I am very open to a combination treatment approach, but I would like to see some more prospective data first.

What are your thoughts about combining KRAS inhibitors with other agents?

Key Points
• Relevance: “This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.”
• The authors focused on the direct KRASG12C inhibitor sotorasib, which was recently approved by the FDA for adults with locally advanced or metastatic NSCLC who have been administered one or more prior systemic therapies. Accelerated FDA approval of sotorasib was due to favorable efficacy and safety results from phase I/II trials.
• The authors highlighted an ongoing global randomized phase III trial (i.e., CodeBreak 200) involving NSCLC, in which investigators are comparing sotorasib daily vs standard-of-care docetaxel as second-line therapy. Sotorasib is also being analyzed in combination with other anticancer therapies, such as EGFR, MEK, SHP2, pan-ErbB, mTOR, and CDK inhibitors, as well as immunotherapy and chemotherapy in the CodeBreaK 101 trial in those with advanced solid tumors.
• “One challenge related to the use of immunotherapy is the potential for rare but serious toxicities,” wrote the authors. “The timing of these may be unpredictable, sometimes emerging months after completion of immunotherapy (possibly due to the long half-life of antibodies, which can impact later-line therapies. If immunotherapy is to form part of combination approaches, appropriate sequencing of KRAS inhibitors and immunotherapy will be crucial.”