PURPOSE: In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy. PATIENTS AND METHODS: Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy). RESULTS: Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS. CONCLUSION: Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

Center for Immuno Oncology University Hospital of Siena Siena University of Siena Italy

Department of Clinical Oncology Instituto de Biomedicina de Sevilla IBiS Hospital Universitario Virgen Macarena CSIC Universidad de Sevilla Hospital University Virgen Macarena Seville Spain

Department of Cutaneous Oncology H Lee Moffitt Cancer Center Tampa FL

Department of Dermatology Aix Marseille University Hôpital de la Timone Marseille France

Department of Dermatology Charles University 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Dermatology Hospices Civils de Lyon Pierre Bénite France

Department of Internal Medicine National and Kapodistrian University of Athens Athens Greece

Department of Internal Medicine University of Western Australia and Sir Charles Gairdner Hospital Nedlands WA Australia

Department of Medical Oncology and Hematology Department of Medicine Department of Immunology University of Toronto Princess Margaret Cancer Centre Toronto ON Canada

Department of Medical Oncology General University Hospital Gregorio Marañón and CIBERONC Madrid Spain

Department of Medical Oncology Hospital Clínic de Barcelona IDIBAPS Barcelona Spain

Department of Medical Oncology Tasman Health Care Southport QLD Australia

Department of Medical Oncology Texas Oncology Baylor Charles A Sammons Cancer Center Dallas TX

Department of Medical Oncology The Royal Marsden NHS Foundation Trust London United Kingdom

Division of Cancer Services Gallipoli Medical Research Foundation University of Queensland Brisbane QLD Australia

Division of Hematology Oncology Department of Internal Medicine University of Michigan Rogel Cancer Center Ann Arbor MI

Istituto Nazionale Tumori IRCCS Fondazione Pascale Naples Italy

Laura and Isaac Perlmutter Cancer Center NYU Langone Health New York NY

Medical Oncology of Melanoma Sarcoma and Rare Tumors IEO European Institute of Oncology IRCCS Milan Italy

Melanoma Institute Australia The University of Sydney and Royal North Shore and Mater Hospitals Sydney NSW Australia

Melanoma Oncology Unit Veneto Institute of Oncology IOV IRCCS Padua Italy

Oncology Center Sf Nectarie Craiova Romania

Oncology Clinical Development Bristol Myers Squibb Princeton NJ

Papa Giovanni XIII Hospital Bergamo Italy

Unit of Melanoma Medical Oncology Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

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