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Background Although combination immune checkpoint inhibition and chemotherapy (ICI+C) is commonly used in patients with advanced non-small cell lung cancer (NSCLC), the benefit is variable. We have previously reported results from the myCare-040 study, 1 where we validated an algorithm capable of distinguishing patients with favorable ICI+C benefit from those with no benefit. Using this algorithm, we have identified a set of genomic markers important for ICI+C benefit.Methods The algorithm (∆TRI) utilizes the Cellworks’ computational modeling of a patient’s tumor-specific genomic profile to predict disease and therapy directed alterations of biomarkers associated with ICI+C benefit. ∆TRI predicts the absolute increase in percentage likelihood of survival at 24 months for patients receiving ICI+C versus ICI alone. In the myCare-040 validation cohort, patients with predicted high ICI+C benefit (∆TRI > 16, n=73) realized a 8.3 month increase in median overall survival when receiving ICI+C versus ICI alone, whereas patients with a low score (∆TRI ≤16, n=255) showed no ICI+C benefit. We analyzed both benefit groups for significant enrichment ( p < 0.05 by Fisher Exact test) of genomic aberrations conferring either sensitivity or resistance to ICI+C.Results Overall, 592 total genomic aberrations (SNVs and CNAs) were identified in the myCare-040 cohort, with 24 (4.1%) showing significant enrichment ( p < 0.05) in either benefit group. Of this set, 3 aberrations were enriched in the no ICI+C benefit group (TP53-SOF, p < 0.0001, FDR < 0.0001; KRAS-SOF, p = 0.007; CD274 amplification, p = 0.006), with the remaining 21 aberrations showing enrichment in the ICI+C benefit group. Aberrations in ATM and ATR, two genes involved in DNA damage response, were among those showing the greatest enrichment in the ICI+C benefit group (ATM-LOF, p < 0.0001, FDR < 0.0001; ATR-LOF p = 0.003), highlighting the interaction between compromised DNA damage response and chemotherapy sensitivity.Conclusions In the myCare-040 cohort, most aberrations impacting ICI+C benefit were enriched in patients showing high ICI+C benefit, with some of these mutations possibly contributing to increased chemosensitivity by compromising DNA damage response. Notably, these aberrations were observed across both benefit groups, limiting their utility as biomarkers for directly predicting ICI+C efficacy and highlighting the benefit of a genomically integrative approach for determining ICI+C benefit.Reference Aggarawal, et al. World Congress Lung Cancer, 2025.