Cancer Cell. 2018 Apr 12. pii: S1535-6108(18)30123-5. doi: 10.1016/j.ccell.2018.03.018. [Epub ahead of print]
Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.
Hellmann MD1, Nathanson T2, Rizvi H3, Creelan BC4, Sanchez-Vega F5, Ahuja A2, Ni A6, Novik JB2, Mangarin LMB7, Abu-Akeel M7, Liu C7, Sauter JL8, Rekhtman N8, Chang E2, Callahan MK9, Chaft JE10, Voss MH11, Tenet M3, Li XM12, Covello K12, Renninger A12, Vitazka P12, Geese WJ12, Borghaei H13, Rudin CM10, Antonia SJ4, Swanton C14, Hammerbacher J15, Merghoub T16, McGranahan N17, Snyder A18, Wolchok JD16.
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.
CTLA-4; PD-1; TMB; immunotherapy; lung cancer; mutation burden