Tuvusertib

Shows activity

Also known as:

M1774 VXc-400 VRT-1363004 MSC2584415A +2 more

Cancer types include:

colon cancer ovarian cancer prostate cancer rectal cancer uterine cancer

HealthScout AI Analysis

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Overview

Tuvusertib (M1774; also known as VXc‑400, VR‑1363004/VRT‑1363004, MSC2584415A) is an oral, selective inhibitor of the DNA damage response kinase ATR under clinical investigation across solid tumors, often in biomarker-enriched cohorts and in combination with other DNA damage response agents. A first‑in‑human (FIH) phase I study in advanced solid tumors established a recommended dose for expansion (RDE) and reported preliminary antitumor activity. Multiple combination studies are ongoing, including with a PARP inhibitor (niraparib), a DNA‑PK inhibitor (lartesertib/M4076), another DNA‑PK inhibitor (peposertib/M3814), a TOP1 inhibitor (PLX038), and an anti‑PD‑1 antibody (cemiplimab). (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Target: ATR (ataxia telangiectasia and Rad3‑related), a serine/threonine kinase that coordinates the cellular response to replication stress and single‑strand DNA breaks via checkpoint signaling (e.g., CHK1). Inhibition of ATR can induce replication catastrophe and apoptosis, particularly in tumors with defects in homologous recombination or chromatin remodeling (e.g., ARID1A). (pubmed.ncbi.nlm.nih.gov)
Preclinical characterization: Tuvusertib suppressed cancer cell viability at nanomolar concentrations, blocked ATR–CHK1 signaling, and showed broad synergy with DNA‑damaging agents (including TOP1 inhibitors). Proteomic analyses suggested that ATR blockade with tuvusertib forces replication and G2–M progression programs, enhancing cytotoxicity when combined with DNA‑targeted drugs. (aacrjournals.org)

Efficacy

Monotherapy (FIH, NCT04170153; 55 patients with metastatic/unresectable solid tumors):
One patient with platinum‑ and PARP inhibitor–resistant, BRCA‑wild‑type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response. Molecular responses in circulating tumor DNA were frequent in the predicted efficacious dose range and included complete molecular responses in ARID1A, ATRX, and DAXX mutations; molecular responses were enriched among patients with radiologic disease stabilization. Objective response rate beyond the single unconfirmed PR was not reported. (pubmed.ncbi.nlm.nih.gov)
Combination with niraparib (phase Ib, ASCO 2024 abstract, Part B1 of NCT04170153):
Recommended doses identified (1 week on/1 week off schedules): tuvusertib 180 mg QD + niraparib 100 mg QD, or tuvusertib 90 mg QD + niraparib 200 mg QD. The abstract focused on dose finding and tolerability; objective response data were not reported. A randomized phase 2 study in PARP inhibitor–pretreated epithelial ovarian cancer (EOC) is ongoing (DDRiver EOC 302; NCT06433219). (ascopubs.org)
Other ongoing combinations (early phase; efficacy results not yet available as of October 7, 2025):
With lartesertib (ATM/DNA‑PK inhibitor) or niraparib in HRD‑positive/BRCA‑mutant EOC after prior PARPi (randomized phase 2; NCT06433219). (ichgcp.net)
With peposertib (DNA‑PK inhibitor) in genomically defined solid tumors (phase 1; NCT05687136). (cdek.pharmacy.purdue.edu)
With PLX038 (pegylated SN‑38; TOP1 inhibitor) in advanced solid tumors (phase 1; NCT06337630). (ichgcp.net)
With cemiplimab (anti‑PD‑1) in advanced non‑squamous NSCLC (phase 1b/2a design poster). (education.iaslc.org)

