of pts had stage IIIA/IIIB/IIIC. By Jan 17, 2022, at approximately 5-yr median follow-up, 532 RFS, 470 DMFS and 382 PRFS2 events were reported. Pembrolizumab compared with placebo significantly prolonged RFS, DMFS and PRFS2 in the ITT population and in the PD-L1+ subgroup (N=853). Consistent improvements were observed across subgroups, in particular by AJCC staging and BRAF-mutation status.Table: 804PEndpointPopulationPembrolizumab*Placebo*HR**95% CI HR**RFSITT55%38%0.610.51-0.72RFSPD-L1+56%40%0.620.51-0.75DMFSITT61%45%0.620.52-0.75DMFSPD-L1+62%46%0.630.51-0.77PRFS2ITT68%56%0.650.53-0.80PRFS2PD-L1+70%58%0.670.53-0.84*: 5-yr rate **: stratified by stage at randomization. Open table in a new tab *: 5-yr rate **: stratified by stage at randomization. At approximately 5-yr median follow-up, adjuvant pembrolizumab provided a clinically meaningful improvement in RFS, DMFS, and PRFS2 in resected high-risk stage III melanoma pts.