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KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup - PubMed

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup - PubMed

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Lung cancer, the leading cause of cancer-related deaths worldwide, can be classified into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common histological type, accounting for 85% of all lung cancers. Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in ...

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    Key Points
    • In the current review article, authors assessed the pathogenesis, treatment status, progress of immunotherapy, and targeted therapy of KRAS-mutant NSCLC .
    • In particular, they stressed promising new treatments including preclinical trial data on AMG510 (sotorasib). “In preclinical studies, the use of AMG510 in immune-competent mice allowed T cells, especially CD8+ T cells, to infiltrate a large number of tumours, resulting in a pro-inflammatory tumour microenvironment that produced durable responses alone or in combination with ICI,” the authors wrote. “Another study also verified the immunomodulatory effect of KRAS G12C inhibitors, that is, the ability to reshape the immune microenvironment. Therefore, the combination therapy model using KRAS G12C inhibitors and anti-PD-1 therapy is expected to become a new treatment direction.”
    • In preclinical studies, AMG501 was shown to inhibit nearly all detectable ERK phosphorylations, which is a key downstream effector of KRAS, thus equipping KRAS G12C mutant mouse models to attain long-lasting regression. In the most recent Codebreak 100 Phase II research data presented at the 21st World Lung Cancer Conference, in 124 patients, the ORR was 37.1%, the DCR was 80.6%, and the median PFS was 6.8 months. In terms of safety, during treatment with AMG510, no dose-limiting side effects were observed, and no treatment-related deaths occurred.
    • According to the authors, such findings suggest that AMG510 is safe, causes remission and long-lasting benefits in patients with KRAS-mutant NSCLC, which resulted in the FDA designating sotorasib breakthrough therapy in December 2020.
    • The authors wrote, “The CodeBreak 101 study investigated AMG510 monotherapy and combination therapy with anti-tumour drugs, and the CodeBreak 200 study compared the effects of AMG510 in second-line treatment with standard chemotherapy. These studies have entered the clinical trial phase, and the results are promising.”