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First-in-Human Study of the Ataxia Telangiectasia and Rad3-Related (ATR) Inhibitor Tuvusertib (M1774) as Monotherapy
Timothy A Yap1, Anthony W Tolcher2, Ruth Plummer3
1University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (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.
Patients And Methods:
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 (MR) were assessed in circulating tumor DNA samples.
Results:
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 3 (n = 8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180 mg tuvusertib QD (once daily), 2 weeks on/1 week off treatment, which was better tolerated than the MTD (180 mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5 to 3.5 hours and mean elimination half-life from 1.2 to 5.6 hours. Exposure-related PD analysis suggested maximum target engagement at ≥130 mg 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.
Conclusions:
Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.
Insights
Tuvusertib, an ATR inhibitor, showed manageable safety and target engagement in a first-in-human study. Further clinical evaluation of this potent cancer therapy is ongoing.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of DNA damage response.
- ATR inhibitors represent a promising class of targeted cancer therapies.
Purpose of the Study:
- Evaluate the safety, tolerability, and pharmacokinetics of tuvusertib, an ATR inhibitor.
- Determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE).
- Assess preliminary efficacy and pharmacodynamics of tuvusertib monotherapy.
Main Methods:
- First-in-human, dose-escalation study of oral tuvusertib in 55 patients with advanced solid tumors.
- Dose escalation guided by Bayesian logistic regression using safety, PK, and PD data.
- Molecular responses assessed in circulating tumor DNA.
Main Results:
- The RDE was determined to be 180 mg QD, 2 weeks on/1 week off, which was better tolerated than continuous dosing.
- Common grade ≥3 adverse events included anemia (36%), neutropenia, and lymphopenia.
- Tuvusertib demonstrated target engagement and induced molecular responses, particularly in patients with specific gene mutations (ARID1A, ATRX, DAXX).
Conclusions:
- Tuvusertib exhibits a manageable safety profile and dose-dependent target engagement.
- The RDE supports further clinical development of tuvusertib.
- Ongoing studies will further elucidate the therapeutic potential of this ATR inhibitor.
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