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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.
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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 1 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