^
    2d
    KEYMAKER-U01 Substudy 01J: A Study of Pembrolizumab Plus MK-1084 in Participants With Non-Small Cell Lung Cancer (NSCLC) With Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) G12C Mutations (MK-3475-01J/KEYMAKER-U01J) (clinicaltrials.gov)
    P2, N=43, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting | N=24 --> 43
    Enrollment open • Enrollment change
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    KRAS (KRAS proto-oncogene GTPase)
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    KRAS mutation • KRAS G12C • KRAS G12
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    Keytruda (pembrolizumab) • Erbitux (cetuximab) • carboplatin • pemetrexed • calderasib (MK-1084)
    5d
    Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C. (PubMed, J Med Chem)
    Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using divarasib as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved.
    Journal
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    KRAS (KRAS proto-oncogene GTPase)
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    KRAS mutation • KRAS G12C
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    divarasib (RG6330)
    5d
    Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C. (PubMed, J Med Chem)
    We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.
    Journal
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    KRAS (KRAS proto-oncogene GTPase)
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    KRAS G12C
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    divarasib (RG6330)
    7d
    A Clinical Study of MK-1084 With Other Treatments for Non-small Cell Lung Cancer (MK-3475-01F) (clinicaltrials.gov)
    P1/2, N=190, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting | Trial completion date: Jul 2036 --> May 2037
    Enrollment open • Trial completion date
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    PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Keytruda (pembrolizumab) • Erbitux (cetuximab) • patritumab deruxtecan (U3-1402) • Jiataile (sacituzumab tirumotecan) • calderasib (MK-1084)
    7d
    A Study of Olomorasib (LY3537982) in Healthy Participants (clinicaltrials.gov)
    P1, N=15, Not yet recruiting, Eli Lilly and Company
    New P1 trial
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    olomorasib (LY3537982)
    9d
    KANDLELIT-013: MK-3475A±MK-1084 in Completely Resected Stage IIA-IIIB (N2) KRAS G12Cm NSCLC (MK-1084-013) (clinicaltrials.gov)
    P3, N=400, Not yet recruiting, Merck Sharp & Dohme LLC
    New P3 trial
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Keytruda (pembrolizumab) • calderasib (MK-1084)
    12d
    Biomarker understanding first lessons from drug development for IgA-driven autoimmune and fibrotic diseases. (PubMed, Camb Prism Precis Med)
    For example, KRAS mutations are used to guide treatment with Sotorasib, while tumor expression of (wild type) human epidermal growth factor receptor 2 and 3 (HER2 and HER3) are used to select patients for trastuzumab and cetuximab, respectively. Moreover, such a patient stratification approach minimizes the risk of including patients who are unlikely to respond, thereby avoiding unnecessary adverse events. This approach was applied during the selection of an anti-CD89 antagonist monoclonal antibody for IgA-mediated autoimmune and fibrotic diseases, serving as an illustrative example of this novel strategy.
    Review • Journal
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    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
    |
    KRAS mutation
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    Herceptin (trastuzumab) • Erbitux (cetuximab) • Lumakras (sotorasib)
    15d
    The polyamine inhibitor SAM486A increases the efficacy of adagrasib in non-small cell lung cancer cells harboring KRASG12C mutation. (PubMed, Biol Res)
    Our results suggest that targeting polyamine metabolism with SAM486A enhances the efficacy of KRASG12C inhibitors and may mitigate resistance. This combination represents a promising therapeutic approach for KRASG12C-mutant NSCLC and warrants further clinical investigation.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • PCNA (Proliferating cell nuclear antigen)
    |
    KRAS mutation • KRAS G12C • KRAS wild-type • RAS wild-type • KRAS G12 • NRAS Q61 • NRAS G12
    |
    Krazati (adagrasib)
    17d
    A Solid Tumor Study for Long Term Treatment of Cancer Patients Who Participated in Adagrasib Studies (clinicaltrials.gov)
    P2, N=170, Not yet recruiting, Mirati Therapeutics Inc.
    New P2 trial
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    Keytruda (pembrolizumab) • Erbitux (cetuximab) • docetaxel • 5-fluorouracil • pemetrexed • oxaliplatin • irinotecan • Krazati (adagrasib) • leucovorin calcium
    17d
    A clinical study of MK-1084 with targeted therapy and chemotherapy in people with colorectal cancer (MK-1084-012). (2024-517232-22-00)
    P2/3, N=141, Recruiting, Merck Sharp & Dohme LLC
    New P2/3 trial
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Avastin (bevacizumab) • Erbitux (cetuximab) • 5-fluorouracil • oxaliplatin • leucovorin calcium • calderasib (MK-1084) • levoleucovorin calcium
    17d
    CO45042: 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 (2024-518365-10-00)
    P2/3, N=282, Recruiting, F. Hoffmann-La Roche AG
    New P2/3 trial
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Keytruda (pembrolizumab) • cisplatin • carboplatin • pemetrexed • divarasib (RG6330)
    17d
    MK-1084-014: A clinical study of MK-1084 in people with advanced solid tumors (MK 1084-014) (2025-521737-91-00)
    P1/2, N=74, Recruiting, Merck Sharp & Dohme LLC
    New P1/2 trial • Pan tumor
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • calderasib (MK-1084)