KRAS & RAS inhibitors
Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021.
Covalent G12C inhibitors (sotorasib, adagrasib, divarasib, olomorasib) work in NSCLC and, with cetuximab, in colorectal cancer. Non-covalent G12D inhibitors (zoldonrasib, MRTX1133) and pan-RAS(ON) tri-complex inhibitors (daraxonrasib RMC-6236, in phase 3 RASolute 302 in second-line pancreatic cancer) aim at pancreatic cancer, where KRAS is near-universal. Degraders and vaccines (ELI-002) follow.
How it works
Inhibitors bind covalently to the mutant cysteine in the switch-II pocket (G12C), or form a cyclophilin-A-mediated tri-complex that blocks effector binding (RAS(ON) inhibitors).
- First drugs for a 40-year-old target
- Modest durability as monotherapy
- Adaptive RTK feedback requires combinations
Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer.
The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours.
Divarasib is Roche's KRAS G12C pill, the first to beat the two approved KRAS drugs head-to-head (July 2026).
A next-generation KRAS G12C drug that hits the active form of the protein, from the same company as daraxonrasib.
MRTX1133 was the first potent chemical tool against KRAS G12D, and proved the mutation could be drugged even though it lacks the reactive handle G12C has.
Olomorasib is Lilly's KRAS G12C pill, designed to combine safely with immunotherapy in first-line lung cancer.
Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure.
The first drug aimed specifically at KRAS G12D, the single most common mutation in pancreatic cancer. Early combination data in 2026 showed half of previously treated patients responding.
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone barely works in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.
Latest papers
topQuery for this technology: (TITLE:"KRAS inhibitor" OR ABSTRACT:"KRAS inhibitor" OR TITLE:"KRAS G12C" OR ABSTRACT:"KRAS G12C" OR TITLE:"KRAS G12D" OR ABSTRACT:"KRAS G12D" OR TITLE:"pan-RAS inhibitor" OR ABSTRACT:"pan-RAS inhibitor"). Results are unfiltered search hits about KRAS & RAS inhibitors, not a curated reading list.