Reference Detail

Ref Type

Journal Article

PMID

(38407317)

Authors

Yap TA, Tolcher AW, Plummer R, Mukker JK, Enderlin M, Hicking C, Grombacher T, Locatelli G, Szucs Z, Gounaris I, de Bono JS

Title

First-in-Human Study of the Ataxia Telangiectasia and Rad3-related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy in Patients with Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2024 Feb 26		Clin Cancer Res

URL

Abstract Text

Tuvusertib (M1774) is a potent, selective, orally administered ATR protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy.Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors. A safety monitoring committee determined dose escalation based on PK, PD, and safety data guided by a Bayesian 2‑parameter logistic regression model. Molecular responses (MRs) were assessed in circulating tumor DNA samples.Most common Grade ≥3 treatment-emergent adverse events were anemia (36%), neutropenia and lymphopenia (both 7%). Eleven patients experienced dose-limiting toxicities, most commonly Grade 2 (n=2) or Grade 3 (n=8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180mg tuvusertib QD, 2 weeks on/1 week off, which was better tolerated than the MTD (180mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5-3.5h and mean elimination half-life from 1.2-5.6h. Exposure-related PD analysis suggested maximum target engagement at ≥130mg tuvusertib QD. Tuvusertib induced frequent MRs in the predicted efficacious dose range, MRs were enriched in patients with radiological disease stabilization and complete MRs were detected for mutations in ARID1A, ATRX and DAXX. One patient with platinum- and PARP inhibitor‑resistant BRCA wild-type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response.Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.

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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
M1774	M1774	3	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
M1774		M-1774\|M 1774\|tuvusertib	ATR Inhibitor 16	M1774 inhibits ATR, potentially resulting in decreased tumor growth (PMID: 38407317).

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 mutant	lung non-small cell carcinoma	predicted - sensitive	M1774	Preclinical - Cell line xenograft	Actionable	In a preclinical study, M1774 inhibited tumor growth in a cell line xenograft model of non-small cell lung cancer harboring an ATM mutation (PMID: 38407317).	38407317
ARID1A mutant	stomach cancer	predicted - sensitive	M1774	Preclinical - Cell line xenograft	Actionable	In a preclinical study, M1774 inhibited tumor growth in a cell line xenograft model of gastric cancer harboring an ARID1A mutation (PMID: 38407317).	38407317