Efficacy of venadaparib plus irinotecan in homologous recombination deficiency (HRD) gene mutations as 3+ line treatment in patients with metastatic gastric cancer (mGC).

4045 Background: Tumors with homologous recombination deficiency (HRD) have been suggested to be associated with a favorable response to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors. The aim of this analysis was to evaluate the association between the presence of HRD gene mutations and the efficacy of venadaparib, a novel PARP inhibitor, plus irinotecan in patients with metastatic gastric cancer (mGC) who had progressed after at least at least 2 lines of therapy. Methods: This was an exploratory analysis from a multi-national, phase 1b/IIa trial of venadaparib plus irinotecan in patients with mGC (NCT04725994). Tumor response was evaluated according to RECIST v. 1.1. Genomic analysis was conducted using ctDNA (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Results of the exploratory genomic analysis, which includes pathogenic or deleterious mutations of following genes: BRCA1/ 2, ATM, ATR, CHEK2, BARD1 were analyzed for association with efficacy outcomes. Results: As of Dec 2024, 43 patients enrolled and objective response (ORR), median progression-free survival (mPFS) and median overall survival (mOS) were 20.9%, 4.2 (2.9-9.6) and 8.1 (6.8-11.5) months. 14 (32.6%) out of the 43 patients had at least one HRD mutation (6 with ATM , 3 with BRCA1 , 2 with BRCA2 , 1 with BARD1 , 1 with CHEK2 and 1 with ATR mutations, respectively). For the 14 patients with HRD mutation and 29 patients with no HRD mutation, the ORR, mPFS (95% CI) and mOS (95% CI) were 35.7% vs. 13.8%, 5.6 (1.3-9.1) vs. 4.0 (2.7-5.4) months and 10.1 (6.8-12.0) vs. 8.0 (5.9-11.5) months respectively. For 11 patients with ATM or BRCA1/2 mutation, mPFS (95% CI) and mOS (95% CI) were 8.4 (1.2-24.0) and 10.1 (6.8-34.4) months. At the maximum tolerable dose (MTD) level of venadaparib 20 mg/d on days 1 to 7 and irinotecan 100 mg/m 2 at day 1 of a 2-week cycle, six of 15 patients had HRD mutation, and mPFS (95% CI) and mOS (95% CI) were 4.1 (2.9-5.4) and 7.9 (5.9-11.5) months; these data are still maturing. Conclusions: Venadaparib in combination with irinotecan demonstrated promising efficacy in patients with mGC, particularly those with HRD gene mutations. Further development of this combination may warrant a biomarker-based approach. Clinical trial information: NCT04725994 . Efficacy results in patients with homologous recombination deficiency mutation. Patient # Mutations in HRD-related Genes Number ofPrior Palliative Treatment Best Overall Response (%) Treatment Duration (months) Overall Survival (months) 82001-2103 BRCA2 3 SD 25.1 33.9 82004-2101 ATM 2 PR 38.3 37.3 82002-2103 ATR 3 PD 1.4 8.0 82004-2103 ATM 3 PD 1.3 6.7 82004-2102 BARD1 2 CR 5.6 11.6 82005-2101 ATM 2 SD 3.1 11.8 82005-2103 ATM 2 PR 4.9 8.3 82003-2203 BRCA2 2 SD 9.4 11.5 82005-2202 BRCA1 2 SD