# KRAS & RAS inhibitors

Source: https://onco.cc/technologies/kras-inhibitors/  
OnCo record `kras-inhibitors` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021.

## Summary

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.

## Fields

- Kind: Technology
- Status: approved
- Last checked: 2026-09-04
- Principle: 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).
- Since: 2021
- Strengths: First drugs for a 40-year-old target
- Limitations: Modest durability as monotherapy; Adaptive RTK feedback requires combinations

## Notes

- Pancreatic cancer biomarkers: the covalent G12C inhibitors reach only the 1 to 2% with that allele (21 to 33% response; Strickler 2023, Bekaii-Saab 2023), whereas the tri-complex RAS(ON) inhibitors address the G12D, G12V, G12R and Q61 alleles that make up the rest, with daraxonrasib giving overall survival 13.2 against 6.6 months in previously treated RAS G12-mutant disease (O'Reilly 2026). Allele-level reporting therefore matters: G12D is both the commonest and the worst-prognosis allele (Bournet 2016).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- Wikipedia: https://en.wikipedia.org/wiki/KRAS

## Connected records

- cancers: [Borderline resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/borderline-resectable-pdac/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [KRAS G12C-mutant colorectal cancer](https://onco.cc/cancers/kras-g12c-colorectal/), [KRAS G12C-mutant non-small-cell lung cancer](https://onco.cc/cancers/kras-g12c-nsclc/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [Locally advanced unresectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/locally-advanced-pdac/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/resectable-pdac/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [NRAS](https://onco.cc/targets/nras/), [SHP2 (PTPN11)](https://onco.cc/targets/shp2/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Divarasib](https://onco.cc/drugs/divarasib/), [Elironrasib](https://onco.cc/drugs/elironrasib/), [Fulzerasib](https://onco.cc/drugs/fulzerasib/), [Garsorasib](https://onco.cc/drugs/garsorasib/), [Glecirasib](https://onco.cc/drugs/glecirasib/), [MRTX1133](https://onco.cc/drugs/mrtx1133/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Zoldonrasib](https://onco.cc/drugs/zoldonrasib/)
- companies: [Amgen](https://onco.cc/companies/amgen/), [BridgeBio Oncology Therapeutics](https://onco.cc/companies/bridgebio-oncology-therapeutics/), [Bristol Myers Squibb](https://onco.cc/companies/bms/), [D3 Bio (Wuxi)](https://onco.cc/companies/d3-bio-wuxi/), [Erasca](https://onco.cc/companies/erasca/), [Frontier Medicines](https://onco.cc/companies/frontier-medicines/), [Insilico Medicine](https://onco.cc/companies/insilico-medicine/), [Kumquat Biosciences](https://onco.cc/companies/kumquat-biosciences/), [Quanta Therapeutics](https://onco.cc/companies/quanta-therapeutics/), [Revolution Medicines](https://onco.cc/companies/revolution-medicines/), [Treeline Biosciences](https://onco.cc/companies/treeline-biosciences/), [Verastem Oncology](https://onco.cc/companies/verastem/)
- key papers: [CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer](https://onco.cc/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/), [CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug](https://onco.cc/key-papers/paper-codebreak-200-lancet-2023/), [CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer](https://onco.cc/key-papers/paper-codebreak-300-nejm-2023/), [Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy](https://onco.cc/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/), [Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer](https://onco.cc/key-papers/paper-daraxonrasib-pancreatic-n-engl-j-med-2026/), [KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population](https://onco.cc/key-papers/paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020/), [KRAS G12D mutation subtype is a prognostic factor for advanced pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-bournet-kras-g12d-prognosis-pancreatic-ctg-2016/), [KRYSTAL-1: adagrasib in advanced solid tumours harbouring a KRAS G12C mutation, including pancreatic cancer](https://onco.cc/key-papers/paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023/), [KRYSTAL-1: adagrasib with or without cetuximab in KRAS G12C-mutated colorectal cancer](https://onco.cc/key-papers/paper-krystal-1-crc-yaeger-nejm-2023/), [Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable](https://onco.cc/key-papers/paper-ostrem-kras-g12c-nature-2013/)
