tuvusertib (M1774) / EMD Serono - LARVOL DELTA

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

Quantitation of Tuvusertib (M1774) in Human Plasma by LC-MS/MS. (PubMed, Biomed Chromatogr) - "With a stable isotopic internal standard, our assay met the criteria outlined by the Food and Drug Administration guidance for bioanalytical method validation, demonstrating robust performance within the range from 5 to 5000 ng/mL. This assay will support ongoing and future clinical studies by defining tuvusertib pharmacokinetics."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

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. (ASCO 2025) - P2 | "Tumor biopsies, blood, and stool specimens will be profiled to gain integrated insight into transcriptomic, proteomic, and metabolic signatures associated with immune-mediated therapeutic outcomes. This orthogonal approach to solid tumor immunotherapy, relevant to analogous cancers, will guide future combination strategies to better harness the anti-tumor immune response."

Clinical • IO biomarker • Metastases • P2 data • Ataxia • Genetic Disorders • Immunology • Merkel Cell Carcinoma • Movement Disorders • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Primary Immunodeficiency • 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=123 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=72 ➔ 123

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

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 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor

M9466 (HRS-1167): A highly potent and selective PARP1 inhibitor with DNA trapping activity, monotherapy antitumor activity and synergistic potential with DDR inhibitors and chemotherapies (AACR 2025) - P1 | "Currently approved PARP inhibitors (PARPis) such as olaparib, niraparib and talazoparib show synthetic lethality in homologous recombination deficient (HRD) cancers including those with BRCA1/2 mutations...The screen highlighted synergistic activity of M9466 with certain DDR inhibitors (ATR and ATM kinase inhibitors) and with topoisomerase I (Topo I) inhibitors and temozolomide...Here, M9466 enhanced the antitumor efficacy of the ATR inhibitor tuvusertib and the chemotherapy carboplatin. Thus, M9466 has strong single agent synthetic lethal activity in HRD models and combinability with selected DDRis and chemotherapies. Based on these data, Phase I clinical trials are evaluating M9466-based combinations in patients with advanced solid tumors, and colorectal cancer (NCT06421935, NCT06509906)."

Monotherapy • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • HRD • PARP2

Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer (clinicaltrials.gov) - P2 | N=20 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: May 2025 ➔ Jun 2026 | Trial primary completion date: May 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SPOP

Immunogenic modulation with the ATR inhibitor tuvusertib enhances NK-mediated killing of prostate cancer [WITHDRAWN] (AACR 2025) - "Furthermore, tuvusertib treatment increased PD-L1 expression on the DU145 cells, which is associated with enhanced donor NK killing in the presence of avelumab and augmented sensitivity to PD-L1 t-haNK cells.Next, the anti-tumor effect of combining tuvusertib with N-803 (provided by ImmunityBio, Culver City, CA, USA) was investigated. Furthermore, tuvusertib synergized with N-803, resulting in a superior anticancer response. This provides a rationale for further investigation of this combination therapy."

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

Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer (clinicaltrials.gov) - P2 | N=20 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SPOP

Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness (clinicaltrials.gov) - P1/2 | N=58 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2025 ➔ Mar 2027 | Trial primary completion date: Jan 2025 ➔ Mar 2027

Trial completion date • Trial primary completion date • Tumor mutational burden • Ataxia • Colorectal Cancer • Hematological Malignancies • Immunology • Lung Cancer • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor

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=92 | Recruiting | Sponsor: Institut Curie | Trial primary completion date: Sep 2027 ➔ Sep 2028

Trial primary completion date • Oncology • Solid Tumor

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=92 | Recruiting | Sponsor: Institut Curie | Not yet recruiting ➔ Recruiting | Trial completion date: Feb 2029 ➔ Sep 2029 | Initiation date: Jun 2024 ➔ Jan 2025 | Trial primary completion date: Jun 2025 ➔ Sep 2027

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Oncology • Solid Tumor