Association between homologous recombination deficiency (HRD) gene mutations and the efficacy of venadaparib in combination with irinotecan as third- or fourth-line treatment in patients with metastatic gastric cancer (mGC).

Abstract

e16057 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 exploratory 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 mGC who had failed at least at least 2 lines of therapy. Methods: This was an exploratory analysis from a multi-national, phase 1b 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, PALB2, RAD51, RAD51B/C/D, CHEK1/2, POLD1/2/3/4, BARD1, BRIP1, were analyzed with the efficacy outcomes. Results: In the dose-finding part of the clinical study, 26 patients were enrolled:13 had received two prior treatments and 13 had received three prior treatments, respectively. Of the 26 patients enrolled, 7 (26.9%) had mutations involved in HRD (4 with ATM, 1 with BRCA2, 1 with BARD1, and 1 with ATR mutations, respectively), and were treated with varying doses of venadaparib plus irinotecan. Among the 7 patients with a mutation in HRD genes, an objective response rate (ORR) was 57.1%, and median progression free survival (mPFS) was 5.6 months (95% confidence interval [CI] 1.2–not reached). For those without a mutation in HRD genes (n = 19), 1 patient achieved partial response and 13 achieved stable disease as best response with a mPFS of 4.0 (95% CI 2.9-5.5) months. Conclusions: Venadaparib in combination with irinotecan showed promising efficacy outcomes in patients with mGC, especially for those with mutations of HRD-related genes. Further development of this combination may consider a biomarker-based approach. Clinical trial information: NCT04725994 . [Table: see text]