A phase 2 single-arm study of berzosertib in combination with irinotecan in patients with progressive TP53 mutant gastric and gastro-esophageal junction cancer

4044 Background: TP53 mutations are reported in 30-70% of patients with metastatic/unresectable gastric (G) and gastro-esophageal junction (GEJ) adenocarcinoma and are associated with a poor prognosis. Novel therapeutics are needed. Gastrointestinal cancer cell lines with TP53 mutations demonstrate reliance on the ataxia telangiectasia and Rad3-related protein kinase (ATR) axis for DNA damage repair (DDR) in vitro. The ATR axis is triggered by single-strand DNA breaks and thus combining ATR inhibitors with topoisomerase I (TopI) inhibitors may have a synergistic effect, particularly in patients with TP53 mutant tumors. Irinotecan, a TopI inhibitor, is an established cytotoxic therapy for gastric and GEJ adenocarcinoma. We evaluated irinotecan in combination with the ATR inhibitor berzosertib (formerly M6620) in patients with TP53-mutated gastric and GEJ adenocarcinoma. Methods: This was a single-arm phase II study in third-line patients with G/GEJ cancers possessing TP53 mutations (exon 2 and exons 4-11). Patients received irinotecan 180 mg/m 2 IV and berzosertib 270 mg/m 2 IV on days 1 and 15 every 28 days. The primary endpoint was overall response rate (ORR) (Ha: 35% and Ho:15%). A subset of patients underwent biopsies on C1D1 post-irinotecan and C2D2 to evaluate the expression of DDR biomarkers Y-H2AX, KAP1 p-Ser 824, and p-ATR. Results: A total of 17 patients were enrolled. Of 16 efficacy-evaluable patients, one experienced a partial response. The ORR was 6.2% thus the primary endpoint was not met. The disease control rate was 56.2%. Median progression-free survival was 4.01 months [95% CI 2.07-Not Reached]. Median overall survival was 6.21 months [95% CI 4.83-8.61]. No new safety signals were observed with the experimental treatment combination and the most common ≥ grade 3/4 treatment-related adverse events were neutropenia (4/17, 23.5% patients), anemia (3/17, 17.6%), febrile neutropenia (2/17, 11.8%), and diarrhea (2/17, 11.8%). No grade 5 events occurred. Conclusions: Although the primary endpoint of ORR was not met, the combination of irinotecan and berzosertib in patients with TP53-mutated G/GEJ adenocarcinoma was well-tolerated and demonstrated anti-tumor activity comparable to other agents with published later-line data (e.g. ramucirumab+paclitaxel, TAS-102). Analyses of pharmacodynamic biomarkers of DNA damage repair are in process. While further clinical development of berzosertib is not planned, other ATR inhibitors are being explored in combination with irinotecan in gastrointestinal malignancies, including G/GEJ cancer. Clinical trial information: NCT03641313 . [Table: see text]