Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with...

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Camonsertib is an oral ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor effective in tumors with DNA damage response gene deficiencies.
• On-target anemia is a primary toxicity, often appearing after dose-limiting toxicity evaluation, necessitating schedule optimization for prolonged treatment.
• The TRESR study aimed to optimize camonsertib dosing and schedule to mitigate toxicity while maintaining efficacy.

Purpose of the Study:

• To evaluate the long-term safety, tolerability, and antitumor efficacy of three camonsertib monotherapy dosing regimens.
• To identify an optimized dosing schedule that reduces the incidence of on-target anemia without compromising efficacy.

Main Methods:

• Assessed safety and efficacy of camonsertib 160 mg QD 3 days on/4 days off (preliminary RP2D), 120 mg QD 3 days on/4 days off, and 160 mg QD for 2 weeks on/1 week off.
• Key safety endpoints included treatment-related adverse events (TRAEs), dose modifications, and transfusions.
• Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and ctDNA-based molecular response rate.

Main Results:

• The 160 mg QD 2 weeks on/1 week off schedule significantly reduced the risk of grade 3 anemia compared to the preliminary RP2D (HR=0.23, P=.02).
• This optimized schedule led to fewer transfusions and dose reductions.
• Antitumor activity was maintained on the intermittent weekly schedule.

Conclusions:

• The 160 mg QD 2 weeks on/1 week off regimen is an optimized schedule for future camonsertib monotherapy studies.
• This optimized regimen substantially reduces anemia incidence without compromising therapeutic efficacy.
• This finding is critical for improving patient tolerability in long-term cancer treatment.