Abstract CT015: Clinical outcomes by genomic markers and ctDNA dynamics with perioperative nivolumab (NIVO) for resectable NSCLC from CheckMate 77T

Abstract Background: In the phase 3 CheckMate 77T study, perioperative NIVO demonstrated statistically significant and clinically meaningful EFS benefit vs placebo (PBO) in patients (pts) with resectable NSCLC. Here, we report comprehensive analyses of EFS by tumor genomic alteration status and ctDNA dynamics from CheckMate 77T (median f/u41.0 mo) to identity potential markers of efficacy with perioperative NIVO in pts with resectable NSCLC. Methods: Pts with resectable stage IIA-IIIB (N2) NSCLC were randomized toneoadjuvant (neoadj) NIVO + chemo followed by surgery and adjuvant (adj) NIVOor neoadj PBO + chemo followed by surgery and adj PBO. Exploratory analyses included EFS by tumor genomic alteration status, ctDNA at baseline, and post-surgical minimal residual disease (MRD), and associations between EFS and clinical or genomic markers (pt characteristics, pCR, ctDNA clearance, tumor genomic alterations) using a random survival forest machine learning model. Additional ctDNA/MRD analyses will be presented. Results: Of229 and 232 randomized pts in the NIVO and PBO arms, respectively, 98 (43%) and92 (40%) pts had marker-evaluable samples. Ofmarker-evaluable pts, 60 (61%) pts in the NIVO arm and 45 (49%) pts in the PBO arm had single or co-alterations in tumor KEAP1, STK11, CDKN2A, and/or SMARCA4. EFS was longer with NIVO vs PBO in pts with single or co-alterations in tumor KEAP1, STK11, CDKN2A, and/or SMARCA4(HR 0.48; 95% CI 0.28-0.83; 30-mo EFS rates 60% vs 30%); the EFS HR in pts with no alterations in these 4 genes was 0.90 (95% CI 0.48-1.69). EFS was similar in the NIVO arm (HR 0.91; 95% CI 0.50-1.69) for pts with single or co-alterations in ≥1 of these 4 genes vs pts without, but it was worse in the PBO arm (HR 1.77;95% CI 1.01-3.11). In pts with detectable ctDNA at baseline (NIVO n = 83; PBO n= 75), EFS was longer with NIVO vs PBO (HR 0.58; 95% CI 0.37-0.92). In pts who were MRD-negative post-surgery (NIVO n = 55; PBO n = 46), landmark EFS from definitive surgery favored NIVO vs PBO (HR 0.75;95% CI 0.40-1.42); small sample sizes precluded analysis of pts who had no detectable ctDNA at baseline or were MRD-positive post-surgery (≤ 12 pts for each tx arm). In all marker-evaluable pts, top predictors for lower risk of worse EFS included definitive surgery, pCR, ctDNA clearance before surgery, and tx with NIVO. Conclusions: In these exploratory analyses, EFS was improved with NIVO vs PBO in pts with tumor genomic alterations associated with poor prognosis; EFS with NIVO was similar regardless of tumor genomic alteration status. These data support a context-dependent model of immunotherapy sensitivity. While tumor genomic alterations have been associated with immune resistance in advanced NSCLC, a combination of distinct biology and immunometabolic features may impact tx efficacy in early-stage NSCLC. Predictive modeling provides insights into pts who may derive the most benefit from perioperative NIVO. Citation Format: Tina Cascone, Mark M. Awad, Jonathan D. Spicer, Jie He, Shun Lu, Fumihiro Tanaka, Robin Cornelissen, Lubos B. Petruzelka, Yang Gao, Jean-Louis Pujol, Hiroyuki Ito, Ludmila de Oliveira Muniz Koch, Tudor-Eliade Ciuleanu, Lin Wu, Sabine Bohnet, Yasutaka Watanabe, Jaclyn Neely, Virginia Ip, Yu-Han Hung, Sumeena Bhatia, Cinthya Coronado Erdmann, Nathanial Eddy, Akshay Yadav, Mariano Provencio. Clinical outcomes by genomic markers and ctDNA dynamics with perioperative nivolumab (NIVO) for resectable NSCLC from CheckMate 77T [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT015.