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    Divarasib

    Other names: RG6330

    Modality: Kirsten rat sarcoma virus gene (KRAS) G12C inhibitor

    Disease State: Non-small cell lung cancer (NSCLC), Metastatic Solid Tumors, Metastatic Colorectal Cancer

    Summary

    Divarasib (GDC-6036, RG6330) is a selective, oral, investigational molecule designed to target KRAS G12C, a driver mutation in cancer.1,2 KRAS is one of the most prevalent oncogenes in human cancers, with the highest mutation rate among all cancers.3-5

    By locking the mutant KRAS G12C into its inactive guanosine diphosphate (GDP)-bound state, divarasib turns off oncogenic signaling in preclinical models.2

    Clinical Trials

    Divarasib
    NCT ID Study Phase Enrollment Status Study Title
    NCT05789082 Phase I / Phase II Recruiting A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation View details
    NCT06793215 Phase III Recruiting A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Participants With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer View details
    NCT04302025 Phase II Recruiting A Study of Multiple Therapies in Biomarker-selected Participants With Resectable Stages IB-III Non-small Cell Lung Cancer (NSCLC) View details
    NCT06497556 Phase III Active, not recruiting A Study Evaluating the Efficacy and Safety of Divarasib Versus Sotorasib or Adagrasib in Participants With Previously Treated KRAS G12C-positive Advanced or Metastatic Non-Small Cell Lung Cancer View details
    NCT03178552 Phase II / Phase III Active, not recruiting A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC) View details

    Proposed Mechanism of Action

    • The KRAS protein is a signaling guanosine triphosphate (GTP)ase that cycles between active GTP-bound and inactive GDP-bound states to regulate intracellular signaling in response to extracellular growth factors3,6-7
    • GTP-bound KRAS activates multiple downstream signaling pathways involved in cell proliferation, migration, and survival, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways6-8
    • Oncogenic mutations in the KRAS protein interfere with the transition from GTP-bound to GDP-bound states.4-6,8 Locking KRAS G12C in its constantly active state increases downstream oncogenic signaling
    • Divarasib (GDC-6036, RG6330) is designed as an orally available small molecule, and in preclinical studies showed potent and selective inhibition of the KRAS G12C protein1,2
    • Selectively binds the switch II pocket of the KRAS G12C protein through a specific interaction with the cysteine residue at position 12 and irreversibly locks it in the inactive GDP-bound state2,3,9
    • By locking the mutant KRAS G12C into its inactive GDP-bound state, divarasib turns off oncogenic signaling in preclinical models2

    AKT=Protein kinase B; ERK=Extracellular signal-regulated kinase; GDC-6036=Genentech 6036; GDP= Guanosine diphosphate; GTP=Guanosine triphosphate; KRASG12C=Kirsten Rat Sarcoma G12C; MEK=Mitogen-activated protein-kinase kinase; mTOR=Mechanistic/mammalian target of rapamycin; PI3K=Phosphatidylinositol 3-kinase; RAF=rapidly accelerated fibrosarcoma; RTK=Receptor tyrosine kinase; SHP2=Src homology 2 domain-containing phosphatase 2

    1. Purkey H. Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. Oral presentation presented at: AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Presentation ND11.
    2. Desai J, Alonso G, Kim SH, et al. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nat Med. 2024;30(1):271-278. doi:10.1038/​s41591-023-02696-8
    3. Uprety D, Adjei AA. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev. 2020;89:102070. doi:10.1016/​j.ctrv.2020.102070
    4. Friedlaender A, Drilon A, Weiss GJ, et al. KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85:101978. doi:10.1016/​j.ctrv.2020.101978
    5. Román M, Baraibar I, López I, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018;17(1):33. doi:10.1186/​s12943-018-0789-x
    6. Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged?. Nat Rev Drug Discov. 2020;19(8):533-552. doi:10.1038/​s41573-020-0068-6
    7. Khan AQ, et al. [Article title]. Cancer Biol. [Year];vol:[pages].
    8. Ostrem JML, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785. doi:10.1038/​nrd.2016.139
    9. Batrash F, Kutmah M, Zhang J. The current landscape of using direct inhibitors to target KRAS(G12C)-mutated NSCLC. Exp Hematol Oncol. 2023;12(1):93. doi:10.1186/​s40164-023-00453-8

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    TOP

    • GDP
      guanosine diphosphate

    • GTP
      guanosine triphosphate

    • KRAS
      Kirsten rat sarcoma virus gene

    • NSCLC
      non-small cell lung cancer

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