In this phase 1b clinical trial, 20 patients with palpable stage III melanoma were divided evenly into groups to receive four doses of combination nivolumab and ipilimumab as adjuvant therapy (4 doses after surgical resection) or neoadjuvant therapy (2 before, 2 after), though high toxicity reduced the median number of doses to 2. The neoadjuvant arm had better pathological responses and fewer relapses, with no responders relapsing within the follow-up period. Neoadjuvant treatment induced higher expansion of tumor-resident T cell clones in peripheral blood. Low T cell infiltration, low clonality, low IFNγ signature, and low PD-L1 associated with relapse.

Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients(1,2). In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy(3). Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy(4). 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.

Author Info: (1) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. (2)

Author Info: (1) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. c.blank@nki.nl. (2) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (3) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (4) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (5) Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (6) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (7) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (8) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (9) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (10) Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (11) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. (12) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. (13) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. (14) Surgical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. (15) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (16) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (17) Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (18) Adaptive Biotechnologies, Seattle, WA, USA. (19) NanoString Technologies, Inc., Seattle, WA, USA. (20) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands. (21) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (22) Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (23) Surgical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands. (24) Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands. t.schumacher@nki.nl.

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