Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer
Matthew D. Hellmann, Tavi Nathanson, Hira Rizvi, Ben Creelan, Francisco Sánchez-Vega, Arun Ahuja, Ai Ni, Jacki B. Novik, Levi Mangarin, Mohsen Abu-Akeel, Cailian Liu, Jennifer L. Sauter, Natasha Rekhtman, Eliza Chang, Margaret K. Callahan, Jamie E. Chaft, Martin H. Voss, Megan Tenet, Xuemei Li, Kelly L. Covello, Andrea Renninger, Patrik Vitazka, William J. Geese, Hossein Borghaei, Charles M. Rudin, Scott Antonia, Charles Swanton, Jeff Hammerbacher, Taha Merghoub, Nicholas McGranahan, Alexandra Snyder, Jedd D. Wolchok
Abstract
Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.