- trials: [A Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations](https://onco.cc/trials/nct06412198/), [A Phase 2 Clinical Study of Combination Therapy With ABSK043 and Glecirasib](https://onco.cc/trials/nct07164170/), [A Phase II Study Evaluating JAB-21822 Monotherapy in Adult Patients With Pancreatic Cancer and Other Solid Tumors Harboring the KRAS p.G12C Mutation.](https://onco.cc/trials/nct06008288/), [A Phase II Study of GFH375 Combined With GFS202A or GFH276 Versus GFH375 Monotherapy in Patients With Previously Treated Locally Advanced Unresectable or Metast](https://onco.cc/trials/nct07784374/), [A Rollover Study Evaluating Sotorasib With or Without Panitumumab in Participants With KRAS p.G12C Mutation](https://onco.cc/trials/nct07172919/), [A Solid Tumor Study for Long Term Treatment of Cancer Patients Who Participated in Adagrasib Studies](https://onco.cc/trials/nct07415031/), [A Study Evaluating Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Participants Wi](https://onco.cc/trials/nct05920356/), [A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Particip](https://onco.cc/trials/nct06793215/), [A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Par](https://onco.cc/trials/nct05789082/), [A Study of Adagrasib Plus Pembrolizumab Plus Chemotherapy vs. Placebo Plus Pembrolizumab Plus Chemotherapy in Participants With Previously Untreated Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-4)](https://onco.cc/trials/nct06875310/), [A Study of Amivantamab and Olomorasib Combination Therapy in Participants With Metastatic Non-Small Cell Lung Cancer](https://onco.cc/trials/nct07227025/), [A Study of BL-B01D1 Combined With Glecirasib in Patients With KRAS G12C-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer](https://onco.cc/trials/nct07827261/), [A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer](https://onco.cc/trials/nct06119581/), [A Study of JAB-21822 in Adult Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation in China](https://onco.cc/trials/nct05009329/), [A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1](https://onco.cc/trials/nct05276726/), [A Study of Olomorasib (LY3537982) in Participants With Advanced Colorectal Cancer and a KRAS G12C Mutation](https://onco.cc/trials/nct07814417/), [A Study to Evaluate the Efficacy and Safety of Divarasib Compared With Investigator's Choice of Immunotherapy or Observation in Participants With Rese](https://onco.cc/trials/nct07541170/), [Adagrasib + SRS for Patients With Metastatic KRAS G12C-mutated NSCLC With Untreated Brain Metastases](https://onco.cc/trials/nct06248606/), [CodeBreaK 100 (pancreatic cancer cohort)](https://onco.cc/trials/codebreak-100/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [CodeBreaK 300](https://onco.cc/trials/codebreak-300/), [Combination Therapies With Adagrasib in Patients With Advanced NSCLC With KRAS G12C Mutation](https://onco.cc/trials/nct05609578/), [D-1553 Tablet Versus Docetaxel Injection for KRAS G12C Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer After Prior Standar](https://onco.cc/trials/nct06300177/), [Fulzerasib Sequential Sintilimab Plus Platinum-Doublet Neoadjuvant Therapy for Resectable KRAS G12C-Mutant NSCLC](https://onco.cc/trials/nct07492342/), [IBI351 Plus Cetuximab β in Untreated Advanced Non-small Cell Lung Cancer With KRAS G12C Mutation](https://onco.cc/trials/nct07198841/), [JAB-21822 in Combination With Cetuximab in Patients With Advanced CRC and Other Solid Tumors With KRAS G12C Mutation](https://onco.cc/trials/nct05194995/), [Krascendo 1](https://onco.cc/trials/krascendo-1/), [KRYSTAL-12](https://onco.cc/trials/krystal-12/), [Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients](https://onco.cc/trials/nct05074810/), [Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation](https://onco.cc/trials/nct05288205/), [Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination in Patients With a KRAS G](https://onco.cc/trials/nct04613596/), [Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN)](https://onco.cc/trials/nct05845450/), [RASolute 302](https://onco.cc/trials/rasolute-302/), [Study Investigating ASP3082 