Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancerMore about Open Access at the Crick
Authors listMatthew D Hellmann Tavi Nathanson Hira Rizvi Benjamin C Creelan Francisco Sanchez-Vega Arun Ahuja Ai Ni Jacki B Novik Levi MB Mangarin Mohsen Abu-Akeel Cailian Liu Jennifer L Sauter Natasha Rekhtman Eliza Chang Margaret K Callahan Jamie E Chaft Martin H Voss Megan Tenet Xue-Mei Li Kelly Covello Andrea Renninger Patrik Vitazka William J Geese Hossein Borghaei Charles M Rudin Scott J Antonia Charles Swanton Jeff Hammerbacher Taha Merghoub Nicholas McGranahan Alexandra Snyder Jedd D Wolchok
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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.
Journal Cancer Cell
Issue number 5