berzosertib (M6620) / Vertex, EMD Serono - LARVOL DELTA

Comparative analysis of molecular targeted radiosensitizers in 2D and 3D cancer cell line models. (PubMed, Acta Oncol) - "Integrating multiple culture models enhances the detection of cell line - and drug-specific radiosensitization. Although 2D and 3D cultures produced largely similar results, and 2D assays provide a practical alternative when 3D methods are not feasible, the 3D cultures reveal additional ECM-dependent responses. These results emphasize the utility of physiologically relevant platforms for robust screening and prioritization of candidate radiosensitizers."

Clinical • Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor

NCI 10211: A Phase II, Single-Arm Study of Berzosertib in Combination with Irinotecan in Patients with Advanced TP53 Mutant Gastroesophageal Cancer. (PubMed, Oncologist) - P2 | "This novel combination of ATR inhibitor berzosertib with irinotecan did not lead to objective responses in patients with TP53-mutated, advanced gastroesophageal adenocarcinoma. The combination regimen was well tolerated without unexpected adverse events. This trial was registered with ClinicalTrials.gov (NCT03641313)."

Journal • P2 data • Ataxia • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Hematological Disorders • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • TP53

Prognostic alternative mRNA splicing in lung adenocarcinoma. (PubMed, Front Oncol) - "Molecular docking identified YM-201636 and VE-822 (Berzosertib) as potential drugs targeting CDKN2A, both showing promise for LUAD treatment in vivo. PASEs constitute a comprehensive biomarker for predicting prognosis and monitoring the TIME in LUAD patients. Specifically, CDKN2A stands out as a potential prognostic biomarker and drug target for LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • CDKN2A

IDENTIFICATION OF A DNA REPAIR INHIBITOR FOR THE COMBINATION WITH LURBINECTEDIN AND RADIOTHERAPY IN SARCOMA CELL LINES (CTOS 2025) - "Objective: Improved multimodal treatment could optimize therapeutic outcomes for sarcoma patients. Our preclinical data suggest that the combination of LU with RT has no sensitizing effect compared to LU treatment alone in sarcoma cell lines. However, combining LU and IR with DNA repair inhibitors such as the ATRi VE-822 is a promising way to improve sarcoma treatment."

Preclinical • Fibrosarcoma • Liposarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Synovial Sarcoma • ANXA5

Phase Ib study of berzosertib, carboplatin, gemcitabine, and pembrolizumab in patients with squamous non-small lung cancer (ETCTN 10313). (PubMed, Oncologist) - P1/2 | "In newly diagnosed advanced squamous NSCLC, berzosertib 135 mg/m2, carboplatin AUC 4, gemcitabine 800 mg/m2 and pembrolizumab 200 mg was the RP2D, which was both tolerable and associated with activity. This study did not proceed to phase II upon discontinuation of berzosertib development. Clinicaltrials.gov Identifier: NCT04216316."

Journal • P1 data • Hematological Disorders • Leukopenia • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia

Identification of Epigenetic Modifiers Essential for Growth and Survival of AML1/ETO-Positive Leukemia (ASH 2023) - "Materials and methodsIn the customized shRNA library screen, 2009 shRNAs developed to target 671 genes were pool-cloned into a retroviral vector allowing doxycycline-inducible expression to generate a plasmid shRNA library (Antonova et al...We validated, genetically and pharmacologically, DNMT1 and ATR using several AML1/ETO-positive (SKNO-1, Kasumi-1) and AML1/ETO-negative cell lines (OCI-AML3, HL60) with median IC50 for decitabine 74 nM (range 44-219), azacytidine 146 nM (range 14-267), berzosertib 219 nM (range 16-460) and ceralasertib 85 nM (range 42-328)...Some of these epigenetic regulators, such as DNMT1 and ATR, are susceptible to pharmacological inhibition by small molecules showing promising preclinical and clinical efficacy, and confirmation studies (Baeten et al. , ASH meeting 2022) appear warranted."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • HDAC8 • KMT5A • PARP2 • RUNX1 • RUNX1T1 • SETD1A • SMARCA4 • SMYD2

TP53 Aberrant B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Are Uniquely Sensitive to a Combination of Pyrimidine De Novo Synthesis Blockade and Replication Checkpoint Inhibition (ASH 2023) - "Preliminary results from in vivo experiments using p53 deficient patient derived xenografts indicate that the combination of Orludodstat and Berzosertib is well tolerated, while significantly delaying leukemic growth (Figure 1 B). ConclusionTogether, our findings suggest that the combined targeting of de novo pyrimidine synthesis and ATR signaling may present a specific and non-genotoxic vulnerability for TP53 aberrant ALL."

