Abstract A013: Clinical Value of Tumor Mutational Burden (TMB) for Neoadjuvant and Adjuvant Immune Checkpoint Inhibitor (ICI) in Early-Stage (I-III) Non-Small Cell Lung Cancer (NSCLC)

Abstract Introduction: TMB and PD-L1 IHC are companion diagnostics utilized to select ICI therapy use in the advanced NSCLC setting. As ICI use is expanding into the early-stage setting, biomarkers for stratifying responders and non-responders to ICI are needed. As EGFR and ALK genomic alterations (GA) are now standard biomarkers for early-stage NSCLC, the ability to multiplex ICI biomarkers in this setting is becoming necessary. Since TMB can be determined via a comprehensive genomic profiling (CGP) assay along with EGFR and ALK GA, we sought to explore the feasibility of utilizing TMB as an ICI biomarker in early-stage NSCLC, specifically for identification of patients (pts) with higher chances of having a pathologic complete response (pCR) in the neoadjuvant setting and for identification of durable responders to ICI in the adjuvant setting. Methods: This study included NSCLC pts who underwent FoundationOne/FoundationOne®CDx tissue CGP and received neoadjuvant or adjuvant chemotherapy-ICI. Clinical data was obtained by the US-wide de-identified Flatiron Health-Foundation Medicine real-world clinicogenomic NSCLC database, from ∼280 cancer clinics (∼800 sites of care) between 1/2011-12/2024. pCR rates were compared between TMB-high (TMB-H, ≥10 mut/Mb) and TMB-low (TMB-L, <10 mut/Mb) among pts receiving neoadjuvant ICI using the Fisher’s exact test. Time to recurrence (TTR) was landmarked at 12 months after treatment initiation and compared TMB-H and TMB-L groups among pts receiving adjuvant ICI using Cox models. Results: A total of 250 pts were included in the study, 38 receiving neoadjuvant and 212 adjuvant ICI. Among pts receiving neoadjuvant ICI, 28.9% had ECOG performance status (PS) 1-2, 86.8% had history of smoking, and 2.6% (n=1), 36.8% (n=14), and 60.5% (n=23) were stages I, II, and III at diagnosis, respectively. We observed nominally enriched pCR rates in the TMB-H (n=9) vs TMB-L group (n=29) with 33.3% pCR in TMB-H and 13.8% in TMB-L (p=0.37). Among pts receiving adjuvant ICI, 51% had ECOG PS 1-3, 94% had history of smoking, and 2.8% (n=6), 24.1% (n=51), and 73.1% (n=155) were stages I, II, and III at diagnosis, respectively. Pts with TMB-H (n=93) vs TMB-L (n=119) showed more favorable TTR (75th percentile 30.9 vs. 10.2 months, HR 0.44, 95% CI 0.24-0.82, p=0.008) when landmarked to 12 months after treatment initiation. When restricting to only pts with PD-L1 <50%, the difference was more pronounced, with pts with TMB-H (n=43) vs. TMB-L (n=61) having even more favorable TTR (75% percentile not reached vs. 6.9 months, HR 0.30, 95% CI 0.11-0.82, p=0.012).). Conclusion: Herein, we saw that TMB could stratify pts with durable responses from adjuvant ICI use, and we observed early signal that TMB could potentially predict pCR in the neoadjuvant setting. TMB should be considered in future early-stage NSCLC ICI clinical trials to further validate these results. Citation Format: Julia Quintanilha, Gerald Li, Ryon Graf, Amaya Gasco, Jerry Mitchell, Richard Huang. Clinical Value of Tumor Mutational Burden (TMB) for Neoadjuvant and Adjuvant Immune Checkpoint Inhibitor (ICI) in Early-Stage (I-III) Non-Small Cell Lung Cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A013.