Camonsertib ATR Inhibitor Shows Activity in DDR-Deficient Solid Tumours Guided by Genomic Biomarkers
This phase 1 trial tested the ATR inhibitor camonsertib in 120 patients with advanced solid tumours harbouring loss-of-function alterations in DNA damage response genes identified through chemogenomic CRISPR screens. Clinical benefit was highest in tumours with biallelic LOF alterations and correlated with ctDNA molecular responses. The study exemplifies biomarker-driven oncology where NGS-based DDR gene panels and ctDNA monitoring directly inform patient selection and treatment response assessment.
The original study
Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results.
- Authors
- Yap TA, Fontana E, Lee EK, Spigel DR, Højgaard M, Lheureux S, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 37277454
Original abstract
Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d-1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116 .