Checkpoint inhibition • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • CHEK1 • TP53

STING pathway activation enhances anti-tumor immune responses and therapeutic efficacy of DNA damage repair inhibition (SITC 2025) - "Interestingly, ATRi also led to significant induction of MHC class I in SCLC in vitro and in vivo models.Analysis of pre- and post-treatment clinical samples from a proof-of-concept study of a first-in-class ATR inhibitor, M6620 (VX970, berzosertib), and TOP1 inhibitor topotecan, in patients with relapsed SCLCs, validated the induction of MHC class I and interferon pathway genes, for the first time in this disease. Single-cell analysis of patient samples revealed how ATR inhibition modulated antigen presentation and confirmed the immunosuppressed phenotype in SCLC.Conclusions Our findings highlight ATRi as a potentially transformative vulnerability of SCLC, paving the way for combination clinical trials with anti-PD-L1. Given the increasing importance of immunotherapy for the management of SCLC and the fact that ATR inhibitors are already in clinical trials, combining an ATR inhibitor with PD-L1 blockade may offer a particularly attractive strategy for the treatment of..."

Clinical • IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • TOP1

Phase 1 clinical trial of the ataxia telangiectasia and Rad3-related inhibitor berzosertib with irinotecan in patients with advanced solid tumors (ETCTN 9938). (PubMed, Cancer) - P1 | "Berzosertib 270 mg/m2 and irinotecan 180 mg/m2 was the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors."

Journal • P1 data • Ataxia • Colorectal Cancer • Febrile Neutropenia • Hematological Disorders • Immunology • Movement Disorders • Neutropenia • Oncology • Pancreatic Cancer • Primary Immunodeficiency • Solid Tumor • ATM • ATR

A novel theranostic approach targeting ATM-deficient pancreatic ductal adenocarcinoma (PDAC) using 177Lu-labeled anti–TRA-1-60 Free (AACRPanCa 2025) - "While the combination of TRA RPT with olaparib (PARPi) (p = 0.00025) also suppressed tumor growth compared to WT, it did not provide a statistically significant benefit over TRA RPT treatment alone. Notably, combining TRA RPT with the ATR inhibitor berzosertib resulted in a pronounced delay in tumor growth in AsPC1 ATM KO models, showing a significant improvement compared to TRA RPT alone. These results highlight the promise of combining TRA RPT with DDR-targeted therapies to improve treatment in DDR-deficient PDAC. Identifying effective drug combinations may be key to better patient outcomes and advancing personalized therapies, especially for cases with DDR mutations."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ATM • TRA

NCI-2015-01779: Testing the Safety of M6620 (VX-970) When Given With Standard Whole Brain Radiation Therapy for the Treatment of Brain Metastases From Non-small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2025 ➔ Sep 2026

Trial completion date • Endocrine Cancer • Lung Cancer • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

TARSARC: Targeting ATR in Soft-tissue Sarcomas (clinicaltrials.gov) - P2 | N=72 | Recruiting | Sponsor: Institut Bergonié | Trial completion date: Apr 2026 ➔ Dec 2027 | Trial primary completion date: Oct 2024 ➔ Jun 2026

Trial completion date • Trial primary completion date • Leiomyosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Therapeutic Strategies Using BRAF and ATR Inhibitors for drug-resistant BRAF-Mutated Poorly Differentiated and Anaplastic Thyroid Cancers (ATA 2025) - "The FDA-approved drug combination dabrafenib and trametinib is initially an effective treatment, but most patients progress over time. This will prevent cellular senescence and apoptosis. Thus, combination treatments of dabrafenib with an ATR inhibitor such as berzosertib, might be useful to prevent or eliminate drug resistance in aggressive thyroid cancer cells and other BRAF-mutated solid tumors."

Late-breaking abstract • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF • PARP1 • TP53

Machine learning-based characterization of a PANoptosis-associated model for enhancing prognosis and immunotherapy response in lung adenocarcinoma patients. (PubMed, Discov Oncol) - "The present study developed a PRS using 101 machine learning combination algorithms, which could aid in risk stratification and prognosis for LUAD patients. The candidate drugs and target may provide new insights in the treatment of high PRS group patients."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TRPA1

Inhibiting the DNA damage repair of HNSCC cells in combination with normo-fractionated radiotherapy influences clonogenicity, senescence and expression of NK cell activation markers. (PubMed, Sci Rep) - "We used AZD0156, an ATM inhibitor, and VE-822, an ATR inhibitor, in combination with normo-fractionated RT to treat two HPV-positive and two HPV-negative HNSCC cell lines. In co-culture with NK cells, an upregulation of activation markers on NK cells was observed, particularly after contact with RT + ATMi-treated HPV-negative HNSCC cells. We conclude that ATM inhibitor-related induction of senescence in HNSCC cells shapes the tumor micro-environment in way that NK cell phenotype is changed."

