BackgroundBefore adjuvant checkpoint inhibition the 5-year overall survival (OS) rate was poor (<50%) in high-risk stage III melanoma patients. Adjuvant CTLA-4 (ipilimumab, IPI) and PD-1 (nivolumab, NIVO, or pembrolizumab) blockade have been shown to improve relapse-free survival (RFS) and OS (latter only for IPI so far). Due to a broader immune activation neoadjuvant therapy with checkpoint inhibitors might be more effective than adjuvant, as suggested in preclinical experiments. The OpACIN trial compared neoadjuvant versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO without adjuvant therapy. High pathologic response rates of 74–78% were induced by neoadjuvant IPI plus NIVO. Here, we present the 36- and 24-months RFS of the OpACIN and OpACIN-neo trial, respectively.Materials and MethodsThe phase 1b OpACIN trial included 20 stage IIIB/IIIC melanoma patients, which were randomized to receive IPI 3 mg/kg plus NIVO 1 mg/kg either adjuvant 4 cycles or split 2 cycles neoadjuvant and 2 adjuvant. In the phase 2 OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant treatment, either in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), or arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as <50% viable tumor cells and in both trials centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method.ResultsOnly 1 of 71 (1.4%) patients with a pathologic response on neoadjuvant therapy had relapsed, versus 16 of 23 patients (69.6%) without a pathologic response, after a median follow-up of 36 months for the OpACIN and 24 months for the OpACIN-neo trial. In the OpACIN trial, the estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm. Median RFS was not reached for any of the arms within the OpACIN-neo trial. Estimated 24-months RFS rate was 84% for all patients (95% CI: 76%-92%); 90% for arm A (95% CI: 80%-100%), 78% for arm B (95% CI: 63%-96%) and 83% for arm C (95% CI: 70%-100%). Baseline interferon-γ gene expression score and tumor mutational burden predict response.ConclusionsOpACIN for the first time showed a potential benefit of neoadjuvant IPI plus NIVO versus adjuvant immunotherapy, whereas the OpACIN-neo trial confirmed the high pathologic response rates that can be achieved by neoadjuvant IPI plus NIVO. Both trials show that pathologic response can function as a surrogate markers for RFS.Clinical trial informationNCT02437279, NCT02977052Disclosure InformationJ.M. Versluis: None. E.A. Rozeman: None. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Roche, Pierre-Fabre. I.L.M. Reijers: None. O. Krijgsman: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS. E.P. Hoefsmit: None. B.A. van de Wiel: None. K. Sikorska: None. C. Bierman: None. P. Dimitriadis: None. M. Gonzalez: None. A. Broeks: None. R.M. Kerkhoven: None. A.J. Spillane: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, MSD, Neon Therapeutics, Novartis. F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Pfizer, AZ/MedImmune, Rocher/Genentech, Ipsen, Bayer, Immunocore, SeattleGenetics, Neon Therapeutics, Celsius Therapeutics, Gadet, GSK. W.J. van Houdt: None. R.P.M. Saw: None. H. Eriksson: None. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD Merck, Merck-Pfizer, 4SC. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. T.N. Schumacher: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; MSD, BMS, Merck. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neogene Therapeutics, Neon Therapeutics. F. Consultant/Advisory Board; Modest; Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech. Other; Modest; Third Rock Ventures. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, NanoString. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Uniti Cars, Neon Therapeutics, Forty Seven. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre-Fabre.
BackgroundThe previous OpACIN and OpACIN-neo studies investigating neoadjuvant IPI plus NIVO have demonstrated high pathologic response rates (74–78%) and favorable long-term outcomes for patients (pts) with a pathological response; at 36 and 18 months follow up only 1/71 (1.4%) responders has relapsed. In contrast, pathological non-responders have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline IFN-γ signature high pts were more likely to respond to IPI plus NIVO. The DONIMI study tests the combination of NIVO ± IPI combined with a class 1 histone deacetylase inhibitor, domatinostat (DOM), according to the pts IFN-γ signature. We have developed a neoadjuvant IFN-γ signature, based on the signature previously described by Ayers et al., that will be used for the first time to classify pts in this prospective trial.Trial designThis two-center investigator-initiated phase 1b study aims to assess the safety and feasibility of neoadjuvant NIVO ± DOM ± IPI in 45 stage III melanoma pts with macroscopic de-novo or recurrent disease. IFN-γ signature high pts (n=20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240 mg q3wk) or Arm B (2 cycles NIVO 240 mg q3wk + DOM 200 mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n=25) will be randomized to Arm C (2 cycles NIVO 240 mg q3wk + DOM 200 mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240 mg q3wk + IPI 80 mg q3wk + DOM 200 mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200 mg BID, d1-14, q3wks), a lower dosing scheme (100 mg OD, d1-14, q3wks) or the same dosing scheme (200 mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 patients cannot adhere to the planned time of surgery (week 6 ± 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. To date, 7 patients have been enrolled.Clinical trial informationNCT04133948Disclosure InformationI.L.M. Reijers: None. E.A. Rozeman: None. P. Dimitriadis: None. O. Krijgsman: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; BMS. L.J.W. Bosch: None. S. Cornelissen: None. J. Bouwman: None. J.M. Versluis: None. D. Rao: None. B. van de Wiel: None. A.J. Spillane: None. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD Oncology, Novartis, Pierre Fabre, Roche. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD, Merck, Merck-Pfizer, 4SC. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, Nanostring. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, Genmab, Pierre Fabre.
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