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

• Published in: The lancet oncology 2022-11, Vol.23 (11), p.1378-1388
• Main Authors: Long, Georgina V, Luke, Jason J, Khattak, Muhammad A, de la Cruz Merino, Luis, Del Vecchio, Michele, Rutkowski, Piotr, Spagnolo, Francesco, Mackiewicz, Jacek, Chiarion-Sileni, Vanna, Kirkwood, John M, Robert, Caroline, Grob, Jean-Jacques, de Galitiis, Federica, Schadendorf, Dirk, Carlino, Matteo S, Mohr, Peter, Dummer, Reinhard, Gershenwald, Jeffrey E, Yoon, Charles H, Wu, Xi Lawrence, Fukunaga-Kalabis, Mizuho, Krepler, Clemens, Eggermont, Alexander M M, Ascierto, Paolo A
• Format: Article
• Language: English
• Subjects: Adjuvant therapy; Adverse events; Antibodies, Monoclonal, Humanized - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biopsy; Cancer; Chemotherapy; Child; Clinical trials; Creatinine; Diarrhea; Double-Blind Method; Double-blind studies; Hepatitis; Humans; Immunotherapy; Lymph nodes; Lymphatic system; Male; Medical research; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Melanoma - surgery; Metastases; Metastasis; Monoclonal antibodies; Neoplasm Recurrence, Local - pathology; Oncology; Patients; Pediatrics; Pembrolizumab; Placebos; Skin Neoplasms - drug therapy; Skin Neoplasms - surgery; Survival; Targeted cancer therapy; Testicular Neoplasms; Toxicity
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(22)00559-9

Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up. KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment. Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1–31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]–NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47–0·88, p=0·0029) versus placebo. Median rec