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 ataxia-telangiectasia and rad3-related (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 ataxia-telangiectasia–mutated (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 those with gynecologic cancers (DCR 59.5%), derived meaningful, durable benefits 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, both as monotherapy and in combination, are ongoing. Significance: This is the largest ATR inhibitor monotherapy study reported to date. A DCR of 49.3% indicated that subpopulations of patients, especially those with gynecologic cancers (DCR 59.5%), derived meaningful benefits from elimusertib. Biomarker studies suggest that early ctDNA response may potentially predict clinical benefit from ATR inhibitors.