Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer

Purpose: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICIs), lacking of randomized clinical trial data has restricted its clinical application. This study aimed at exploring the significance and feasibility of biomarker combination based on TMB and copy number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. Experimental Design: Non-ICI treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts including non-small cell lung cancer (NSCLC, n = 240), skin cutaneous melanoma (SKCM, n = 174) and mixed cancer (Dana-Farber, n=98) patients from previous studies were analyzed for efficacy of ICIs therapy. Results: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. Conclusions: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogenous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.