Predictive value of homologous recombination-related gene mutations in survival outcomes of first-line nivolumab plus chemotherapy for gastric cancer.

4048 Background: Homologous recombination repair (HRR) gene mutations are associated with genomic instability; however, their clinical value in the context of immune checkpoint inhibitor (ICI)-based treatments in gastric cancer remains unclear. We investigated the efficacy of nivolumab plus chemotherapy according to the HRR mutation status in advanced gastric cancer patients. Methods: This single-center study included gastric cancer patients with available panel sequencing results who were treated with first-line nivolumab plus chemotherapy (n = 115) or chemotherapy alone (n = 172) between July 2021 and March 2024. Mutation status of 17 HRR genes ( BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, RAD52, RAD54L, and XRCC2 ) was assessed using targeted next-generation sequencing. Treatment outcomes were compared according to the presence of HRR mutations. Results: Among patients treated with nivolumab plus chemotherapy, 36.5% harbored HRR mutations. Compared to the no HRR mutation group, the HRR mutation group exhibited a higher objective response rate (92% vs. 63.2%, P = 0.010), longer progression-free survival (PFS) (median 12.8 vs. 6.5 months; hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36–0.91, P = 0.019) and overall survival (OS) (median not reached vs. 14.2 months; HR 0.40, 95% CI 0.23–0.71, P = 0.002). Among patients with HRR mutation, those treated with nivolumab plus chemotherapy showed favorable survival outcomes compared to those treated with chemotherapy alone (PFS: HR 0.44, 95% CI 0.27–0.71, P < 0.001; OS: HR 0.45, 95% CI 0.25–0.80, P = 0.007), but this was not the case for patients without HRR mutation (PFS: HR 0.79, 95% CI 0.56–1.10, P = 0.156; OS: HR 0.90, 95% CI 0.63–1.28, P = 0.554). Conclusions: The presence of HRR mutations was associated with favorable survival outcomes in patients treated with nivolumab plus chemotherapy. Our findings suggest that HRR mutations may serve as a potential predictive biomarker for first-line ICI-based chemotherapy in gastric cancer.