30 months relapse-free survival, overall survival, and long-term toxicity update of (neo)adjuvant ipilimumab (ipi) + nivolumab (nivo) in macroscopic stage III melanoma (OPACIN trial)
Authors: E.A. Rozeman, K. Sikorska, B.A. van de Wiel, L.F. Fanchi, O. Krijgsman, H.V. van Thienen, L.M. Pronk, A. Broeks, L. Grijpink-Ongering, S. Ter Meulen, A. Bruining, W.M.C. Klop, H. van Tinteren, D. Peeper, J.B.A.G. Haanen, A.C.J. van Akkooi, T.N. Schumacher, C.U. Blank
Journal: Annals of Oncology (2018)

Background: Outcome of high-risk stage III melanoma patients (pts) has been poor, with a 5-year overall survival (OS) rate of < 50%. Adjuvant IPI improved 5-year relapse-free survival (RFS) and OS and adjuvant (adj) anti-PD1 improved RFS further. Neoadjuvant (neoadj) IPI + NIVO has been shown in 3 investigator-initiated trials to induce high pathologic response rates. While standard dosing regimen of IPI 3mg/kg + NIVO 1mg/kg has been too toxic for broader application, OpACIN-neo identified 2 courses IPI 1mg/kg + NIVO 3mg/kg as well tolerated and effective scheme to proceed to phase 3. Pathologic response was a good predictor for early outcome (none of the pts relapsed), but longer follow-up (FU) data are missing so far. Methods: Between August 2015 and October 2016, 20 high risk, stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase 1b feasibility OpACIN trial. Pts were randomized to receive IPI 3mg/kg plus NIVO 1mg/kg, either adj 4 courses, or split 2 courses neoadj and 2 adj. Pathological response was reviewed by a blinded pathologist, response was defined as < 50% viable tumor cells. The study was not powered to compare both arms, all efficacy endpoints are descriptive. Results: After a median FU of 31.6 months (minimum 23.5 months FU of pts alive) none of the 7 pts that achieved a pathologic response in the neoadj arm have relapsed. Two non-responding pts in the neoadj arm have relapsed, and 4 pts in the adj arm. 1 pt died in the neoadj arm and 3 in the adj arm. Estimated 30 months RFS rates were 80% for the neoadj arm and 60% for the adj arm and 30 months OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed one or more grade 3-4 adverse events, all recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal suppletion therapy that are ongoing in 8 (50%) of 16 pts alive. Conclusions: OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. None of the pts with a pathologic response has relapsed, suggesting that this could become a primary read-out for subsequent neoadj immunotherapy trials and a surrogate marker for RFS and OS. Clinical trial identification: NCT02437279. Legal entity responsible for the study: Netherlands Cancer Institute. Funding: BMS. Disclosure: E.A. Rozeman: Travel support: MSD, NanoString. H.V. van Thienen: Travel support: Roche. D. Peeper: Research support: BMS. J.B.A.G. Haanen: Fees to NKI for advisory roles: BMS, MSD, Roche, Neon Therapeutics, Immunocore, Novartis, AstraZeneca/MedImmune, Pfizer, Ipsen; Grants to NKI: BMS, Merck, Novartis, Neon Therapeutics. A.C.J. van Akkooi: Personal fees for advisory role: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer; Grants: Amgen, Novartis, all outside the submitted work. T.N. Schumacher: Consultant: Adaptive Biotechnologies, AIMM Therapeutics, Amgen, Neon Therapeutics, Scenic Biotech; Grant/research support: Merck, BMS, Merck KGaA; Stockholder: AIMM Therapeutics, Neon Therapeutics. C.U. Blank: Personal fees for advisory roles: MSD, BMS, Roche, GSK, Novartis, Pfizer, Lilly; Grants: BMS, Novartis. All other authors have declared no conflicts of interest.