Daraxonrasib (RMC-6236)

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%.

What comes next

The phase 1–2 study was not randomized against chemotherapy, so it cannot establish comparative superiority. A phase 3 first-line study is evaluating daraxonrasib alone or with gemcitabine/nab-paclitaxel against chemotherapy in untreated metastatic pancreatic cancer.

Serial blood-based analyses in first-line combination work have shown deep reductions in RAS ctDNA. These molecular responses are promising, but ctDNA clearance remains a biomarker rather than evidence of cure.

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.