Key Points
• In the current study, researchers assessed the preclinical and clinical evidence underlying the efficacy of KRAS-G12C inhibitor monotherapy, as well as examining combination therapies created to overcome primary resistance and extend durability of response.
• “It is expected that these inhibitors will have a limited efficacy as monotherapies; therefore, combination strategies will be needed,” the authors wrote. “Vertical pathway inhibition targeting downstream or upstream nodes of the RAS pathway could be an effective therapeutic strategy for those tumours that show KRAS dependency, whereas tumours with reduced KRAS dependency could require co-targeting of other pathways. Therefore, there is a need to identify biomarkers that can determine which patient can benefit from each strategy. Moreover, this will likely need to be done for each tumour type.”
• The authors highlighted the need to identify mechanisms of resistance, and cited a study examining KRAS resistance affecting the binding of the inhibitor.
• The authors touched on the ongoing development of agents targeting other RAS alleles, such as KRAS-G12D (e.g., Mirati’s inhibitor MRTX1133), which is moving toward clinical studies. Pan-RAS-specific drugs are also on the horizon, and target tumors possessing mutations that lack a specific inhibitor. Of note, such compounds may elicit toxicity secondary to blocking RAS activity in non-tumoral cells.