Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma
Authors: Christian U Blank, Minke W Lucas, Richard A Scolyer, Bart A van de Wiel, Alexander M Menzies, Marta Lopez-Yurda, Lotte L Hoeijmakers, Robyn P M Saw, Judith M Lijnsvelt, Nigel G Maher, Saskia M Pulleman, Maria Gonzalez, Alejandro Torres Acosta, Winan J van Houdt, Serigne N Lo, Anke M J Kuijpers, Andrew Spillane, W Martin C Klop, Thomas E Pennington, Charlotte L Zuur, Kerwin F Shannon, Beatrijs A Seinstra, Robert V Rawson, John B A G Haanen, Sydney Ch'ng, Kishan A T Naipal, Jonathan Stretch, Johannes V van Thienen, Michael A Rtshiladze, Sofie Wilgenhof, Rony Kapoor, Aafke Meerveld-Eggink, Lindsay G Grijpink-Ongering, Alexander C J van Akkooi, Irene L M Reijers, David E Gyorki, Dirk J Grünhagen, Frank M Speetjens, Sonja B Vliek, Joanna Placzke, Lavinia Spain, Robert C Stassen, Mona Amini-Adle, Céleste Lebbé, Mark B Faries, Caroline Robert, Paolo A Ascierto, Rozemarijn van Rijn, Franchette W P J van den Berkmortel, Djura Piersma, Andre van der Westhuizen, Gerard Vreugdenhil, Maureen J B Aarts, Marion A M Stevense-den Boer, Victoria Atkinson, Muhammad Khattak, Miles C Andrews, Alfons J M van den Eertwegh, Marye J Boers-Sonderen, Geke A P Hospers, Matteo S Carlino, Jan-Willem B de Groot, Ellen Kapiteijn, Karijn P M Suijkerbuijk, Piotr Rutkowski, Shahneen Sandhu, Astrid A M van der Veldt, Georgina V Long
Journal: New England Journal of Medicine (2024)

BackgroundPhase 1–2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy.MethodsIn this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival.ResultsA total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group.ConclusionsAmong patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)