Reference Detail

Ref Type

Journal Article

PMID

(32988960)

Authors

Yap TA, Tan DS, Terbuch A, Caldwell R, Guo C, Goh BC, Heong V, Haris NRM, Bashir S, Drew Y, Hong DS, Meric-Bernstam F, Wilkinson G, Hreiki J, Wengner AM, Bladt F, Schlicker A, Ludwig M, Zhou Y, Liu L, Bordia S, Plummer R, Lagkadinou E, de Bono JS

Title

First-in-Human Trial of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery			2020 Sep 28	80-91	Cancer Discov

URL

Abstract Text

Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses greater than or equal to 40 mg BID. Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency.

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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 negative	collecting duct carcinoma	predicted - sensitive	BAY1895344	Case Reports/Case Series	Actionable	In a Phase I trial, BAY1895344 treatment resulted in a partial response with a 69% decrease in tumor size in a patient with renal collecting duct carcinoma harboring ATM protein loss, treatment was ongoing at 385 days (PMID: 32988960; NCT03188965).	32988960
ATM I2629fs ATM neg	endometrial clear cell adenocarcinoma	predicted - sensitive	BAY1895344	Case Reports/Case Series	Actionable	In a Phase I trial, BAY1895344 treatment resulted in a partial response with a 53% decrease in tumor size in a patient with clear cell endometrial cancer harboring ATM I2629fs with ATM protein loss, treatment was ongoing at 433 days (PMID: 32988960; NCT03188965).	32988960
ATM negative	Advanced Solid Tumor	predicted - sensitive	BAY1895344	Phase I	Actionable	In a Phase I trial, BAY1895344 treatment was tolerated and resulted in an objective response rate of 36.4% (4/11, all partial responses) and a disease control rate of 63.6% (7/11) in patients with advanced solid tumors harboring ATM inactivating mutations and/or ATM protein expression loss (PMID: 32988960; NCT03188965).	32988960
ATM inact mut	Advanced Solid Tumor	predicted - sensitive	BAY1895344	Phase I	Actionable	In a Phase I trial, BAY1895344 treatment was tolerated and resulted in an objective response rate of 36.4% (4/11, all partial responses) and a disease control rate of 63.6% (7/11) in patients with advanced solid tumors harboring ATM inactivating mutations and/or ATM protein expression loss (PMID: 32988960; NCT03188965).	32988960
ATM T2333fs ATM neg	Her2-receptor negative breast cancer	predicted - sensitive	BAY1895344	Case Reports/Case Series	Actionable	In a Phase I trial, BAY1895344 treatment resulted in a partial response with a 54% decrease in tumor size in a patient with heavily treated, hormone receptor-positive, ERBB2 (HER2)-negative breast cancer harboring ATM T2333fs and ATM protein loss, who remained on treatment for 349 days (PMID: 32988960; NCT03188965).	32988960
ATM V1268fs	appendix cancer	predicted - sensitive	BAY1895344	Case Reports/Case Series	Actionable	In a Phase I trial, BAY1895344 treatment resulted in a partial response with a 35% decrease in tumor size in a patient with appendix cancer harboring ATM T2333fs, treatment was ongoing at 472 days (PMID: 32988960; NCT03188965).	32988960