Characterization of DNA damage repair (DDR) alterations and the tumor immune microenvironment (TIME) in advanced non-small cell lung cancer (NSCLC)

Authors Kamya Sankar, Jacob Mercer, Ellen B. Jaeger, Jen Godden, Jonathan David Berkman, Edward Williams, Michael A. Thompson, Shetal Arvind Patel, Karen L. Reckamp, Frank Weinberg

Background: Exploiting the DDR pathway with synthetic lethality agents such as PARP inhibitors has been clinically validated in several cancers. In NSCLC, novel agents leveraging defects in the DDR pathway are being studied alone and in combination with checkpoint inhibitors. To expand on combination approaches and inform biomarker selected strategies, we analyzed DDR alteration prevalence and impact on the TIME in metastatic NSCLC.

Methods: We retrospectively analyzed de-identified next-generation sequencing data from patients (pts) with metastatic NSCLC in the Tempus Database. Tumors were sequenced with the Tempus xT DNA and xR RNA assays. DDR pathway genes were defined as previously described (PMID 29617664). Pts were stratified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. The associations of DDR alteration with immune cell infiltration predicted from gene expression patterns, PD-L1 from IHC, TMB (TMB-H, >10 mut/Mb), and microsatellite instability (MSI) were examined. Wilcoxon rank-sum and Pearson’s Chi-squared/Fisher’s exact tests were used to assess statistical significance (p<0.05, q<0.05 for false discovery rate correction for multiple testing).

Results: Across 14,127 samples, 5,255 (37%) were DDRmt and 8,872 (63%) were DDRwt. The median age at diagnosis was 67 (IQR 60-74). Current/former smokers (83%; n=10,445) had a higher prevalence of DDRmt (86% vs. 82%; p<0.001). The most prevalent DDRmt was SMARCA4 (18%), followed by PTEN (13%), BRCA2 (11%), ATM (9.0%), ERCC3 (6.6%), PMS2 (6.0%), and MUTYH (5.1%). TMB-H was more common (18% [n=931] vs. 11% [n=1001]; p<0.001) and median TMB was higher (5.4 vs. 4.6; p<0.001) in DDRmt pts compared to DDRwt. MSI-H was more prevalent in the DDRmt group (1.1% [n=57] vs. <0.1% [n=7]; p<0.001), while PD-L1 positivity was similar in DDRmt and DDRwt pts (55% [n=1918] vs. 58% [n=3314]; p=0.071). Compared to DDRwt, pts with DDRmt exhibited modest changes in immune cell infiltration patterns (Table).

Conclusions: In this large, real-world cohort of pts with metastatic NSCLC, DDRmt was associated with distinct TIME patterns including high TMB, MSI-H, and modest changes in immune cell infiltrates. These findings warrant further studies to understand how DDR pathway alterations mediate changes in the TIME to inform novel combinatorial immunotherapeutic approaches in NSCLC.

Immune cell infiltration among DDRmt and DDRwt metastatic NSCLC.
Immune Cell Proportions Overall, N=14,1271 DDRmt, n=5,2551 DDRwt, n=8,8721 p-value2
Total 21 (11, 31) 21 (12, 32) 21 (11, 31) 0.12
B 14 (6, 26) 14 (6, 26) 14 (5, 25) 0.011
CD4+ T 21 (15, 29) 21 (15, 29) 21 (14, 29) >0.9
CD8+ T 5.9 (0.0, 10.4) 6.3 (0.0, 10.4) 5.6 (0.0, 10.4) 0.003
Macrophage 39 (26, 53) 38 (26, 52) 40 (26, 53) 0.001
NK 12 (7, 19) 12 (7, 19) 12 (7, 19) 0.4

1Median (IQR).

2Wilcoxon rank-sum test.