Dr Riess on the Differences Between KRAS(ON), KRAS(OFF), and KRAS(ON/OFF) Inhibitors in Lung Cancer

“The major difference between the KRAS(OFF) and the KRAS(ON) inhibitors is that the OFF inhibitors bind to the GDP-bound form of RAS, and the ON inhibitors bind to the GTP-bound form of KRAS.”

Jonathan Wesley Riess, MD, MS, director of Thoracic Oncology and an associate professor of medicine at UC Davis Comprehensive Cancer Center, discussed the evolving landscape of KRAS inhibitors, including the distinction between KRAS(OFF) and (ON) inhibitors, a topic covered in the Bridging the Gaps in Lung Cancer meeting.

Riess outlined several major classes of KRAS inhibitors, starting with KRAS(OFF) inhibitors such as adagrasib (Krazati) and sotorasib (Lumakras), both FDA-approved for KRAS G12C–mutant non–small cell lung cancer (NSCLC). He also highlighted divarasib, another (OFF) inhibitor, noting encouraging press-released data showing improvements in progression-free and overall survival compared with earlier-generation KRAS(OFF) inhibitors.

Riess then turned to KRAS(ON) inhibitors, including daraxonrasib, for which data in pancreatic cancer were presented at the 2026 ASCO Annual Meeting, as well as more allele-specific (ON) inhibitors such as the G12D-directed inhibitor zoldonrasib. He explained the key mechanistic distinction between the 2 classes: (OFF) inhibitors bind the GDP-bound, inactive form of RAS, while (ON) inhibitors bind the GTP-bound, active form.

Riess noted that this distinction may offer a path to overcoming resistance, such as using an (ON) inhibitor following progression on an (OFF) inhibitor. He emphasized that a major focus of ongoing drug development in this space is determining the optimal sequencing of these agents, since transitioning from an (OFF) inhibitor to an (ON) inhibitor may help restore treatment sensitivity and improve responses to RAS-targeted therapy.