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Ref Type Journal Article
PMID (37277454)
Authors Yap TA, Fontana E, Lee EK, Spigel DR, Højgaard M, Lheureux S, Mettu NB, Carneiro BA, Carter L, Plummer R, Cote GM, Meric-Bernstam F, O'Connell J, Schonhoft JD, Wainszelbaum M, Fretland AJ, Manley P, Xu Y, Ulanet D, Rimkunas V, Zinda M, Koehler M, Silverman IM, Reis-Filho JS, Rosen E
Title Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results.
Journal Vol Issue Date Pages Journal Short Title
Nature medicine 29 6 2023 Jun 1400-1411 Nat Med
URL
Abstract Text 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 .

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM R3008H prostate cancer predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a 29% tumor reduction in a castration-resistant prostate cancer patient harboring ATM R3008H, who remained on treatment for more than 61 weeks (PMID: 37277454; NCT04497116). 37277454
ATM inact mut lung non-small cell carcinoma predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a partial response after 37 weeks of treatment in a patient with advanced non-small cell lung cancer harboring germline biallelic ATM inactivation (PMID: 37277454; NCT04497116). 37277454
CDK12 inact mut Advanced Solid Tumor predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 12% (13/113), clinical benefit rate (CBR) of 42% (47/113), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including CDK12 with a CBR of 28.6% (2/7), and with a CBR of 75% and mPFS of 35 weeks in 20 ovarian cancer patients (PMID: 37277454; NCT04497116). 37277454
ATM inact mut pancreatic cancer predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a partial response at week 54 in a patient with advanced pancreatic cancer harboring a germline ATM frameshift mutation (PMID: 37277454; NCT04497116). 37277454
RAD51C inact mut ovarian cancer predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a partial response with complete resolution of the target lesion at 19 weeks in a patient with ovarian cancer harboring a RAD51C inactivating mutation (PMID: 37277454; NCT04497116). 37277454