Reference Detail

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
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	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 advanced solid tumor patients with inactivating mutations in DNA damage repair genes, including ATM with a CBR of 44.1% (15/34) and CBR was 54% (7/13) with biallelic vs 11% (1/9) with monoallelic ATM inactivation, and CBR of 75% and mPFS of 35 weeks in 20 ovarian cancer patients (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