6P Response and survival according to the interferon-gamma (IFN-γ) signature and tumor mutational burden (tmb) in the PRADO trial testing neoadjuvant ipilimumab and nivolumab in stage III melanoma

The PRADO trial (n=99) tested different surgical and adjuvant therapy strategies based on the pathologic response after neoadjuvant IPI 1mg/kg and NIVO 3mg/kg in stage III melanoma patients (pts). The pathologic response rate (pRR: ≤50% viable tumor) was 72%, including 61% major pathologic responses (MPR: ≤10% viable tumor). After a median follow-up of 28.1 months, the 2-year (2y) event-free survival (EFS) rate was 80%. Here, we report the response and EFS data of PRADO according to the IFN-γ signature and TMB. TMB and the IFN-γ gene expression signature (GES) were examined in baseline tumor biopsies by whole exome sequencing (n=76) and mRNA sequencing (n=80). Association with pRR, MPR or EFS was examined by logistic/Cox regression analyses. Cutoffs between high (H) and low (L) were calculated using ROC curves. The table shows the association between IFN-γ GES and TMB with pRR, MPR, and EFS. IFN-γ GES and logTMB were not correlated (R = 0.065; p = 0.579). Pts with a high IFN-γ GES had a higher pRR and MPR rate than pts with a low IFN-γ GES (87% vs 50%, p=0.001 and 77% vs 35%, p<0.001, respectively), and also a higher 2y EFS rate (87% vs 68%, log-rank p=0.015). Pts with a high TMB were more likely to achieve a pathologic response (pRR 83% vs 58%, p=0.024) and MPR (80% vs 38%, p<0.001), but did not have a lower risk of relapse (2y EFS 77% vs 76%, log-rank p=0.531). When combined, the pRR for pts with IFN-γ H/TMB H was 90%, IFN-γ H/TMB L 79%, IFN-γ L/TMB H 67% and IFN-γ L/TMB L 42%. For MPR rates this was 85%, 63%, 67% and 19%, respectively.Table: 6PUnivariable analysisOR / HR95% CIp-valuepRRIFN-γ score (continuous)1.089(1.027-1.156)0.004IFN-γ high vs low6.800(2.208-20.944)0.001logTMB (continuous)1.311(0.988-1.741)0.061TMB high vs low3.654(1.183-11.286)0.024MPRIFN-γ score (continuous)1.092(1.031-1.157)0.003IFN-γ high vs low6.190(2.304-16.634)<0.001logTMB (continuous)1.376(1.037-1.826)0.027TMB high vs low6.588(2.240-19.374)0.001EFSIFN-γ score (continuous)0.965(0.922-1.011)0.130IFN-γ high vs low0.308(0.112-0.846)0.022logTMB (continuous)0.935(0.726-1.205)0.604TMB high vs low0.747(0.298-1.872)0.533 Open table in a new tab Similar to findings in our previous trials, baseline IFN-γ GES and TMB were independent biomarkers for pathologic response and MPR, and the IFN-γ GES was associated with EFS. However, TMB was not associated with risk of relapse, possibly owing to the different response-driven surgical and adjuvant therapy strategies in PRADO.