Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non–Small Cell Lung Cancer

Abstract

Purpose: DNA damage response and repair (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with clinical outcomes to PD-(L)1 blockade in non-small cell lung cancer (NSCLC) is unknown. Experimental Design: Tumors from patients treated with PD-(L)1 inhibitors were analyzed using targeted next-generation sequencing (NGS). Cancers were categorized based on the presence or absence of deleterious mutations across a panel of 53 DDR genes. Clinical outcomes to PD-(L)1 inhibitors were evaluated according to DDR mutation status. Results: Of 266 patients with successful NGS who received PD-(L)1 inhibitors, 132 (49.6%) were identified as having deleterious DDR mutations (DDR-positive). DDR-positive and DDR-negative groups were similar in terms of baseline clinicopathological characteristics. The median TMB was significantly higher in the DDR-positive group compared to the DDR-negative group (12.1 vs 7.6 mutations/megabase, P<0.001). Compared to DDR-negative patients (N=134), DDR-positive patients had a significantly higher objective response rate (30.3 vs 17.2%, P=0.01), longer median progression-free survival (5.4 vs 2.2 months, HR: 0.58 [95%CI:0.45-0.76], P<0.001), and longer median overall survival (18.8 vs 9.9 months, HR: 0.57 [95%CI:0.42-0.77], P<0.001) with PD-(L)1 therapy. After adjusting for PD-L1, TMB, PS, tobacco use, and line of therapy, DDR-positive status was associated with a significantly longer PFS (HR: 0.68 [95%CI:0.51-0.92], P=0.01) and OS (HR: 0.60 [95%CI:0.43-0.85], P=0.004) in multivariate analysis. Conclusions: Deleterious DDR mutations are frequent in NSCLC and are associated with improved clinical outcomes in patients with NSCLC treated with PD-(L)1 blockade.