Comprehensive genomic profiling to identify tumor mutational burden (TMB) as an independent predictor of response to immunotherapy in diverse cancers.

Abstract

e14508 Background: Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. Methods: We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Results: Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036) (Table). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Comparable data was observed when patients with melanoma (N = 52) and NSCLC (N = 36) were excluded (N = 63 patients; 19 tumor types). Interestingly, anti-CTLA4/anti-PD-1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Conclusions: Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. [Table: see text]