Phase Ib Basket Expansion Trial and Alternative-Schedule Dose-Escalation Study of ATR Inhibitor Elimusertib in...

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.

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.