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

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 2026 ➔ Aug 2027

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

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

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial. (PubMed, JAMA Oncol) - P2 | "However, the combination treatment significantly improved OS. ClinicalTrials.gov Identifier: NCT03896503."

Clinical • Journal • Ataxia • Hematological Disorders • Immunology • Lung Cancer • Movement Disorders • Oncology • Primary Immunodeficiency • Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia • ATR

Diosgenin enhances 5-fluorouracil sensitivity in drug-resistant colorectal cancer cells via inhibition of ATR/Chk1-mediated DNA damage response. (PubMed, Cancer Treat Res Commun) - "The findings of this study suggest that diosgenin may contribute to reducing 5-FU resistance by affecting ATR/CHK1-associated DNA damage response mechanisms, weakening DNA repair mechanisms, and suppressing drug efflux pumps. The combination of diosgenin with an ATR inhibitor may have a strong combined effect in inducing DNA damage, inhibiting drug resistance, and promoting apoptosis-associated molecular changes. This combination approach may represent a potential chemosensitizing approach for further investigation in colorectal cancer; however, additional validation in diverse models and in vivo studies is required."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • ABCB1 • ABCC1 • ABCG2 • BCL2 • CASP3 • CHEK1 • H2AX

Randomized phase 2 study of gemcitabine with or without ATR inhibitor berzosertib in platinum-resistant ovarian cancer: Final overall survival (OS) and biomarker analyses. (ASCO 2023) - P2 | "In the ITT population, gemcitabine/berzosertib did not significantly improve OS versus gemcitabine alone. Pts with PFI≤3 months and pts with RS-low tumors may derive a survival advantage from addition of berzosertib to gemcitabine in the platinum-resistant setting. Clinical trial information: NCT02595892."

Biomarker • Clinical • P2 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

ATR inhibitors synergise with mitomycin C to enhance cytotoxicity in patient-derived non-muscle invasive bladder cancer organoids. (PubMed, Br J Cancer) - "This study demonstrates synergy between ATR inhibitors and chemotherapy in NMIBC PDOs. Combining intravesical chemotherapy instillations with DNA damage response inhibitors should be further evaluated as a promising strategy to reduce recurrence rates for NMIBC."

Journal • Ataxia • Bladder Cancer • Genito-urinary Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. (PubMed, Lancet Oncol) - P2 | "To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting."

Clinical • Journal • P2 data • Gynecologic Cancers • Infectious Disease • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pneumonia • Septic Shock • Solid Tumor

Targeting genomic instability in extrapulmonary small cell neuroendocrine cancers: A phase II study with ATR inhibitor berzosertib and topotecan. (ASCO 2022) - P1/2 | "Combination of berzosertib and topotecan is a novel therapeutic paradigm for patients with EP-SCNCs. Both SCLCs and EP-SCNCs responding to this approach show a similar transcriptional phenotype characterized by high replication stress."

IO biomarker • P2 data • Ataxia • Breast Cancer • Endocrine Cancer • Immunology • Lung Cancer • Movement Disorders • Neuroendocrine Tumor • Oncology • Primary Immunodeficiency • Small Cell Lung Cancer • Solid Tumor • CCND1 • KRAS

Mechanistic insights into phosphorylation-driven activation and therapeutic inhibition of human ATR-ATRIP. (PubMed, Nat Struct Mol Biol) - "Here, we present high-resolution cryo-electron microscopy structures of the human ATR-ATRIP complex in distinct functional states, including two ATPγS-bound precatalytic states, a Chk1-bound catalytic state, a TopBP1-bound activated catalytic state and four inhibitor-bound states with gartisertib, berzosertib, ceralasertib and elimusertib. In addition, inhibitor-bound structures reveal how potent and selective ATR inhibition is achieved through multipocket engagement and exploitation of active-site conformational plasticity. Together, our findings provide a structural framework for understanding multiple routes of ATR activation and inhibition, offering insights for developing next-generation ATR-targeted cancer therapies."

Journal • Oncology • CHEK1 • TOPBP1

ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer (AACR 2022) - P1/2 | "A trial testing the combination of lurbinectedin and doxorubicin failed to improve survival compared with standard-of-care. Conversely in a non-NE low p21 mouse model, lurbinectedin treatment alone was less effective, however the addition of berzosertib was synergistic and significantly improved efficacy. Overall, this work demonstrated berzosertib augments lurbinectedin efficacy in the recalcitrant non-NE SCLC subsets, and supported the development of a clinical trial testing lurbinectedin and berzosertib in SCLC patients NCT04802174."

