Abstract 4066: Development and validation of a gene mutation-based signature to predict response to PD-1 inhibitors in nonsquamous NSCLC

Background: Genetic variations in nonsquamous NSCLC displayed significant impact on immune microenvironment and response to programmed cell death protein 1 (PD-1) blockade immunotherapy. We undertook an unbiased analysis to develop a gene mutation-based signature (GMS) and predict the efficacy of anti-PD-1 treatment. Methods: Two independent cohorts (MSK-IMPACT and CheckMate 012) consist of 265 nonsquamous NSCLC patients treated with anti-PD-1 were analyzed for gene mutation via next-generation sequencing. A GMS was built in a randomly selected 123 samples from MSK-IMPACT training cohort, using multivariate cox analysis of high-frequency mutation genes (≥10%) associated with progression-free survival (PFS) after anti-PD-1 treatment. We then validated our findings in the remaining 83 samples (internal validation cohort) and in CheckMate-012 external validation cohort (n=59). Results: A GMS that consisted of 6 genes (KRAS, EGFR, TP53, STK11, PTPTD and KMT2C), was generated to classify patients into high and low GMS groups in the training cohort. Patients with high GMS in the training cohort had longer PFS (p Conclusion: Our study highlights the potential predictive value of GMS for immunotherapeutic benefit in nonsquamous NSCLC. The combination of GMS and PD-L1 may be a feasible and promising biomarker in guiding treatment decisions for anti-PD-1 therapy. Citation Format: Zhong-Yi Dong, Xin-Ran Tang, Li Liu, De-Hua Wu. Development and validation of a gene mutation-based signature to predict response to PD-1 inhibitors in nonsquamous NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4066.