Oncodrivers in Advanced or Metastatic NSCLC: Current and Future Standards of Care - Episode 6
Panelists discuss how next-generation KRAS G12C inhibitors like divarasib, lifirafenib, and RMC-6291 (a RAS-ON inhibitor) show promising enhanced potency with response rates in the 50% range and extended PFS, offering hope for more effective treatment options and potential sequencing strategies.
Next-Generation KRAS G12C Inhibitors and Future Directions
The KRAS G12C therapeutic landscape continues expanding with next-generation inhibitors including divarasib, lifirafenib, and RMC-6291. These agents differ in potency and mechanism of action, with traditional KRAS-OFF inhibitors (divarasib, lifirafenib) showing response rates in the 50% range and progression-free survival of 13 to 15 months. RMC-6291 represents a novel KRAS-ON inhibitor targeting the active form of KRAS, demonstrating 30% response rates and nearly 10-month median PFS in pretreated patients.
Multiple first-line combination strategies are under investigation, including KRAS G12C inhibitors with immunotherapy for PD-L1–high patients and quadruple approaches combining chemotherapy, immunotherapy, and KRAS inhibitors for PD-L1–low populations. These diverse strategies reflect the complexity of optimizing treatment based on patient characteristics and biomarker profiles. The dynamic phase of clinical development will help determine optimal combination therapies for specific patient subsets.
The proliferation of treatment options transforms KRAS from an “undruggable” target to a therapeutically rich landscape. Future success depends on identifying the most effective combinations while managing potential toxicities, particularly hepatotoxicity with immunotherapy combinations. Overall survival data and long-term tolerability profiles will ultimately determine which approaches become standard care, with the goal of replacing current chemoimmunotherapy standards like KEYNOTE-189.