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

Abstract

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.

Figure 1.

Patient disposition. Bold box indicates recommended dose for expansion (RDE). ^aOne patient had a small bowel obstruction requiring surgery, and another initially met all eligibility criteria, but low hemoglobin later made them ineligible; ^bOne patient in dose cohort not evaluable for DLTs; ^cMTD declared; ^dRDE declared; ^eAnemia grade 2 requiring transfusion; ^fAnemia grade 3 requiring transfusion; ^gAnemia grade 3 requiring transfusion (n = 1), upper gastrointestinal hemorrhage grade 3 and platelet count decreased (n = 1); ^hAnemia grade 2 (n = 1), Anemia grade 3 (n = 2), all requiring transfusion; ⁱPatients were treated until disease progression or death; BID, twice daily; DLT, dose-limiting toxicity; MTD, maximum-tolerated dose; QD, once daily; RDE, recommended dose for expansion; TEAE, treatment emergent adverse event; 2 w/1 w, 2 weeks on treatment/1 week off treatment; 4 d/3 d, 4 days on treatment/3 days off treatment.

Figure 2.

A, Clinical responses and tuvusertib dose levels, and molecular responses in patients treated with tuvusertib doses <130 and ≥130 mg (B). A, Change in target lesion sum of longest diameters and best response (RECIST v1.1) is shown per patient. B, MRs are enriched in patients treated with biologically active doses of ≥130 mg tuvusertib. Reduction of somatic allele frequencies from baseline by more than 50% is highlighted in blue. TP53 mutation status (red) is shown below. BID, twice daily; MR, molecular response; NE, not evaluable; PD, progressive disease; QD, once daily; RECIST, response evaluation criteria in solid tumours; SD, stable disease.

Figure 3.

Mean steady-state tuvusertib plasma concentration–time profiles during cycle 1. 2 w/1 w, 2 weeks on treatment/1 week off treatment; 4 d/3 d, 4 days on treatment/3 days off treatment; BID, twice daily; QD, once daily.

Figure 4.

Aggregated data grouped by single tuvusertib dose levels for NK cells (A) and monocytes (B). For each parameter, measurements obtained at each visit are grouped by dose level. Each graph visualizes the relative change (% RC) from the baseline of each measurement. C, cycle; D, day; MDSC, myeloid-derived suppressor cells; NK, natural killer; QD, once daily.