tuvusertib (M1774) / EMD Serono - LARVOL DELTA

Targeting cyclin K-CDK12 synergizes with ATR inhibition by limiting RPA chromatin loading in triple-negative breast cancer (AACR 2026) - "This impaired ATR activation is further exacerbated when combined with tuvusertib (ATRi), leading to marked DNA damage specifically in replicating cells...Collectively, our work identifies cyclin K-CDK12 as a critical regulator of RPA dynamics and uncovers ATR dependency driven by cyclin K-CDK12 depletion. These insights extend the rationale for cyclin K-CDK12 targeted therapy beyond HR repair-focused applications, supporting its use in RS-high tumors including TNBC, as monotherapy or in combination with ATR inhibition."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK12 • ER • MYC • PRPF19 • TOPBP1

Pathway -targeted combination screening in 3D -spheroids reveals synergistic interactions with everolimus in pancreatic neuroendocrine tumors (ENETS 2026) - " The AKT inhibitor Tuvusertib showed the strongest mo - notherapy effect, although its synergy combined with everolimus was limited. Cytostatic synergy with everolimus was observed with JAK/STAT pathway inhibitors (Conteltinib, Pacritinib) in BON spheroids and with ERK1/2 and PI3K α inhibitors (ASTX029, Gil - melisib) in BON-R spheroids...Cytoto - xic synergy with everolimus was mainly associated with inhibition of the MAPK/ERK pathway, involving ERK inhibitors (Tizaterkib, Ulexertinib) in BON-R spheroids and MEK inhibitors (Binimetinib, Cobimetinib, Trametinib) in both models. High-content 3D spheroid screening integrating NOGR-based growth metrics identified multiple synergistic inter - actions between everolimus and inhibitors targeting interconnec - ted signaling cascades. These findings highlight the potential of rational pathway-targeted combinations to overcome resistance and enhance therapeutic efficacy in pNET, warranting further preclinical investigation to..."

Gastrointestinal Neuroendocrine Tumor • Neuroendocrine Tumor • Oncology • Solid Tumor • PIK3CA

GEINO-2401: Efficacy of Tuvusertib in Recurrent IDH mutant Astrocytoma with ATRX mutation, a phase II prospective trial. (clinicaltrialsregister.eu) - P1/2 | N=56 | Recruiting | Sponsor: Grupo Espanol De Investigacion En Neurooncologia

New P1/2 trial • Astrocytoma • Brain Cancer • Oncology • Solid Tumor • ATRX • CDKN2A • TP53

TUVASTRAT: Tuvusertib in Astrocytoma With ATRX Mutation (clinicaltrials.gov) - P2 | N=56 | Recruiting | Sponsor: Grupo Español de Investigación en Neurooncología

New P2 trial • Astrocytoma • Brain Cancer • Oncology • Solid Tumor • ATRX • CDKN2A • TP53

Comparing and combining xevinapant with ATR and PARP inhibition for the radiosensitization of HPV-negative HNSCC cells. (PubMed, Sci Rep) - "Both tuvusertib and olaparib induced stronger radiosensitization than xevinapant and combining both agents resulted in especially profound radiosensitization in three out of the four cell lines tested, whereas their combination with xevinapant or the combination of xevinapant with cisplatin was less effective. Assessment of cell death induction via annexin V/DAPI staining failed to generally predict cytotoxicity or radiosensitization of these approaches. Overall, our data are in line with the recent failure of the phase 3 TrilynX trial and suggest further investigation of ATR and PARP inhibition for the curative treatment of HPV-negative HNSCC."

Clinical • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2028 ➔ Jun 2026 | Trial primary completion date: Jan 2028 ➔ Sep 2025

Trial completion date • Trial primary completion date • Breast Cancer • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD

An Integrated Nonclinical and Clinical Risk Assessment of the Effects of Investigational ATRi Tuvusertib on QTc Interval in Patients With Solid Tumors. (PubMed, Clin Transl Sci) - "There was no relationship between tuvusertib plasma concentration and RR interval, suggesting no effect on HR. Early integrated concentration-QTc assessments of tuvusertib monotherapy in Phase I were crucial in informing the low risk for clinically relevant QTc prolongation, thereby facilitating efficient evaluation of investigational tuvusertib combination strategies in ongoing clinical development."

