From the Guidelines
KRAS cancers are characterized by mutations in the KRAS gene, with KRAS G12C being a specific subtype that has shown responsiveness to targeted therapies, such as sotorasib and adagrasib.
Characteristics of KRAS Cancers
- KRAS mutations are often mutually exclusive with other driver mutations, such as EGFR 1
- KRAS G12C mutations are present in approximately 17% of KRAS-mutated non-small cell lung cancer (NSCLC) cases 1
- KRAS mutations have been reported in around 40% of metastatic colorectal cancer (mCRC) cases, with KRAS G12D being the most common mutation 1
Treatment Options for KRAS Cancers
- Sotorasib and adagrasib are oral small molecule inhibitors that target KRAS G12C and have shown efficacy in patients with advanced NSCLC and mCRC 1
- Sotorasib has been shown to improve progression-free survival (PFS) and overall response rate (ORR) compared to docetaxel in patients with KRAS G12C-mutated NSCLC 1
- Adagrasib has been shown to have activity in patients with KRAS G12C-mutated mCRC, with a confirmed ORR of 19% and median PFS of 5.6 months 1
- Combination therapy with sotorasib or adagrasib and cetuximab or panitumumab may be considered for patients with KRAS G12C-mutated mCRC 1
Key Considerations
- KRAS mutations can be detected through molecular testing, and RAS genotyping can be performed on archived specimens of either the primary tumor or a metastasis 1
- The presence of a KRAS mutation can help predict a lack of benefit to other targeted therapies, such as EGFR inhibitors 1
From the Research
Characteristics of KRAS Cancers
- KRAS mutations account for approximately 86% of cases worldwide, particularly in lung, pancreatic, and colon cancers, contributing to poor prognosis and reduced overall survival 2
- KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer 3
- The most frequently found oncogene in human cancers, including non-small-cell lung cancer (NSCLC) 4
Treatment Options for KRAS Cancers
- Targeted therapies for KRAS-mutated lung, colon, and pancreatic cancers have shown promising breakthroughs in recent years 2
- Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies 3
- Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC 4
- Combination strategies are being evaluated to overcome resistance mechanisms 4, 5
- Novel KRAS inhibitors are currently under development, with the most promising therapeutic results obtained with molecules targeting KRAS G12C 5
Challenges and Future Opportunities
- KRAS has been acknowledged as "undruggable" due to its structure and difficult targeting, but recent advances have changed the therapeutic landscape 2, 4, 5
- Understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations 3
- Further research is needed to bring therapeutic results in this field, with several combination strategies currently under evaluation in clinical trials 5