Direct pharmacological inhibition of KRAS, for decades considered undruggable: G12D and RAS(ON) inhibitors, the response rates they achieve, and the resistance mechanisms that emerge as tumours escape them.
Paired ctDNA profiling of 44 patients with RAS-mutant metastatic pancreatic cancer who progressed on daraxonrasib monotherapy found acquired RAS pathway alterations in 26 of 44 patients (59%), with mutant KRAS amplification the dominant mechanism (36%, 16 of 44).
Open-label, single-arm phase 1b/2 trial of HRS-4642 — an intravenous, liposomal-nanoparticle KRAS-G12D inhibitor — added to gemcitabine and nab-paclitaxel (the "AG" backbone) in advanced KRAS-G12D-mutant pancreatic ductal adenocarcinoma (PDAC); 68 patients screened, 31 treated, 30 treatment-naive