Clinical • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • CDKN1A • ERCC5

Effects of ATR Inhibition in Small Cell Lung Cancer Differ According to Transcription Factor-Defined Subtype (IASLC-WCLC 2026) - "Representative SCLC cell lines corresponding to each subtype were used to evaluate the antitumor effects of the ATR inhibitor VE-822...The observed heterogeneity in treatment response across subtypes supports the clinical relevance of transcription factor-based classification for therapeutic stratification. These findings provide a biological rationale for incorporating subtype-based patient selection in future clinical trials of ATR inhibitors and highlight a potential path toward personalized treatment strategies in SCLC."

Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • NEUROD1 • POU2F3

ATR inhibition enhances radiosensitivity in p53-deficient colorectal cancer cells. (PubMed, Discov Oncol) - "We investigated whether inhibition of ataxia telangiectasia and Rad3-related (ATR) kinase by VE-822 (berzosertib) enhances radiation response and whether p53 status is associated with the magnitude of response...Increased phospho-Histone H3 positivity after combined treatment was consistent with increased mitotic entry. These in vitro findings suggest that impaired p53 function is associated with increased sensitivity to combined ATR inhibition and irradiation and support further evaluation of p53 status as a candidate response biomarker."

Journal • Ataxia • Colorectal Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • TP53

Phase 1b Trial of Berzosertib as a Radiosensitizer in the Post-Neoadjuvant Treatment of Chemotherapy-Resistant HER2-Negative Breast Cancer (ASTRO 2026) - No abstract available

Clinical • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

A Phase 2 Study of Berzosertib in Combination with Carboplatin compared to Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer. (PubMed, Cancer Res Commun) - P2 | "Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969."

Journal • P2 data • Ataxia • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Prostate Cancer • Solid Tumor • HRD

SEZ6-Targeted PET Imaging and Alpha-Particle Radioimmunotherapy is Effective for Detection and Treatment of Small Cell Lung Cancer. (PubMed, Cancer Res) - "Treatment with [225Ac]Ac-Macropa-SEZ6-Ab induced complete tumor regression, while co-administration of the ATR inhibitor berzosertib enhanced efficacy at lower radioactivity doses without added toxicity. Together, these findings identify tumor-localized SEZ6 shedding as a biological barrier to SEZ6-targeted therapy, define dosing strategies to overcome it, and demonstrate potent antitumor activity of SEZ6-directed α-particle radioimmunotherapy in SCLC."

IO biomarker • Journal • CNS Disorders • Epilepsy • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • SEZ6

A Three-Gene Prognostic Signature Driven by an ER Stress-Associated ceRNA Network: Integrating Single-Cell Transcriptomics and Cross-Platform Validation in Hepatocellular Carcinoma. (PubMed, Curr Issues Mol Biol) - "Drug sensitivity analysis indicated that the high-risk group was more sensitive to drugs such as docetaxel and AZD5582, consistent with the upregulation of proliferation pathways in this group; in the low-risk group, VE-822 exhibited selective sensitivity. This study established a three-gene prognostic signature based on the ERS-associated ceRNA network. The signature demonstrated robust prognostic stratification capabilities in cross-platform validation and revealed molecular characteristics centered on uncontrolled cell-cycle progression, as well as an immunosuppressive microenvironment, in the high-risk group, providing an exploratory tool for prognostic assessment and treatment strategy selection in hepatocellular carcinoma (HCC)."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ATF3 • CCL2 • CKS1B • PSAT1 • STC2

A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer, Extra-Pulmonary Small Cell Neuroendocrine Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors (clinicaltrials.gov) - P1/2 | N=35 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Mar 2029 ➔ Jul 2026 | Trial primary completion date: Mar 2028 ➔ May 2026

Trial completion • Trial completion date • Trial primary completion date • Endocrine Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • BARD1 • BRCA • BRCA1 • BRCA2 • BRIP1 • CDK12 • CHEK1 • CHEK2 • FANCL • HRD • PPP2R2A • RAD51B • RAD51C • RAD51D • RAD54L