in Patients With Metastatic/Locally Advanced Non-small-cell Lung Cancer (NSCLC) and Pancreatic Ductal Adenocarcinoma (PDAC), With Bi](https://onco.cc/trials/nct07483983/), [Study of Daraxonrasib (RMC-6236) in Patients With RAS Mutated NSCLC (RASolve 301)](https://onco.cc/trials/nct06881784/), [Study of Daraxonrasib (RMC-6236) in Patients With Resected Pancreatic Ductal Adenocarcinoma (PDAC)](https://onco.cc/trials/nct07252232/), [Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma](https://onco.cc/trials/nct07491445/), [Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors](https://onco.cc/trials/nct06128551/), [Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)](https://onco.cc/trials/nct04956640/), [Study of Olomorasib (LY3537982) in Combination With Standard of Care in Participants With Resected or Unresectable KRAS G12C-mutant Non-Small Cell Lung Cancer](https://onco.cc/trials/nct06890598/), [Study of Pembrolizumab + Pemetrexed + Platinum Chemotherapy With or Without Zoldonrasib as First Line Treatment in Metastatic Non-squamous RAS G12D-Mu](https://onco.cc/trials/nct07777822/), [Study of RMC-6236 in Patients With Advanced Solid Tumors Harboring Specific Mutations in RAS](https://onco.cc/trials/nct05379985/), [Study of RMC-9805 in Participants With KRAS G12D-Mutant Solid Tumors](https://onco.cc/trials/nct06040541/), [Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal](https://onco.cc/trials/nct06252649/), [Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mut](https://onco.cc/trials/nct07805954/), [Study of Zoldonrasib + Chemo of Investigator's Choice vs Placebo + Chemo of Investigator's Choice as First-line Treatment in Metastatic KRAS G12D-muta](https://onco.cc/trials/nct07621718/), [Study to Evaluate D-1553 in Combination With IN10018 in Subjects With Solid Tumors](https://onco.cc/trials/nct05379946/), [Study to Evaluate D-1553 in Subjects With Solid Tumors](https://onco.cc/trials/nct04585035/), [Trial of Two Adagrasib Dosing Regimens in NSCLC With KRAS G12C Mutation (KRYSTAL 21)](https://onco.cc/trials/nct05853575/)
- ideas: [Covalent chemistry for the RAS mutations that still have no drug](https://onco.cc/ideas/idea-bio1-pan-ras-covalent-g12d/), [Making microsatellite-stable colorectal cancer immunotherapy-responsive](https://onco.cc/ideas/idea-immunotherapy-mss-crc/), [Off-the-shelf KRAS vaccines after pancreatic cancer surgery](https://onco.cc/ideas/idea-shared-kras-vaccine-adjuvant/), [RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression](https://onco.cc/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/), [RAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable](https://onco.cc/ideas/idea-ras-inhibitor-neoadjuvant-pdac/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/), [KRAS roadmap: undruggable → G12C → pan-RAS](https://onco.cc/roadmaps/kras-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- terms: [Colorectal cancer trials open today (registry snapshot)](https://onco.cc/terms/colorectal-trials-open-today/), [Hallmark: sustaining proliferative signalling](https://onco.cc/terms/sustaining-proliferative-signaling/), [Inhibitor](https://onco.cc/terms/inhibitor/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [Targeted therapy](https://onco.cc/terms/targeted-therapy-term/)
- pairings: [KRAS G12C inhibitor + anti-EGFR antibody (colorectal)](https://onco.cc/pairings/kras-plus-egfr-crc/)
- people: [Andrew J. Aguirre](https://onco.cc/people/andrew-aguirre/), [Ferdinandos Skoulidis](https://onco.cc/people/ferdinandos-skoulidis/), [Frank McCormick](https://onco.cc/people/frank-mccormick/), [Kevan M. Shokat](https://onco.cc/people/kevan-shokat/)
- bottlenecks: [Incentives reward me-too drugs and marginal gains](https://onco.cc/bottlenecks/b-incentive-misalignment/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- pathways: [Autophagy](https://onco.cc/pathways/autophagy/)
- institutions: [Beatson West of Scotland Cancer Centre / CRUK Scotland Institute](https://onco.cc/institutions/beatson-glasgow/), [Centro Nacional de Investigaciones Oncológicas (CNIO)](https://onco.cc/institutions/cnio/), [Frederick National Laboratory for Cancer Research](https://onco.cc/institutions/frederick-national-lab/), [Lustgarten Foundation](https://onco.cc/institutions/lustgarten-foundation/)

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