Abstract P032: Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study

Autor: Satya Das, G. Dan Ayers, Jennifer Whisenant, Anwaar Saeed, Edward Kim, Vaia Florou, George Yacoub, Percy Ivy, Charles Kunos, Jordan Berlin
Rok vydání: 2021
Předmět:
Zdroj: Molecular Cancer Therapeutics. 20:P032-P032
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-21-p032
Popis: Background: Nearly 50% of patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma possess somatic TP53 mutations, with most mutations falling within exons 2 or 4-11. Though the presence of TP53 mutations has historically been considered a poor prognostic factor in advanced gastric/GEJ adenocarcinoma, cancer cells with mutations in TP53 tend to depend on ataxia telangiectasia and Rad3-related protein kinase (ATR) as a primary mediator of DNA damage repair (DDR). In preclinical studies, topoisomerase 1 inhibitors and ATR inhibitors demonstrate synergy in TP53 mutant gastrointestinal cancer cell lines. Based on the dearth of active later-line treatments in patients with advanced gastric/GEJ adenocarcinoma, we initiated a combinatorial study of the highly selective ATR inhibitor berzosertib (formerly VX-970/M6620) with irinotecan in this disease population. Methods: The study is a single arm phase II trial of berzosertib plus irinotecan in patients with advanced (progressive on at least one prior line of therapy) TP53 mutant (with mutations in exons 2 or 4-11) gastric/GEJ adenocarcinoma and is sponsored by the National Cancer Institute [NCT03641313]. The primary endpoint of the study is objective response rate (ORR) with key secondary endpoints of overall survival (OS), progression-free survival (PFS), duration of response (DOR) and measuring pharmacodynamic biomarkers of DNA damage induction (γ-H2AX, KAP1 p-Ser 824 and p-ATR) from on-treatment biopsies in select patients. Exploratory aims of the study are to assess ORR, OS, PFS and DOR in patients based upon the presence of other tumor DDR mutations (e.g. BRCA1, BRCA2, MRE11, RAD50, RAD51, NBN, ATM). The study utilizes a Simon's Optimal two-stage design to assess ORR. If 2 or more responses are not observed in the first 9 response-eligible patients on the study, it will close for futility. If the interim efficacy threshold is achieved, 14 more response-eligible patients will be enrolled for a total of 23. A safety lead-in is being utilized for the initial 6 patients as the RP2D of the experimental combination had not yet been fully defined from its preceding phase I study. Results: The initial 6 patients have been treated with irinotecan (180 mg/m2 D1,D15 every 28 days) and berzosertib (270 mg/m2 D1,D15 every 28 days). No dose limiting toxicities were observed during cycle 1 in these patients and thus this dose was established as a safe dose for the remainder of the study patients. Patients have experienced grade 3/4 adverse events in 7 instances (most have been hematologic with 1 case of grade 4 neutropenia and 1 case each of grade 3 anemia, neutropenia and thrombocytopenia). Of the initial 6 patients, 1 has demonstrated a partial response while 3 others have demonstrated stable disease on initial response assessment (by RECIST 1.1). Conclusion: Berzosertib plus irinotecan appears to be safe in patients with TP53 mutated gastric/GEJ adenocarcinoma. The interim efficacy analysis, along with pharmacodynamic assessments of DNA damage induction, remain pending. Citation Format: Satya Das, G. Dan Ayers, Jennifer Whisenant, Anwaar Saeed, Edward Kim, Vaia Florou, George Yacoub, Percy Ivy, Charles Kunos, Jordan Berlin. Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P032.
Databáze: OpenAIRE
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