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    DRUG:

    berzosertib (M6620)

    i
    Other names: M6620, VX-970, M 6620, VX970, VX 970, VE822, VE-822
    Company:
    EMD Serono, Vertex
    Drug class:
    ATR inhibitor
    Related drugs:
    2d
    NCI 10211: A Phase II, Single-Arm Study of Berzosertib in Combination with Irinotecan in Patients with Advanced TP53 Mutant Gastroesophageal Cancer. (PubMed, Oncologist)
    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).
    P2 data • Journal
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation
    |
    irinotecan • berzosertib (M6620)
    1m
    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)
    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.
    P1 data • Journal
    |
    ATM (ATM serine/threonine kinase) • ATR (Ataxia telangiectasia and Rad3-related protein)
    |
    irinotecan • berzosertib (M6620)
    3ms
    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
    |
    IL6 (Interleukin 6) • CXCL8 (Chemokine (C-X-C motif) ligand 8)
    |
    berzosertib (M6620) • AZD0156
    3ms
    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.
    Journal • IO biomarker
    |
    TRPA1 (Transient Receptor Potential Cation Channel Subfamily A Member 1)
    |
    gemcitabine • docetaxel • berzosertib (M6620) • BI2536 • GSK461364 • patupilone (EPO 906)
    4ms
    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 • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2)
    |
    Lynparza (olaparib) • Talzenna (talazoparib) • berzosertib (M6620) • CC-115
    4ms
    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, 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
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    berzosertib (M6620)
    4ms
    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
    |
    TMB (Tumor Mutational Burden) • FUT8 (Fucosyltransferase 8)
    |
    berzosertib (M6620)
    5ms
    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 • BRCA Biomarker • PARP Biomarker
    |
    BRCA (Breast cancer early onset) • RAD51 (RAD51 Homolog A)
    |
    BRCA wild-type
    |
    cisplatin • veliparib (ABT-888) • berzosertib (M6620)
    5ms
    Berzosertib and Irinotecan in TP53 Mutant Gastric or Gastroesophageal Junction Cancer (clinicaltrials.gov)
    P2, N=19, Active, not recruiting, National Cancer Institute (NCI) | N=14 --> 19
    Enrollment change
    |
    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • MSI (Microsatellite instability)
    |
    HER-2 positive • TP53 mutation • MSI-H/dMMR
    |
    FoundationOne® CDx
    |
    irinotecan • berzosertib (M6620)
    5ms
    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.
    Journal • Tumor mutational burden • PARP Biomarker • IO biomarker
    |
    TMB (Tumor Mutational Burden) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CASP3 (Caspase 3) • IGF2BP1 (Insulin Like Growth Factor 2 MRNA Binding Protein 1) • LY96 (Lymphocyte Antigen 96)
    |
    Tagrisso (osimertinib) • cyclophosphamide • JQ-1 • berzosertib (M6620) • ceralasertib (AZD6738)
    5ms
    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
    |
    SLFN11 (Schlafen Family Member 11)
    |
    berzosertib (M6620) • Zepzelca (lurbinectedin)
    6ms
    Avelumab and M6620 for the Treatment of DDR Deficient Metastatic or Unresectable Solid Tumors (clinicaltrials.gov)
    P1/2, N=25, Active, not recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2025 --> Nov 2024
    Trial primary completion date
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ATM (ATM serine/threonine kinase) • ARID1A (AT-rich interaction domain 1A) • BAP1 (BRCA1 Associated Protein 1) • MSH2 (MutS Homolog 2) • CDK12 (Cyclin dependent kinase 12) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51C (RAD51 paralog C) • CD4 (CD4 Molecule) • RAD51D (RAD51 paralog D) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin)) • FANCF (FA complementation group F) • FANCM (FA Complementation Group M) • FANCD2 (FA Complementation Group D2) • FANCE (FA Complementation Group E) • FANCC (FA Complementation Group C)
    |
    Bavencio (avelumab) • berzosertib (M6620)