Dr Riess on Sequencing Considerations for KRAS and BRAF Inhibitors in NSCLC

"My general approach is immunotherapy-based combinations in the first line, such as chemoimmunotherapy, and then giving the KRAS G12C inhibitor in the second line."

Jonathan Wesley Riess, MD, MS, director of Thoracic Oncology and associate professor of medicine in the Division of Hematology and Oncology at the University of California, Davis Comprehensive Cancer Center, highlighted treatment sequencing considerations for KRAS and BRAF inhibitors in non–small cell lung cancer (NSCLC), as discussed during the 2025 Bridging the Gaps in Lung Cancerconsensus meeting,

Riess noted that, unlike EGFR-, ALK-, and ROS1-altered NSCLC, which typically demonstrates limited benefit from single-agent PD-1 inhibition, KRAS- and BRAF-mutated tumors can be responsive to immune checkpoint blockade. For KRAS-mutant NSCLC, he emphasized that current approvals are limited to KRAS G12C inhibitors in the second-line setting, where median progression-free survival is less than 6 months. Given these data, Riess shared that he favors immunotherapy-based combinations, such as chemoimmunotherapy, are usually favored in the first-line setting, followed by KRAS G12C inhibition at progression. This sequence aligns with the design of pivotal randomized studies comparing KRAS-targeted therapy with second-line docetaxel, he explained.

Regarding BRAF V600E–mutated NSCLC, Riess highlighted differences in treatment strategy compared with melanoma, where first-line immunotherapy demonstrated superiority over targeted therapy. Although BRAF-mutated lung tumors may respond to immunotherapy, Riess typically initiates therapy with BRAF/MEK inhibition in advanced, treatment-naïve disease, citing more favorable outcomes with targeted therapy in the frontline setting compared with post-treatment use.

For patients with BRAF V600E mutations, approved first-line targeted regimens include dabrafenib (Tafinlar) plus trametinib (Mekinist) or encorafenib (Braftovi) plus binimetinib (Mektovi). Riess favors initiating one of these combinations in the metastatic setting, reserving immunotherapy for subsequent lines as appropriate.

Overall, sequencing decisions for KRAS and BRAF inhibitors in NSCLC should account for mutation subtype, responsiveness to immune checkpoint inhibition, and the line of therapy in which the targeted agent has demonstrated optimal efficacy, Riess concluded.