Phase Ib basket expansion trial and alternative-schedule dose-escalation study of ATR inhibitor elimusertib in advanced solid tumors with DNA damage response defects

Abstract In this Phase Ib basket expansion trial and alternative-schedule dose-escalation study, we evaluated the ATR inhibitor elimusertib at 40 mg twice daily (3 days on/4 days off) in 143 patients with advanced cancer with tumor-associated DNA damage response defects, comprising gynecologic (n=45), prostate (n=19), colorectal (n=24), and breast (n=19) cancer, and ATM loss (n=36). An alternative schedule (3 days on/11 days off) was assessed in patients with ATM loss and/or ATM mutations (n=32). Elimusertib-related reversible hematologic toxicities were observed. Objective responses were modest (4.5%), but a disease control rate (DCR) of 49.3% indicated that subpopulations of patients, especially with gynecologic cancers (DCR 59.5%), derived meaningful durable benefit from elimusertib. There was no association between ATM protein loss or ATM alterations and progression-free survival or overall response. Further studies to define optimal predictive biomarkers for ATR inhibitors as monotherapy and in combination are ongoing.