1081P DNA damage response and repair (DDR) gene mutations as an alternative mechanism to generate high TMB in never smoker NSCLC patients

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Immune checkpoint inhibitors (IO) single agent or in combination with platinum-based chemotherapy (CT-IO) are standard of care for Stage IV and not oncogene addicted non-small cell lung cancer (aNSCLC) according to PD-L1 expression. The presence of a high tumor mutation burden (H-TMB) is one of the most debated biomarkers for IO response. Smoking-induced harm is a mechanism that generates an H-TMB in aNSCLC smoking patients (S-pts), whereas never-smoking patients (NS-pts) usually have a low TMB and are unresponsive to IO. However, the subgroup of NS-pts with an H-TMB has not yet been well characterized molecularly. We retrospectively collected clinical data from a single-center cohort of 142 aNSCLC pts with PD-L1 ≥ 50% treated with first-line pembrolizumab between January 2017 to March 2021. Next-generation sequencing (NGS) analysis using the FoundationOne®CDx assay (Foundation Medicine, Cambridge, MA, USA) was performed to correlate genetic alterations with clinical characteristics and response outcomes. We classified all detected mutations into eleven main pathways: cell cycle pathway, Hippo pathway, Myc pathway, Notch pathway, Oxidative stress/Nrf2 pathway, PI3K pathway, RTK/RAS/MAP pathway, TGF beta pathway, p53 pathway, beta-catenin/Wnt pathway and DDR pathway. Lastly, we identified the pathways with at least one mutation for each patient and performed enrichment analysis to characterize patients’ subgroups in terms of mutated pathways. With a median follow-up of 22 months (m), mPFS was 9.9 m, and mOS was 10.6 m. There were 111 S-pts and 31 NS-pts. The cohort of S-pts had higher TMB than the NS-pts cohort (TMB average 10.05 vs. 8.86 Mut/Mb). However, a subgroup of 11 NS-pts with high TMB (39-11 Mut/Mb) was identified. This subgroup was particularly enriched in DDR pathway mutations (p-value=0.0016) compared to the rest of the series and the H-TMB/S-pts subgroup. All H-TMB/NS-pts responded to IO treatment with an mPFS of 10.9 m and mOS of 12.7 m. Our data suggest a potential role of DDR signatures as an alternative mechanism to generate H-TMB in NS-pts. This preliminary observation could identify a subgroup of NS-pts responsive to IO and with a better prognosis.