Abstract 4625: The optimal tumor mutational burden cutoff value for predicting the efficacy of the PD-1 checkpoint inhibitor combined with chemotherapy in advanced gastric cancer

Abstract Purpose: Chemotherapy is associated with an increase in tumor mutational burden (TMB). When receiving the combination of programmed cell death-1 (PD-1) checkpoint inhibitor and chemotherapy, TMB can be a better option for predicting the response, especially for tumors with initially low TMB. We aimed to investigate the optimal TMB cutoff value that could predict the efficacy of PD-1 checkpoint inhibitors combined with chemotherapy in advanced gastric cancer. Materials and Methods: Patients with AGC who received nivolumab with capecitabine and oxaliplatin as the 1st line palliative treatment, between September 1, 2021, and July 15, 2023, at Samsung Medical Center in Korea were retrospectively analyzed. The TMB levels were measured using a next-generation sequencing assay. Based on receiver operating characteristic curve analysis, the TMB cutoff value was determined. Results: A total of 101 patients were analyzed. The TMB cutoff value for predicting the overall response rate (ORR) to nivolumab combined with capecitabine and oxaliplatin was defined as 10.2 mutations per megabase (mt/Mb) with 97.7% sensitivity and 22.4% specificity. Based on this definition, 14 (13.9%) patients were TMB-high (TMB-H). The ORR differed between the TMB-low (TMB-L) and TMB-H groups (51.7% vs. 92.9%, P=0.004). The progression-free survival (PFS) and overall survival (OS) for 101 patients were 11.8 (95% confidence interval [CI], 8.46-15.14) and 27.9 months (95% CI, 20.34-35.45), respectively. The median PFS tended to be longer in the TMB-H group (22.0 months; 95% CI, 11.86-32.14) than in the TMB-L group (11.1 months; 95% CI, 8.56-13.64; P=0.217). The median follow-up duration of the TMB-H group was 23.7 months, and the median OS was not reached. The median OS of the TMB-L group was 27.9 months (95% CI 20.50-35.23; P=0.241). Conclusions: The TMB cutoff value for predicting treatment response in AGC patients who received the PD-1 checkpoint inhibitor combined with capecitabine and oxaliplatin as the 1st line palliative treatment was 10.2 mt/Mb. When applying the programmed death ligand-1 status to TMB, patients who would benefit from PD-1 checkpoint inhibitors can be selected. Citation Format: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Sung Hee Lim, Jeeyun Lee, Seung Tae Kim. The optimal tumor mutational burden cutoff value for predicting the efficacy of the PD-1 checkpoint inhibitor combined with chemotherapy in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4625.