An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer
Creators: name: Tenekeci, Ates Kutay
name: Unal, Ahmet Arda
name: Ceylan, Furkan
name: Sendur, Mehmet Ali Nahit
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Medicine
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: The discovery of <i>KRAS</i> mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: “sotorasib”, “adagrasib”, “divarasib” and “KRAS G12C inhibitors.” The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease. Covalent inhibitors like sotorasib, adagrasib and divarasib represent significant advancements in targeted therapy aimed specifically at tumors harboring the KRASG12C mutation. Clinical trials have shown that KRAS G12C inhibitors improved objective response rates and progression-free survival compared with standard treatments. These trials have obtained promising results in personalized cancer therapy for non-small cell lung cancer (NSCLC) patients harboring the KRASG12C mutation. Co-mutations in genes like KEAP1, SMARCA4 and CDKN2A can significantly impact patient outcomes and response to KRAS G12C inhibitors, with certain co-mutations associated with poor prognosis. Each KRAS G12C inhibitor comes with its own pharmacokinetics profile. Sotorasib and adagrasib are both well tolerated, though gastrointestinal adverse events are common and can be managed with supportive care. Liquid biopsies show promise in detecting KRAS mutations, monitoring treatment response and predicting overall survival, making them a valuable tool in managing NSCLC. Development of resistance to KRAS inhibitors can occur through various genetic alterations and activation of alternative pathways. Combination therapies may help overcome these resistance mechanisms. Ongoing and future clinical trials aim to further explore the efficacy of KRAS G12C inhibitors, their combinations with immunotherapies, and other novel compounds to improve treatment outcomes in NSCLC.