Potency and Safety of KRAS G12C Inhibitors in Solid Tumors: A Systematic Review
Background: The Kirsten rat sarcoma viral oncogene homolog gene, commonly known as KRAS, and specifically a mutation at a cysteine residue denoted as KRAS (G12C), has become a focal point of considerable research interest as a potential therapeutic target for individuals with solid tumors harboring this specific KRAS mutation. Despite the significant attention this target has received, a comprehensive understanding of the effectiveness and safety profiles associated with KRAS G12C inhibitors remains to be fully established. The present investigation aims to provide a thorough evaluation of the efficacy and toxicity of several relevant KRAS G12C inhibitors, namely Sotorasib, Adagrasib, Garsorasib, and Divarasib, in patients diagnosed with colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), and pancreatic ductal adenocarcinomas (PDAC).
Methods: This systematic review was conducted in accordance with the guidelines established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The review process involved a careful examination of the available clinical trial data pertaining to the use of KRAS G12C inhibitors in solid tumors characterized by the KRAS G12C mutation. A comprehensive search for relevant clinical trials was performed across several prominent databases, including PubMed, EMBASE, and the Cochrane Library, as well as major international conference proceedings, covering the period from January 2020 to August 2023.
Results: A total of 17 studies met the eligibility criteria for inclusion in this review. The use of Sotorasib and Adagrasib as KRAS G12C inhibitors was each reported in 7 of these studies, representing 41.2% of the included studies for each drug. Divarasib was investigated in 2 studies (11.8%), and Garsorasib was evaluated in 1 study (6.7%). Sotorasib demonstrated significant clinical benefit as indicated by the objective response rate (ORR), which ranged from 7.1% to 47%, the progression-free survival (PFS), which ranged from 4 to 6.8 months, and the overall survival (OS), which ranged from 4 to 24 months. Notably, Sotorasib appeared to be more effective in patients with non-small-cell lung cancer, showing a 2-year overall survival rate, a progression-free survival of 6.3 months, and an objective response rate of 41%. Adagrasib also exhibited substantial clinical activity, with an objective response rate ranging from 19% to 53%, a progression-free survival ranging from 3.3 to 11.1 months, and an overall survival ranging from 10.5 to 23.4 months. Similar to Sotorasib, Adagrasib showed greater effectiveness in non-small-cell lung cancer patients, with an overall survival of 23.4 months, a progression-free survival of 11.1 months, and an objective response rate of 53.3%. In patients with pancreatic ductal adenocarcinomas, Adagrasib demonstrated a higher objective response rate of 35.1%, a progression-free survival of 7.4 months, and an overall survival of 14 months, compared to Sotorasib, which showed an objective response rate of 21%, a progression-free survival of 4 months, and an overall survival of 6.9 months in this specific cancer type. However, both Adagrasib and Sotorasib exhibited only moderate efficacy in clinical trials involving colorectal cancer.
Conclusion: The findings of this systematic review confirm that patients treated with these KRAS G12C inhibitors, either as a standalone therapy or in combination with conventional cancer treatments, achieve improved treatment responses and experience a modulation in the progression of these solid tumors characterized by the KRAS G12C mutation.