In a Phase Ib expansion trial, elimusertib — a potent and highly selective ATR inhibitor — demonstrated promising antitumor activity against a range of advanced solid tumours with different putative deleterious DDR alterations.
ATR is a critical component of the DDR network that is activated by DNA damage or replication stress.
By binding to ATR and blocking ATR-mediated signalling, ATR inhibitors prevent DNA damage checkpoint activation, disrupt DNA damage repair and stop the growth of tumor cells, Yap explained.
The data was presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.
In the study, 143 patients with advanced solid tumours with different putative deleterious DDR alterations — including 45 gynecologic cancers, 24 colorectal cancers, 19 HER2-negative breast cancers, 19 castration-resistant prostate cancers, and 36 advanced cancers with loss of alternative DDR protein ATM — received at least one dose of elimusertib.
Thirty-two patients with ATM protein loss and/or mutations were enrolled in the dose-escalation arm of the study.
The most frequent drug-related grade ≥3 treatment emergent adverse events (TEAEs) were hematologic, including anemia (65.7%) and neutropenia (47.6%).
Overall, these hematologic TEAEs were reversible and manageable with dose interruptions or reductions and supportive measures, and infrequently resulted in permanent drug discontinuation.
An alternative schedule of three days on and 11 days off, which also was explored, may reduce the risk of hematologic events and offer a potential alternative to be further evaluated in future studies of elimusertib.
Elimusertib achieved clinical benefit with disease control for at least 16 weeks in approximately 35% of patients enrolled in the three days on, four days off dose expansion, with durable objective responses observed across a variety of cancer types.
Results showed a durable clinical benefit lasting greater than six months in 27.8% of patients with advanced ovarian cancer, including those resistant to platinum-based therapy and those who previously had received PARP inhibitor therapy.
In patients with ATM loss, the best overall response included RECIST partial responses in 8.9% of patients and RECIST stable disease in 55.9% of patients, with durable clinical benefit lasting >6 months in 26.5% of patients.
“While we observed durable responses and prolonged stable disease in patients with ATM alterations and BRCA1 and BRCA2 defects, including patients previously treated with PARP inhibitor therapy, further studies are needed to better identify molecular biomarkers to predict which patients are most likely to benefit from elimusertib monotherapy,” Yap said. “Rational combination studies are also ongoing and investigating elimusertib in combination with the PARP inhibitor niraparib and with the PD-1 inhibitor pembrolizumab.”
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