Repare Therapeutics has announced promising Phase 1 data highlighting the clinical benefits of camonsertib, a potential best-in-class oral small molecule ATR inhibitor, when combined with palliative radiation for treating metastatic tumors harboring ataxia-telangiectasia-mutated (ATM) mutations. The data, presented at the American Society for Radiation Oncology (ASTRO) annual meeting, suggests that the combination may radiosensitize tumors, leading to improved clinical outcomes.
The study, conducted in collaboration with Memorial Sloan Kettering Cancer Center, enrolled seventeen patients with metastatic tumors harboring ATM mutations. Twelve patients had pathogenic ATM mutations, while five had ATM mutations with variants of unknown significance (VUS). The primary cancer histologies included gastrointestinal, pancreas, breast, lung, bladder, and thyroid cancers.
Key Findings from the Phase 1 Trial
The recommended Phase 2 dose for camonsertib was determined to be 160 mg given once daily prior to radiation (4Gy) on days 1-5. Interim response information was available for 16 patients at the time of submission. At 2 months, the pathogenic ATM mutation group showed 2 complete responses (CR), 5 partial responses (PR), and 4 stable disease (SD), while the VUS group had 1 PR and 4 SD. At 6 months, among 9 evaluable patients, the pathogenic group reported 2 CR, 4 PR, and 1 SD, compared to 1 SD and 1 progressive disease (PD) in the VUS group.
"These encouraging early Phase 1 data build further support for the broad clinical potential of camonsertib," said Maria Koehler, MD, PhD, Executive Vice President and Chief Medical Officer of Repare. "This first-in-human study combining camonsertib, an ATR inhibitor, with palliative radiation provides early clinical data showing that the combination has the potential to radiosensitize for higher clinical benefit in patients with tumors harboring pathogenic ATM mutations versus those with variants of unknown significance. We are highly encouraged by this early look at the response rate and safety profile of this combination in the Phase 1 setting."
Implications for ATM-Mutated Cancers
ATM mutations are implicated in various cancers, contributing to genomic instability and impaired DNA damage repair. The observed clinical activity of camonsertib in combination with radiation suggests a potential strategy to overcome resistance in these tumors. The results warrant further investigation in larger, controlled trials to confirm the efficacy and safety of this combination therapy.