Journal • Cardiovascular • Oncology • Solid Tumor

DDRiver Solid Tumours 301: Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301) (clinicaltrials.gov) - P1 | N=161 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2026 ➔ Jan 2027 | Trial primary completion date: Jan 2026 ➔ Jan 2027

First-in-human • Trial completion date • Trial primary completion date • Solid Tumor • ARID1A • ATRX

POP-ART: A Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=10 | Terminated | Sponsor: Institut Curie | N=92 ➔ 10 | Trial completion date: Sep 2029 ➔ Nov 2025 | Recruiting ➔ Terminated | Trial primary completion date: Sep 2028 ➔ Nov 2025; Although no safety signal has been observed, given that the industrial development of tuvusertib has been halted regardless of the results, we see no scientific and ethical justification for continuing the study

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Solid Tumor

M9466 Alone or in Combination in Advanced Solid Tumors (DDriver 501) (clinicaltrials.gov) - P1 | N=141 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Solid Tumor

The ATR inhibitor tuvusertib (M1774) sensitizes prostate carcinoma to natural killer cell-mediated cytotoxicity, which is further augmented by the IL-15 receptor superagonist N-803. (PubMed, Cancer Immunol Immunother) - "Enhanced avelumab-mediated antibody-dependent cell-mediated cytotoxicity and lysis by PD-L1 targeting high-affinity NK (PD-L1 t-haNK) cells were observed in tuvusertib-treated DU145. In vivo in the DU145 PCa xenograft model, tuvusertib and N-803 combination therapy demonstrated marked and significant antitumor efficacy relative to either monotherapy, eliciting superior tumor growth control and prolonging survival. Our findings support further investigation into the use of ATRi with immune checkpoint blockade and/or immune-stimulating agents in prostate cancer."

Journal • Ataxia • Genito-urinary Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Prostate Cancer • Solid Tumor • BCL2L1 • CDKN1A • IL15 • NKG2D • TNFRSF10B

ATR inhibitor tuvusertib induces immunogenic modulation and sensitizes prostate carcinoma to natural killer cell-mediated cytotoxicity which is further enhanced by the IL-15 superagonist N-803 (SITC 2025) - "Impedance-based real-time cell analysis was used to assess the lysis of tuvusertib-treated PCa cells upon co-incubation with PBMC-derived NK cells in the presence or absence of anti-PD-L1 avelumab, PD-L1 targeting high-affinity NK cell line (PD-L1 t-hANK) cells, or TRAIL ligand. TRAIL signaling blockade mitigated the NK cell lysis of tuvusertib-treated cells. In vivo, tuvusertib and N-803 combination therapy resulted in the significant tumor growth control of the DU145 xenograft (p<0.0001) and the prolonged survival of the animals (p<0.05).Conclusions This study supports the combination of the ATR inhibitor tuvusertib with the anti-PD-L1 avelumab and/or IL-15 superagonist N-803 for prostate carcinoma.Acknowledgements This work was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health and via Cooperative Research and Development Agreements (CRADAs) between the NCI and the..."

IO biomarker • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • CDKN1A • TNFRSF10B

The MATRiX trial: A multicenter, randomized, phase II study of ATR inhibition (via tuvusertib) with or without avelumab in patients with advanced anti-PD-(L)1-refractory Merkel cell carcinoma (SITC 2025) - P2 | "EDDOP Leadership Award-P30 Administrative Supplement, the Mark Foundation for Cancer Research, the Kelsey Dickson Team Science Courage Research Team Award, and the MCC Patient Gift Fund. This study is financially supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755), which provides avelumab and tuvusertib.Trial Registration NCT05947500Ethics Approval The study is reviewed by NCI's Central Institutional Review Board; approval number is 10592.Abstract 599 Figure 1Request permissionsAn overview of the multicenter, NCI-sponsored Phase II study designed to test the efficacy of tuvusertib, with or without avelumab, to address anti-PD-(L)1 resistance in advanced, refractory MCC; NCT05947500">NCT05947500Abstract 599 Figure 2Request permissionsTimeline of treatment regimen and biospecimen acquisition for patients randomized to arm 1 and 2"

