Next-Generation Design Drives Divarasib Gains in Krascendo 1 Trial

Divarasib significantly improved progression-free survival (PFS) and overall survival (OS) compared with first-generation KRAS G12C inhibitors in the KRASCENDO-1 study, according to data presented at the European Society for Medical Oncology (ESMO) Congress. In an interview, Bo Wang, MD, of Willamette Valley Cancer Institute and Research Center, discussed the results and the drug-design features that may explain them.

The median PFS was 9.8 months with divarasib vs 5.7 months in the control arm, which received sotorasib (Lumakras) or adagrasib (Krazati), with an HR of 0.58. At 12 months, 44% of patients receiving divarasib had not progressed, compared with 24% in the control arm. Wang said this nearly doubled proportion shows that the therapy stayed active longer for many patients.

OS also improved significantly. Median OS was 17.7 months with divarasib vs 12 months with control, a gain of almost 6 months that Wang called clinically meaningful. At 1 year, 67% of patients receiving divarasib were alive, compared with less than 50% in the control arm. In Wang’s view, the combined PFS and OS benefit shows a clear advantage for a next-generation KRAS G12C inhibitor that targets the protein in its inactive, or OFF, state.

Wang attributed the results to drug design. Preclinical studies showed that small molecules can bind the switch II pocket of KRAS G12C in the OFF state, but only at picomolar concentrations. First-generation agents succeeded in proving that this pocket could be targeted and KRAS G12C inhibited. Newer agents such as divarasib have potency and selectivity 10 to 100 times greater than the first-generation drugs, which he said is consistent with their stronger efficacy.

Wang said the greater selectivity also improves tolerability and safety. Less than 5% of patients receiving divarasib stopped treatment because of toxicities associated with KRAS G12C inhibitors, compared with nearly 12% in the control arm. Serious and high-grade adverse events fell from 35% with control to 24% with divarasib.

Wang concluded that improved drug design and molecular selectivity allow patients to stay on therapy much longer at a tolerable dose.