Background
Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets GTP-bound mutant and wild-type RAS, broadening the reach of RAS-directed therapy beyond single-allele inhibitors.
Phase 1–2 results
In 168 patients with previously treated RAS-mutated PDAC, the 26 patients with RAS G12 mutations receiving 300 mg in second line achieved an ORR of 35%, median duration of response 8.2 months, mPFS 8.5 months, and mOS 13.1 months. Grade ≥3 treatment-related adverse events occurred in 30%.
RASolute 302 (phase 3)
The phase 3 RASolute 302 trial, led by Dr. Eileen M. O’Reilly and the RASolute 302 Trial Investigators, showed that daraxonrasib doubled overall survival versus chemotherapy in previously treated metastatic pancreatic cancer (13.2 vs 6.6 months; HR 0.40).
Molecular structure
The RCSB PDB 9BGC structure captures daraxonrasib (RMC-6236) in a tri-complex with KRAS G12R and CypA, illustrating how the inhibitor occupies a composite pocket at the protein-protein interface.
Daraxonrasib bound in the RAS(ON) tri-complex
X-ray structure of daraxonrasib (A1AHB/RMC-6236) bridging KRAS G12R and CypA, with GNP/Mg marking the active nucleotide-bound state.
- KRAS
- chain A
- CypA
- chain C
- Daraxonrasib
- A1AHB
- GNP/Mg
- RAS(ON)