ATR senses stiff extracellular matrix to promote epithelial-to-mesenchymal transition and immune suppression. (PubMed, J Clin Invest) - "Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor, Berzosertib, in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR targeted therapy may be optimized by considering both DNA damage dependent and EMT inducing effects of ATR."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ITGAE

Duocarmycin-Bearing Antibody-Mimetic Drug Conjugate Combined With an ATR Inhibitor Results in Complete Tumor Regression in a KPL-4 Xenograft Model. (PubMed, Cancer Med) - "Synergistic interactions with Duo-HER2 were further confirmed in vitro using three clinically relevant ATR inhibitors-tuvusertib, ceralasertib, and berzosertib. Together, these findings indicate that Duo-HER2 combined with ATR inhibitors synergistically suppresses tumor growth in HER2-positive breast cancer models. Further studies employing optimized formulations, expanded in vivo cohorts, and additional tumor models will be required to fully define the therapeutic potential of this strategy and its relevance for overcoming ADC resistance."

Journal • Preclinical • Ataxia • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • HER-2

Carboplatin, Gemcitabine Hydrochloride, and Berzosertib in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ Jun 2027

Platinum sensitive • Trial completion date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

TARGETING THE DNA DAMAGE RESPONSE IN DORMANT MYELOMA CELLS (EHA 2026) - "When tumour burden was high mice were treated with chemotherapy 50mg/kg lenalidomide and 0.75mg/kg bortezomib...Activity of DNA damage response inhibitor drugs (olaparib, abemaciclib, berzosertib and Ku55933) on dormant and proliferating myeloma cells was assessed using resazurin viability assay after 1 week of treatment...Summary/Conclusion Dormant myeloma cells exhibit higher levels of DNA damage across modelling approaches. Thus, targeting the DNA damage response is a promising approach to target chemo-resistant dormant myeloma cells."

Hematological Malignancies • Multiple Myeloma • AXL • BRCA • CDKN1A

Dormant myeloma cells exhibit higher DNA damage levels – a new vulnerability in cancer cell dormancy? (EACR 2026) - "Study 1 did not incur any treatment and study 2 used standard of care (SOC) chemotherapy 50mg/kg lenalidomide and 0.75mg/kg bortezomib...Activity of DNA damage response inhibitor drugs (olaparib, abemaciclib, berzosertib and Ku55933) on proliferating myeloma cells was investigated using resazurin viability assay 1 week after dosing... Dormant myeloma cells exhibit higher levels of DNA damage across in vitro and in vivo modelling approaches. Thus, targeting the DNA damage response could be a promising new approach to target chemo-resistant dormant myeloma cells."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • AXL • BRCA • CDKN1A

Randomized Trial of Topotecan With M6620, an ATR Kinase Inhibitor, in Small Cell Lung Cancers and Small Cell Cancers Outside of the Lungs (clinicaltrials.gov) - P2 | N=104 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2026 ➔ May 2027

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

Avelumab and M6620 for the Treatment of DDR Deficient Metastatic or Unresectable Solid Tumors (clinicaltrials.gov) - P1/2 | N=23 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2025 ➔ Jan 2027

Trial completion date • Oncology • Solid Tumor • ARID1A • ATM • ATRX • BAP1 • BARD1 • BRCA1 • BRCA2 • BRIP1 • CD4 • CDK12 • CHEK2 • FANCA • FANCC • FANCD2 • FANCE • FANCF • FANCM • MSH2 • NBN • RAD51 • RAD51C • RAD51D • SMARCB1

Extrapulmonary small cell carcinoma treated with conventional or tumor-targeted topoisomerase I inhibition plus ATR blockade: Clinical outcomes and molecular correlates. (ASCO 2026) - P1/2, P2 | "We evaluated ATR inhibition with berzosertib combined with topoisomerase I (TOP1) inhibition with topotecan or sacituzumab govitecan (SG) and explored molecular correlates of response. In relapsed or refractory EPSCC targeting tumor replication stress through combined ATR and TOP1 pathway inhibition yielded clinically meaningful activity. Tumor-targeted TOP1 delivery with SG plus berzosertib achieved disease-control rate and a manageable safety profile. UGT1A1 phenotype was associated with toxicity in the SG cohort, supporting the relevance of pharmacogenomic-guided risk stratification."

Clinical • Clinical data • Alopecia • Endocrine Cancer • Immunology • Oncology • Solid Tumor • TOP1 • UGT1A1