Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg−1 and nivolumab 1 mg kg−1, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.
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The RNA and DNA sequencing datasets generated during the current study have been deposited into the European Genome-phenome Archive under accession number EGAS00001003099 and are available on request. Every request will be reviewed by the institutional review board of the NKI; the researcher will need to sign a data access agreement with the NKI after approval. The TCR sequencing data that support the findings of this study are available from Adaptive Biotechnologies; however, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. However, data are available from the authors on reasonable request and with the permission of Adaptive Biotechnologies. The DSP data that support the findings of this study are available from NanoString; however, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. However, data are available from the authors on reasonable request and with permission from NanoString.
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We thank the patients and their families for participating in the study. We thank A. Gangaev for performing the experiments involving MHC tetramer staining; M. Valenti, T. Kuilman, and other members from the Blank, Peeper, and Schumacher laboratory for valuable discussions; W. Uyterlinde, A. Koenen, M. Wouters, and J. vd Hage for the clinical care of the patients included in the trial; C. Bierman for assisting with the pathological revisions of tumor samples; the NKI-AVL flow facility and the NKI-AVL Core Facility Molecular Pathology & Biobanking for supplying the NKI-AVL biobank material and/or laboratory support; E. Hooijberg for supervising the immunohistochemistry analysis; S. Vanhoutfin for financial management; A. Cesano for scientific input on the NanoString analyses; and D. Walker, C. Pfeiffer, B. Lamon, B. Stegenga, and V. Goodman from Bristol-Myers Squibb for scientific input and support.