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    Home > Medical News > Latest Medical News > Amgen KRAS inhibitor complete Phase I data out of non-small cell lung cancer queue ORR up to 32.2%

    Amgen KRAS inhibitor complete Phase I data out of non-small cell lung cancer queue ORR up to 32.2%

    • Last Update: 2020-10-02
    • Source: Internet
    • Author: User
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    KraS mutations occur in about 25 percent of cancer cases and are associated with very poor disease prognostics, so scientists believe blocking KRAS signals is a potential anti-cancer route.
    However, previous decades of research have shown that the protein may be a "drug-free" target because its surface is so smooth except for a GTP binding pocket that it is difficult for drug developers to find a binding pocket for small molecule candidates on its surface.
    2013, a paper published in Nature by Kevan Shoka, a chemical biologist at the University of California, San Francisco, brought an important turn to drug development targeting KRAS.
    Shoka and colleagues first reported the feasibility of combining KRASG12C mutants with small molecule co-prices.
    they designed a co-priced small molecule inhibitor that irreversibly targets the cysteine residue on KRAS's Code 12 cobase, locking the protein into an inactive state.
    KRASG12C mutation is present in about 13 percent of lung adenocarcinomas, 3 percent in colorectal cancer, and 2 percent in other solid tumors, referring to the 12-bit Glycine mutation of KRAS as cysteine.
    because newly introduced cysteine is easy to form co-price bonds, small molecules can be co-priced in combination with KRASG12C mutants, which is expected to be used to treat patients carrying such KRAS mutations.
    's sensational discovery by the Shokat team confirms that KRAS is actually more targeted than thought, contributing significantly to the development of KRASG12C inhibitors.
    , Amjin's KRASG12C inhibitor Sotarasib (AMG510) was first entered into clinical studies in August 2018 and was the first KRASG12C inhibitor to enter clinical testing.
    last year's ESMO, AMSM released preliminary data on Sotorasib's Phase I/II trials.
    the data at the time, 7 (54%) of the 13 NSCLC patients treated with Sotorasib received partial remission and smaller tumor size, while the other 6 patients were treated in stable condition.
    addition, the patient appears to be well-to-do with Sotorasib and does not show dose-limiting toxicity.
    : NEJM published the full Phase I trial results of Sotorasib on September 20 in the journal NEJM, a leading medical journal.
    Phase I trial (NCT03600883) was conducted on patients with advanced solid tumors with KRASG12C mutation, who were orally available once a day in four doses: 180 mg, 360 mg, 720 mg, 960 mg.
    end of the study is safety, and the key secondary endpoint is pharmacodynamics and objective mitigation.
    baseline patient characteristics (source: NEJM) Specifically, the trial recruited 129 patients, 59 cases of non-small cell lung cancer (NSCLC), 42 cases of colorectal cancer, 28 cases of other types of solid tumors.
    the majority of patients had under been treated extensively before joining the group, and 78 (60.5%) had previously received third- or above-line treatment.
    that no dose-limiting toxic effects or treatment-related deaths were observed in terms of safety.
    73 patients (56.6%) had treatment-related adverse events (treatment-related adverse events, TRAEs), of which 15 (11.6%) had level 3 or 4 TRAEs.
    common TRAEs include diarrhea, fatigue and nausea.
    level 3 TRAEs include elevated levels of alanine transaminase (4.7%), diarrhea (3.9%), and anemia (3.1%).
    with regard to the efficacy of Sotorasib in all tumor types (source: NEJM), anti-cancer activity was visible in all dose groups in the non-small cell lung cancer (NSCLC) queue, with 32.2% (19 cases) of patients showing clear objective remission (CR or PR), 88.1% (52 cases) of patients with disease under control (objective remission or stable condition), with a medium survival period of 6.3 months.
    in the colorectal cancer queue, 7.1% (3 cases) of patients showed clear remission, 73.8% (31) of patients had disease under control, and the medium progression-free survival period was 4.0 months.
    was also observed in patients with pancreatic, endometrial, appendicoma and melanoma (1 case each).
    on tumor burden changes in NSCLC patients treated with Sotorasib (Source: NEJM) The data suggest that Sotorasib showed encouraging anti-cancer activity in patients with advanced solid tumors with KRASG12C mutations.
    the results are key clinical evidence that KRAS is indeed "drug-ready."
    The efficacy of Sotorasib in NSCLC patients (Source: NEJM) NEJM's opinion paper on the results of the Phase I trial points out that the total lifetime of advanced KRASG12C non-small cell lung cancer (NSCLC) or colorectal cancer patients is about 1 to 2 years, a staggering number that has fueled industry research on KRAS targeted drugs for nearly 40 years.
    Because KRAS has picomolar-grade affinity for GTP and the concentration of GTP in cells is extremely high, the early strategy of looking for priority combinations with KRAS-GTP pockets failed (KRAS is activated when combined with GTP, and abnormal activation of KRAS is closely related to a variety of cancers).
    other strategies have tried to interfere with KRAS activity by blocking kras membrane positioning or suppressing downstream kinase signals, but they have also failed because of resistance caused by compensation signals.
    so far, no treatments targeting KRAS mutations in cancer have been approved for sale.
    , however, the industry has rekindled interest in developing treatment strategies that directly target KRAS, thanks to important findings published by the Shokat team on Nature.
    Sotorasib showed good safety in this Phase I study, as well as positive data showing anti-cancer activity in multiple doses, indicating its potential in combination with other therapies.
    summary, the results of this trial are very encouraging and represent another critical step forward in targeting non-drugable targets.
    reference: . . . Jonathan M. Ostrem etal. K-Ras (G12C) resors allosterically control GTP affinity and effector interactions. Nature (2013). [2] David S. Hong et al. KRASG12CInhibition with Sotorasib in Advanced Solid Tumors. NEJM (2020). [3] Clinical Data From Full Phase 1 Cohort Of Investigational Sotorasib Published In New England Journal Of Medicine.
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