Neoadjuvant Treatment Impact on Macroscopic Stage III Melanoma

Resectable stage III melanoma recurrence-free survival (RFS) is better with adjuvant anti-PD1 therapy. Adjuvant nivolumab had a 4-year RFS of 52.5% in the Checkmate-238 study, and adjuvant pembrolizumab showed a 3-year RFS of 63.7% in the KEYNOTE-054 trial. Despite the better results, many patients still experience a recurrence in the years following therapeutic lymph node dissection (TLND). Neoadjuvant therapy with nivolumab (NIVO) and ipilimumab (IPI) is possible and causes a stronger and more widespread T-cell response, as demonstrated by the OpACIN trial. The PRADO trial supported the findings of the later OpACIN-neo trial, which found that 2 cycles of NIVO 3mg/kg + IPI 1mg/kg was an effective neoadjuvant dosage scheme with reduced toxicity and maintained high pathologic response rates (77%). Overall, the OpACIN-neo population had a satisfactory 2-year RFS (83,6%), although patients with a pathological partial or non-response have a poorer prognosis and may benefit from different adjuvant therapy. Before neoadjuvant therapy can be deemed a routine choice for this patient population, the efficacy of neoadjuvant checkpoint inhibition relative to the present standard of adjuvant therapy must be demonstrated in a phase III trial.

Macroscopic stage III melanoma patients will be randomly assigned to receive either neoadjuvant IPI + NIVO or adjuvant NIVO in this worldwide, randomized, phase 3 trial. Up to three in-transit metastases (ITMs) are permitted, and 420 individuals with recurrent or de novo melanoma with at least one pathologically verified, clinically detectable lymph node will be randomly assigned to either neoadjuvant or adjuvant treatment. Population subgroups will be established according to ITM presence, continental origin, and BRAF mutation status. Participants assigned to Arm A will be given IPI 80mg + NIVO 240mg for 2 cycles, with TLND performed after 6 weeks. Adjuvant NIVO (11 cycles) or adjuvant dabrafenib + trametinib (46 weeks) will be administered after surgery if a pathological partial response or non-response occurs, depending on the presence or absence of a BRAFV600-mutation. Participants in Arm B will get TLND up front, followed by NIVO 480mg in a 12-cycle treatment schedule. Time to progression to unresectable stage III or stage IV melanoma, recurrence of melanoma, development of a new primary melanoma, or death from melanoma or therapy will be measured as the primary outcome. After 132 occurrences have been observed, or at least 2 years after the last patient is included, a final analysis will be done. For translational studies, we will collect biopsies and blood at the beginning of the study (screening, weeks 0-3, 6-9, and 12).

Source: https://meetings.asco.org/abstracts-presentations/213385

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT04949113

Minke W. Lucas, Judith Lijnsvelt, Saskia Pulleman, Richard A. Scolyer, Alexander M. Menzies, Alexander Christopher Jonathan Van Akkooi, Winan J. van Houdt, Kerwin Frank Shannon, Thomas Pennington, Karijn Suijkerbuijk, Ellen Kapiteijn, Astrid Aplonia Maria Van Der Veldt, Matteo S. Carlino, Shahneen Sandhu, Maria Gonzalez, Charlotte L. Zuur, W. Martin. C. Klop, Georgina V. Long, Christian U. Blank/The NADINA trial: A multicenter, randomised, phase 3 trial comparing the efficacy of neoadjuvant ipilimumab plus nivolumab with standard adjuvant nivolumab in macroscopic resectable stage III melanoma/J Clin Oncol 40, 2022 (suppl 16; abstr TPS9605)DOI10.1200/JCO.2022.40.16_suppl.TPS9605