Menon, Suraj

TPS3184 Background: Replication stress (RS) creates cancer cell vulnerability to which the critical DNA damage response kinase, ATR (Ataxia-Telangiectasia and Rad3-related) responds. ATR senses the stress, halts the cell cycle, and promotes DNA repair to allow proliferation. Alnodesertib is an ATR inhibitor developed to prevent cancer cells from successfully repairing RS and proliferating further. In earlier stages of alnodesertib development, preclinical and translational research demonstrated that tumor cells experience three combined biological insults: irinotecan-induced RS, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and RS rescue prevention by ATR inhibition. Data from the dose escalation and initial dose expansion cohorts of this trial in a tumor agnostic population showed encouraging results in ATM-negative cancers (confirmed Overall Response Rate of 50% in 20 patients with ATM negative cancers and responses across 8 cancer types including complete responses, Ulahannan et al, AACR 2025). Tumor-specific dose expansion cohorts are now enrolling, including colorectal cancer (CRC) and pancreas ductal adenocarcinoma (PDAC). Methods: Two tumor-specific cohorts are now open, each enrolling approximately 50 patients (pts): ATM-negative CRC and ATM-negative PDAC. Pts will receive the recommended dose of alnodesertib 200mg orally on days 1-3 and 8-10 combined with low-dose irinotecan 60mg/m 2 IV on days 1 and 8, of each 21-day cycle. Tumor tissue is prescreened by immunohistochemistry for ATM protein loss (H score 0) for enrollment eligibility. Pts with CRC must have received a maximum of 2 prior chemotherapies excluding prior trifluridine/tipiracil, fruquintinib, or regorafenib, and pts with PDAC must have received a maximum of 1 prior chemotherapy for advanced disease. Prior targeted agents are allowed and do not count as prior lines of therapy. Key objectives include safety, tolerability, and preliminary efficacy. Clinical trial information: NCT04657068 .