Background: Neoadjuvant anti-PD1 has been shown to be superior to adjuvant administration. Combination of neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) induces even higher pathologic response rates (pRR) and event-free survival (EFS), but at the cost of higher toxicity. We previously showed that the interferon gamma (IFN-γ) signature is associated with a higher pRR after neoadjuvant IPI+NIVO. We hypothesized that IFN-γ high patients (pts) might benefit from less toxic anti-PD1 monotherapy (mono), while IFN-γ low pts might need an escalated regimen with IPI 3mg/kg + NIVO 1mg/kg. Methods: In this pooled analysis, pts with macroscopic nodal melanoma who received neoadjuvant NIVO 1mg/kg + IPI 3mg/kg (IPI3/NIVO1), IPI 1mg/kg + NIVO 3mg/kg (IPI1/NIVO3), sequential IPI 3mg/kg and NIVO 3mg/kg (IPI3>NIVO3), or NIVO mono (240mg; IFN-γ high pts only) from the OpACIN-neo, PRADO and DONIMI trials, were analyzed according to their baseline IFN-γ signature. RNA gene expression from baseline tumor biopsies was analyzed using the Nanostring nCounter platform. The IFN-γ scores were calculated using an algorithm and cut-off previously developed at the NKI and prospectively tested in the DONIMI trial. Results: Baseline tumor material was available from 151 pts (Table). Median follow-up was 42 months for the entire cohort and 19 months for NIVO mono pts. Combined IPI+NIVO in IFN-γ high pts induced similar major pathologic response (MPR) rates compared to NIVO mono in IFN-γ high pts (71% vs 80%, p=0.715), and significantly higher MPR rates compared to IPI+NIVO in IFN-γ low pts (71% vs 45%, p=0.003). At 18-months, EFS rates were 87%, 100% and 73% respectively, and overall survival (OS) rates were 98%, 100% and 96%. Notably, IPI3/NIVO1 seemed to induce a higher MPR rate than IPI1/NIVO3 in IFN-γ low pts (64% vs 41%), which was not statistically significant due to small subgroups. At 36 months, EFS was 91% vs 62% and OS was 91% vs 82%. Conclusions: Neoadjuvant NIVO mono seems to have equal outcomes as IPI+NIVO in IFN-γ high pts. IFN-γ low pts may benefit from IPI+NIVO with higher doses of IPI. Incorporating baseline biomarkers like the IFN-γ signature algorithm in neoadjuvant treatment decisions will optimize the risk-benefit ratio for these pts.

*1 patient not evaluable.