Clinical • IO biomarker • Metastases • P2 data • Endocrine Cancer • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Tuvusertib (M1774) Human Mass Balance and Absolute Bioavailability Study (DDRIVER Solid Tumors 303) (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Recruiting ➔ Active, not recruiting

Enrollment closed • Solid Tumor

Phase I/II study of tuvusertib, an ATR inhibitor in combinaison with fulvestrant in hormone receptor-positive and HER2-negative, advanced breast cancers, resistant to CDK4/6 inhibitors plus aromatase inhibitor-based endocrine treatments and in various molecular contexts (MATRIx) (ESMO 2025) - P1/2 | "In the phase I part (n=3-12), tuvusertib will be administrated at doses of 130 mg QD to 180 mg QD orally 2 weeks on/1 week off with 500 mg fulvestrant IM on days 1, 15, 29, and once monthly thereafter, dose-escalation being guided by a 3+3 design. In the phase II part, tuvusertib will be administered at the R2PD in combination with fulvestrant in 45 patients across 3 molecularly-defined cohorts: Germline or somatic BRCA1, BRCA2 or PALB2 mutations, resistance to PARP inhibitors (cohort 1), germline or somatic alteration of other HRD genes (cohort 2), oncogenic driver alterations associated with replication stress (cohort 3)."

Metastases • P1/2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • CCNE1 • ER • HER-2 • HRD • PALB2

Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial (clinicaltrials.gov) - P2 | N=50 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Study of Tuvusertib (M1774) in Combination With DNA Damage Response Inhibitor or Immune Checkpoint Inhibitor (DDRiver Solid Tumors 320) (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Checkpoint inhibition • dMMR • Enrollment closed • IO biomarker • Colorectal Cancer • Endometrial Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting | N=130 ➔ 63

Enrollment change • Enrollment closed • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Integrated Population Pharmacokinetic, Pharmacodynamic, and Safety Analyses to Inform Dosage Selection in the Clinical Development of the ATR Inhibitor Tuvusertib. (PubMed, Clin Pharmacol Ther) - P1 | "The analysis supports tuvusertib 180 mg QD 2w on/1w off as the RDE and 100 mg QD as the no-regret dose for clinical evaluation. This example underscores the value of integrated quantitative pharmacology analyses to inform dose selection using a totality of evidence approach."

Journal • PK/PD data • Hematological Disorders • Oncology • Solid Tumor • ARID1A

Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer (clinicaltrials.gov) - P2 | N=20 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Active, not recruiting

Enrollment closed • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SPOP

M9466 Alone or in Combination in Advanced Solid Tumors (DDriver 501) (clinicaltrials.gov) - P1 | N=141 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=96 ➔ 141 | Trial completion date: Mar 2026 ➔ Feb 2027 | Trial primary completion date: Mar 2026 ➔ Feb 2027

Enrollment change • Trial completion date • Trial primary completion date • Solid Tumor

Tuvusertib (M1774) in Combination With Cemiplimab in Participants With Non-Squamous NSCLC (DDRiver NSCLC 322) (clinicaltrials.gov) - P1/2 | N=61 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial primary completion date: May 2025 ➔ Mar 2026

Trial primary completion date • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tuvusertib Combined With Niraparib or Lartesertib in Participants With Epithelial Ovarian Cancer (DDRiver EOC 302) (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=60 ➔ 130

Enrollment change • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

Tuvusertib (M1774) Human Mass Balance and Absolute Bioavailability Study (DDRIVER Solid Tumors 303) (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Trial completion date: Nov 2025 ➔ Mar 2026 | Trial primary completion date: Nov 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Solid Tumor