KRAS 突變的非小細胞肺癌 (NSCLC) - 一個新興的有望治療的亞組

Lung cancer has the highest mortality rate of all cancer types and can be classified mainly based on the genetic mutations that cause it. KRAS represents a specific mutation that occurs in a group of genes that play a vital role in controlling cell growth and division. More than 80% of KRAS mutations occur in Exon 12, and the most common mutations are KRAS G12C (glycine to cysteine; about 40%), KRAS G12V (glycine to valine; about 18-21%), and KRAS G12D (glycine to aspartate; about 17-18%). Patients diagnosed with non-small cell lung cancer (NSCLC) carrying KRAS mutations usually respond poorly to chemotherapy and have a poor overall prognosis. The advent of immunotherapy has brought a ray of hope to these patients, as it has been shown to improve clinical outcomes for patients with KRAS mutant NSCLC. Although there are currently no targeted drugs designed specifically for KRAS mutant NSCLC, clinical trials involving novel small molecule inhibitors targeting KRAS G12C, such as Sotorasib (AMG510) and Adagrasib (MRTX849), have announced encouraging results at recent international conferences, showing their potential to treat this form of non-small cell lung cancer. In addition, many other targeted drugs are currently under development. Please refer to the figure below for more information:

Sotorasib is taken orally once daily at a dose of 960 mg. The objective response rate (ORR) was 37.1%, and the median duration of response was 11.1 months. The median overall survival of participants was 12.5 months, and the disease control rate (DCR) was 80.6%. Treatment-related adverse events (TRAEs) were reported in 69.8% of patients, of which 19.8% were grade 3 events. Most side effects were related to the gastrointestinal system, such as diarrhea (31.7%), nausea (19%), and mild elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (15.1%), producing low-grade hepatotoxicity. The U.S. Food and Drug Administration (FDA) recently granted sotorasib a designation for the treatment of adult patients with advanced KRAS-G12C mutant NSCLC.

Adagrasib (MRTX849) is another direct KRAS G12C inhibitor with irreversible and selective effects. A phase I/II study called KRYSTAL-1 (NCT03785249) evaluated the ORR and DCR of adagrasib in patients with similar characteristics to sotolacib and showed that in 51 patients with NSCLC, the ORR and DCR were 45% and 96%, respectively, at a dose of 600 mg twice daily. Grade 3 or 4 TRAEs were reported in 30% of patients; the most frequent were fatigue (6%) and increased AST/ALT (5%). In the subpopulation of patients with STK-11 co-mutations, the ORR was 64%, which may indicate a beneficial effect of this co-mutation in treatment progression.

References:

[1] Karimi N, Moghaddam SJ. KRAS-Mutant Lung Cancer: Targeting Molecular and Immunologic Pathways, Therapeutic Advantages and Restrictions. Cells. 2023; 12(5):749. https://doi.org/10.3390/cells12050749.

[2] Xie M, Xu PMC8126715.

[3] https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug Last assessed date: 4 Oct 2023