A practical framework categorizes TKIs into three classes to guide adjuvant use. Class 1 (e.g., osimertinib, alectinib) has high efficacy and low toxicity, making extrapolation easy. Class 2 (e.g., BRAF/MET inhibitors) has moderate efficacy and higher toxicity, requiring trials. Class 3 (e.g., KRAS inhibitors) has lower activity and needs trials.

A new class of drugs, "RAS on" inhibitors (e.g., daxorarasib), targets the active, GTP-bound state of KRAS. This mechanism is distinct from first-generation "RAS off" inhibitors (e.g., sotorasib) and is designed to treat patients who develop resistance, offering a subsequent line of targeted therapy.

Contrary to the idea that a pan-RAS inhibitor is superior, Varistem suggests a more targeted approach. Patients should first receive an inhibitor specific to their mutation (e.g., G12D). If resistance develops via a new RAS mutation, then a broader pan-RAS inhibitor should be used, creating a more rational, sequential treatment paradigm.

The new drug avutometinib uses a "RAF-MEK clamp" mechanism, blocking two nodes in the RAS pathway simultaneously (RAF and MEK). This dual-inhibition strategy is more effective than single-node targeting because it preempts the cancer cell's adaptive resistance mechanisms, where the pathway reactivates itself in response to upstream blocking.

While pan-RAS inhibitors like daroxiracib can target multiple mutations, they cause significantly more GI and skin toxicity. For a homogenous KRAS G12C mutation, a mutant-selective inhibitor is preferred as it offers comparable efficacy with a much more manageable side effect profile, crucial for maintaining dose intensity.

There is emerging evidence for sequencing KRAS inhibitors based on their mechanism. The "on-state" inhibitor Eliron-RASIB has shown a 50% response rate in patients previously treated with "off-state" inhibitors like adagrasib, suggesting that the resistance mechanism determines the effectiveness of subsequent therapy.

A patient who failed trametinib later responded to the avutametinib/defactinib combination. This suggests that resistance to one MEK inhibitor does not preclude a response to a different agent or combination targeting the same pathway, offering a viable later-line treatment strategy.

Patients progressing on first-generation KRAS G12C inhibitors may still respond to subsequent KRAS-targeted agents. Newer drugs with different binding mechanisms or greater potency are showing response rates over 40% in this post-progression setting, offering a potential new line of therapy.

While the avutometanib/defactinib combination is newly approved for KRAS-mutated ovarian cancer, its significant toxicity profile—causing up to a third of patients to stop treatment—creates a clear clinical need for agents like specific KRAS inhibitors that may offer similar efficacy with better tolerability.