Revolution in the next KRAS battleground

With Revolution Medicines initiating dosing in the first-in-human study of its KRAS G12D inhibitor RMC-9805, the industry pipeline now comprises six clinical-stage projects with this modality. If the KRAS G12C space, now featuring the approved drugs Lumakras from Amgen and Krazati from Mirati, fast became crowded, then that targeting KRAS G12D-driven tumours might follow suit, given that G12D is said to be the most common driver of RAS-addicted human cancers. Revolution’s phase 1 study is enrolling patients with G12D-driven cancers, and is designed to inform the phase 2 dose; the company, which recently acquired EQRX for the latter’s cash balance, is also developing projects targeting various other KRAS mutations, in addition to assets with companion mechanisms including SHP2 and SOS1. The competition, meanwhile, includes Mirati’s MRTX1133 and Astellas’s degrader project ASP3082, as well as engineered T-cell receptor approaches at the NCI (this had been in Kite’s pipeline, so Gilead presumably has some rights over it), Medigene and the private companies Affini-T and Anocca. KRAS G12D inhibitor pipelineProjectCompanyMechanism of actionStatussiG12D LODERSilenseedKRAS G12D siRNAPh2 in pancreatic cancerMRTX1133Mirati TherapeuticsKRAS G12D inhibitorPh1/2 in G12D-mutant solid tumoursAnti-KRAS G12D mTCR PBLGilead (ex Kite)/ NCIHLA-A11-restricted KRAS G12D TCRPh1/2 in G12D-mutant HLA-A*11:01 cancersRMC-9805Revolution MedicinesKRAS G12D inhibitorPh1 in G12D-mutant solid tumoursHRS-4642Jiangsu HengRui MedicineKRAS G12D inhibitorPh1 in G12D-mutant solid tumoursASP3082AstellasKRAS G12D degraderPh1 in G12D-mutant solid tumoursTD010Tyligand BioscienceKRAS G12D inhibitorPreclinicalUnnamedTen63 TherapeuticsKRAS G12D inhibitorPreclinicalVRTX153VRise TherapeuticsKRAS G12D inhibitorPreclinicalQTX3046Quanta TherapeuticsKRAS G12D inhibitorPreclinicalVRTX144VRise TherapeuticsKRAS G12D inhibitorPreclinicalERAS-4ErascaKRAS G12D inhibitorPreclinicalNT-0300NeuBase TherapeuticsKRAS G12D/V inhibitorPreclinicalPP-008Primary PeptidesKRAS G12D degraderPreclinicalJAB-22000Jacobio PharmaceuticalsKRAS G12D InhibitorPreclinicalAFNT-212Affini-T TherapeuticsHLA-A11-restricted KRAS G12D TCRPreclinicalMDG2021MedigeneHLA-A11-restricted KRAS G12D TCRPreclinicalUnnamedAnoccaHLA-A11-restricted KRAS G12D TCRPreclinicalNote: *comprises clinical and selected preclinical projects only. Source: OncologyPipeline.