Journal • Ataxia • Head and Neck Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CXCL8 • IL6

Homologous Repair-Deficient Pancreatic Cancer: Refined Targeting of DNA Damage Response is an Effective Therapeutic Strategy. (PubMed, United European Gastroenterol J) - "Here, we demonstrate a remarkable potency of the PARPi talazoparib in HRD PDAC. Substituting olaparib, currently the only approved inhibitor in PDAC, with talazoparib in our PAD regimen enhanced its efficacy while maintaining comparable tolerability in vivo. Importantly, we show that PAD is an effective therapeutic regimen that can be extended to the most prevalent HR-defective genotypes in PDAC including ATM, BRCA1, BRCA2 and PALB2 in a preclinical setting. Collectively, these data provide a strong rationale to implement the refined regimen, talazoparib-based PAD, as a therapeutic concept tailored for HRD PDAC patients."

Journal • Breast Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRCA1 • BRCA2 • PALB2

Gemcitabine Hydrochloride Alone or With M6620 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2025 ➔ Aug 2026

Platinum resistant • Trial completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

Evaluation of pleural mesothelioma sensitivity to targeted DNA damage response inhibitors (EACR 2025) - "Long-term cell proliferation assays lasting 7 to 15 days were conducted using various concentrations of the following DDR inhibitors: berzosertib and ceralasertib (ATR inhibitors), AZD0156 (an ATM inhibitor), olaparib (a PARP inhibitor), adavosertib (a WEE1 inhibitor), and rabusertib (a CHEK1 inhibitor). These results represent a preclinical rationale for designing clinical trials with DDR for MPM patients."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Sarcoma • Solid Tumor • BAP1 • RAD51

Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C. (EACR 2025) - "We tested whether inhibitors of the DNA damage response (DDR) could prevent recurrence in an in vitro HIPEC model.Material and Peritoneal metastasis-derived organoids (PMDOs; n=10) were treated with inhibitors of ATR (berzosertib, ceralasertib, elimusertib), CHK1 (rabusertib), and WEE1 (adavosertib) alone, and in combination with MMC, oxaliplatin, or irinotecan. PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may, therefore, have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC."

Colorectal Cancer • Oncology • Solid Tumor • CHEK1

Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia-Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors. (PubMed, JCO Precis Oncol) - "This combination shows antitumor activity, including in patients with and without homologous recombination-compromised tumors and those previously treated with platinum. Adding berzosertib further increases the DDR response elicited by combination cisplatin/veliparib treatment in BRCA-wildtype patients, indicating increased replication stress at the RP2D/MTD."

Journal • Ataxia • Hematological Disorders • Immunology • Leukopenia • Movement Disorders • Neutropenia • Oncology • Primary Immunodeficiency • Solid Tumor • Thrombocytopenia • BRCA • RAD51

Testing the Addition of an Anti-cancer Drug, Berzosertib, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2025 ➔ Apr 2026 | Trial primary completion date: Nov 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR

Identification of hub gene associated with colorectal cancer: Integrating Mendelian randomization, transcriptome analysis and experimental verification. (PubMed, PLoS Genet) - "FUT8 is a crucial gene that causes colon cancer and is linked to tumour immunity. VE-822 is a promising candidate for treating CRC by targeting FUT8."

Journal • Tumor mutational burden • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • FUT8 • TMB

Berzosertib and Irinotecan in TP53 Mutant Gastric or Gastroesophageal Junction Cancer (clinicaltrials.gov) - P2 | N=19 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=14 ➔ 19

Enrollment change • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • HER-2 • MSI • TP53

Comprehensive machine learning analysis of PANoptosis signatures in multiple myeloma identifies prognostic and immunotherapy biomarkers. (PubMed, Sci Rep) - "Drug sensitivity analysis revealed heightened sensitivity to cyclophosphamide, Sinularin, Wee1 inhibitor, osimertinib, JQ1, VE-822, and AZD6738 in high-risk patients. Furthermore, CCK-8 assays and Wright-Giemsa staining confirmed the crucial role of PARP1 in regulating MM cell viability. This PANoptosis-based prognostic model provides a valuable tool for predicting MM prognosis and guiding personalized treatment."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Hematological Malignancies • Multiple Myeloma • Oncology • CASP3 • IGF2BP1 • LY96 • PARP1 • TMB • ZBP1

Synergistic Effects of ATR Inhibition and Lurbinectedin in Soft-Tissue Sarcomas: The Predictive Role of SLFN11 Expression. (PubMed, Clin Cancer Res) - "This study highlights the potential of combining lurbinectedin with ATR inhibitors in STS treatment and validates SLFN11 as a predictive biomarker for this combination therapy. These findings support further clinical evaluation of this therapeutic strategy in STS patients."

Journal • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma • SLFN11