(Neo-)adjuvant ipilimumab + nivolumab (IPI + NIVO) in palpable stage 3 melanoma – initial data from the OpACIN trial

Background: IPI + NIVO induces high response rates and improved overall survival in late stage melanoma. This raises the question whether IPI + NIVO could also become an option for adjuvant treatment of melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering. As the amount of antigen that can provide the TCR triggering correlates with tumor load, we postulated, that adjuvant immunotherapy will work most efficiently, when initiated prior to surgery. Methods: Two-arm Phase 1b trial consisting of 20 high risk AJCC stage 3B/C melanoma patients ( palpable nodes) receiving IPI 3mg/kg plus NIVO 1mg/kg, either adjuvant four courses after surgery, or split neo-adjuvant and adjuvant (each 2 courses). Results: To date, 17 patients are evaluable (9 in the neoadjuvant arm, updated data will be presented at ESMO 2016). Neo-adjuvant application of IPI + NIVO was feasible, as all 9 patients have undergone the planned lymph node dissection, without delay, 6 weeks after first infusion of IPI + NIVO. No surgery-associated adverse events attributed to (neo-)adjuvant immunotherapy were observed. 2/17 patients received all 4 courses. All other patients (88%) had to stop earlier due to treatment-related toxicities. Neo-adjuvant IPI + NIVO reduced tumor load after 6 weeks (time-point of surgery) in 7/9 patients (3 pCR, 3 near pCRs with only minimal remaining micrometastases, 1 pPR with remaining metastasis of 0.5mm, 1 SD and 1 PD). ORR was 78%. So far, none of the responding patients within the neoadjuvant arm has relapsed. Post-surgery relapse was observed for 1 non-responding (SD) patient within the neo-adjuvant arm and for 3 patients within the adjuvant arm. Conclusions: The combination of IPI + NIVO in the (neo-)adjuvant treatment setting for high risk stage 3 melanoma patients is feasible. However, grade 3/4 toxicity was more frequent than expected from stage 4 melanoma patient study data. In parallel, response rate and depth of response also may be higher than in stage 4 melanoma patients. These results indicate that IPI + NIVO is a promising combination for neo-adjuvant treatment in stage 3 melanoma, which will be tested in adjusted schemes in the upcoming phase 2 OpACIN-neo trial, with the aim of preserving efficacy, but reducing toxicity.