Safety

Monotherapy (FIH, NCT04170153): The most common grade ≥3 treatment‑emergent adverse events were anemia (36%), neutropenia (7%), and lymphopenia (7%). Eleven patients experienced dose‑limiting toxicities, most commonly grade 2–3 anemia requiring transfusion. No persistent detrimental effects on peripheral T‑ and B‑cell populations were observed in immunophenotyping. The maximum tolerated dose (continuous 180 mg QD) was less well tolerated than the RDE (180 mg QD, 2 weeks on/1 week off). Median Tmax 0.5–3.5 h; mean half‑life 1.2–5.6 h. (pubmed.ncbi.nlm.nih.gov)
Combination with niraparib (ASCO 2024 dose‑finding): The combination on an intermittent 1‑week‑on/1‑week‑off schedule had a “manageable safety profile,” and two RDEs were declared as above; detailed adverse event rates were not provided in the abstract. (ascopubs.org)

Active trials using Tuvusertib

Found 4 active trials using this drug:

A Phase 2 Study of Avelumab in Combination With ATR Inhibitor M1774 in Patients With ARID1A-mutated Recurrent Endometrial Cancer Who Have Received Prior Immunotherapy

Sponsor: Panagiotis Konstantinopoulos, MD, PhD (other) Phase: 2 Start date: Nov. 14, 2024

HealthScout AI summary: Enrolling adults with recurrent endometrial cancer harboring ARID1A loss‑of‑function mutations who have previously received PD‑1/PD‑L1 therapy; prior chemotherapy required, ECOG 0–2. Single-arm treatment is avelumab (anti–PD‑L1 mAb) plus M1774/tuvusertib, an oral ATR kinase inhibitor targeting DNA damage response to exploit synthetic lethality in ARID1A‑mutant tumors.

ClinicalTrials.gov ID: NCT06518564

An Open Label, Multicenter, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of the PARP1 Inhibitor M9466 Alone or in Combination in Participants With Advanced Solid Tumors

Sponsor: EMD Serono Research & Development Institute, Inc. (industry) Phase: 1 Start date: Aug. 7, 2024

HealthScout AI summary: Adults with advanced solid tumors, including cohorts for mCRPC/mHSPC and EOC, eligible after or unsuitable for standard therapy (ECOG 0–1), receive the oral, selective PARP1 inhibitor M9466 as monotherapy, combined with the ATR inhibitor tuvusertib, or combined with abiraterone/prednisone for prostate cancer. Aims include safety/PK and preliminary activity, with particular interest in HRR/HRD tumors and potential synergy with ATR inhibition.

ClinicalTrials.gov ID: NCT06421935

A Phase 1B Study of Combination ATR (M1774) and BET Inhibition (ZEN00-3694) to Exploit ARID1A Loss in Recurrent Ovarian and Endometrial Cancer

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1 Start date: Dec. 18, 2023

HealthScout AI summary: Adults with recurrent clear cell or endometrioid ovarian carcinoma, platinum‑resistant HGSOC (dose‑escalation only), or recurrent FIGO grade 1 endometrioid/clear cell endometrial carcinoma receive oral tuvusertib (ATR inhibitor) plus ZEN‑3694 (pan‑BET inhibitor), with biomarker‑driven expansion enrolling both ARID1A‑mutated and ARID1A‑wild‑type cohorts. Aims include defining RP2D and assessing safety and preliminary activity, with mandated biopsies to explore pharmacodynamic effects and ARID1A‑related response.

ClinicalTrials.gov ID: NCT05950464

A Phase 1/2 Trial Evaluating the Combination of Temozolomide and the Ataxia Telangiectasia and Rad3-Related Inhibitor M1774

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1/2 Start date: Sept. 28, 2023

HealthScout AI summary: This trial enrolls adults with advanced metastatic solid tumors—particularly those with MGMT promoter hypermethylation or for whom temozolomide is standard therapy—and evaluates the combination of oral temozolomide with tuvusertib (M1774), a selective ATR kinase inhibitor that targets the DNA damage response pathway. The phase 2 focus is on patients with mismatch repair proficient/microsatellite stable colorectal cancer with MGMT promoter hypermethylation.

ClinicalTrials.gov ID: NCT05691491