KRAS mutation of Non-Small Cell Lung Cancer (NSCLC) - An Emerging Promisingly Treatable Subgroup
Lung cancer, which has the highest mortality rate among all cancer types, can primarily be classified based on the genetic mutations responsible for its development. KRAS represents a specific mutation occurring in a cluster of genes that play a crucial role in controlling cell growth and division. Over 80% of KRAS mutations occur in codon 12, and the most common mutations are KRAS G12C (mutation of glycine to cysteine; approximately 40%), KRAS G12V (mutation of glycine to valine; approximately 18–21%), and KRAS G12D (mutation of glycine to aspartic acid; approximately 17–18%), amongst others. Patients diagnosed with non-small cell lung cancer (NSCLC) that carries KRAS mutations generally exhibit poor response to chemotherapy and have an unfavorable overall prognosis. The emergence of immunotherapy has provided a ray of hope for these patients, as it has shown to enhance clinical outcomes in individuals with KRAS-mutant NSCLC. Although there are presently no targeted drugs specifically designed for KRAS-mutant NSCLC, encouraging results from clinical trials involving novel small-molecule inhibitors targeting KRAS G12C such as Sotorasib (AMG510) and Adagrasib (MRTX849) have presented at latest international conferences, suggesting their potential in treating this form of NSCLC. Furthermore, numerous other targeted drugs are currently under development. See below the fig to understanding more:
Sotorasib (AMG510):
Sotorasib was administered orally once per day at a dosage of 960 mg. The objective response rate (ORR) was 37.1% with a median response duration of 11.1 months. The median overall survival was 12.5 months with a disease control rate (DCR) of 80.6% in participants. Treatment-related adverse events (TRAEs) were reported in 69.8% of patients, with 19.8% grade 3 events. The majority of side effects related to the gastrointestinal system, such as diarrhea (31.7%), nausea (19%), and slightly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (15.1%), offering low-grade hepatic toxicity. The U.S. Food and Drug Administration (FDA) recently granted sotorasib designation for the treatment of advanced KRAS-G12C-mutated NSCLC in adult patients[1].
Adagrasib (MRTX849):
Adagrasib (MRTX849) is another direct KRAS G12C inhibitor that acts irreversibly and selectively. A phase I/II study called KRYSTAL-1 (NCT03785249), in patients with a similar profile to that mentioned for sotorasib, evaluated the ORR and DCR of adagrasib and the results showed that in 51 patients with NSCLC, with a dosage of 600 mg twice per day, the ORR and DCR were 45% and 96% respectively. TRAEs of grade 3 or 4 were reported in 30% of patients; those with the highest frequency were fatigue (6%) and increased AST/ALT (5%). In a subgroup of patients with the STK-11 co-mutation the ORR was 64%, which may indicate the beneficial role of this co-mutation in therapeutic progress.
[1] 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
[1] https://www.targetedonc.com/view/treatment-of-gist-recent-changes-and-recommendations. Last accessed date: 19 Oct 2023.
[2] Mazzocca A, Minelli A, Paternostro F, Silletta M, Napolitano A, Vincenzi B. New molecularly targeted drugs for gist after imatinib, sunitinib and regorafenib: a narrative review. Gastrointest Stromal Tumor 2022;5:4.
