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Published on: July 25, 2020
Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results
Timothy A Yap1, Elisa Fontana2, Elizabeth K Lee3
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tyap@mdanderson.org.
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 .
Insights
This Phase 1 trial of camonsertib (ATRi) showed promising safety and preliminary efficacy in advanced solid tumors with DNA damage response (DDR) gene alterations. Clinical benefit was observed, particularly in ovarian cancer and tumors with specific DDR alterations.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Targeted cancer therapies require predictive biomarkers for treatment selection.
- Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) demonstrate synthetic lethality with loss of function (LOF) in ataxia telangiectasia-mutated (ATM) kinase.
- Preclinical data suggest other DNA damage response (DDR) gene alterations can sensitize tumors to ATRi.
Purpose of the Study:
- To evaluate the safety and determine the recommended Phase 2 dose (RP2D) of the ATR inhibitor camonsertib (RP-3500).
- To assess preliminary anti-tumor activity, pharmacokinetics, and pharmacodynamic biomarkers of camonsertib.
- To explore methods for identifying ATRi-sensitizing biomarkers in patients with advanced solid tumors.
Main Methods:
- A Phase 1 trial (Module 1) involving 120 patients with advanced solid tumors harboring DDR gene LOF alterations.
- Patients received camonsertib, with dose escalation to determine safety and RP2D.
- Clinical response, benefit, and molecular response rates were evaluated in patients receiving biologically effective doses.
Main Results:
- Camonsertib was generally well-tolerated, with grade 3 anemia as the most frequent toxicity (32%).
- The preliminary recommended Phase 2 dose (RP2D) was established at 160 mg weekly.
- Overall clinical response, clinical benefit, and molecular response rates were 13%, 43%, and 43%, respectively, in patients receiving effective doses.
- Highest clinical benefit was observed in ovarian cancer and tumors with biallelic LOF alterations.
Conclusions:
- Camonsertib demonstrates a manageable safety profile and preliminary anti-tumor activity in patients with specific DDR-altered advanced solid tumors.
- The study identified a potential RP2D and highlighted specific patient populations and tumor types that may benefit most from ATR inhibition.
- Further investigation in Phase 2 trials is warranted to confirm efficacy and refine patient selection based on DDR alterations.
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