{"entity":{"id":"sotorasib","kind":"drug","name":"Sotorasib","aka":[],"tldr":"Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure.","summary":"Sotorasib is a covalent inhibitor that binds cysteine 12 in the switch-II pocket of mutant KRAS, locking KRAS G12C in its inactive GDP-bound state; it was the first drug to hit KRAS, approved in 2021 after four decades of failure. CodeBreaK 100 gave a 37% response rate in previously treated NSCLC, CodeBreaK 200 showed a progression-free survival advantage over docetaxel, and CodeBreaK 300 with panitumumab in colorectal cancer gave PFS 5.6 versus 2.2 months (HR 0.49), leading to approval in January 2025. The label dose is 960 mg daily, with 240 mg an optional lower dose in NSCLC; hepatotoxicity (25%, 12% grade 3 or higher) is the main concern. Full approval in NSCLC still awaits confirmatory data, and resistance emerges faster than with EGFR or ALK drugs. For a newcomer: proof that the 'undruggable' KRAS could be drugged, with modest but real benefit.","status":"approved","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Sotorasib","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Sotorasib"},{"label":"Strickler et al., CodeBreaK 100 pancreatic cohort (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2208470"},{"label":"Lumakras label (openFDA): indications","url":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22LUMAKRAS%22"},{"label":"FDA oncology approval notifications","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications"},{"label":"NICE TA781: sotorasib for previously treated KRAS G12C mutation-positive advanced non-small-cell lung cancer","url":"https://www.nice.org.uk/guidance/ta781"}],"tags":[],"related":["kras-g12c"],"cancers":["nsclc","colorectal","kras-g12c-colorectal","kras-g12c-nsclc","kras-g12c-pdac","pancreatic","lung-cancer"],"sections":[],"technologies":["kras-inhibitors"],"targets":["kras"],"drugs":[],"companies":["amgen"],"institutions":[],"pathways":[],"terms":["cancer-drugs-fund"],"trials":["codebreak-300","nct05920356","nct06252649","nct07563738","nct05074810","nct07172919","codebreak-100","codebreak-200"],"people":[],"bottlenecks":[],"keyPapers":["paper-codebreak-300-nejm-2023","paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020"],"journals":[],"dependsOn":[],"notes":["Pancreatic cancer: the Lumakras label (effective 22 January 2025) covers KRAS G12C lung cancer and, with panitumumab, colorectal cancer, not pancreatic cancer; the EMA and NICE (TA781, lung cancer) likewise. The CodeBreaK 100 pancreatic cohort (38 patients: response 21 percent, median overall survival 6.9 months) is the basis of the NCCN listing for KRAS G12C pancreatic cancer after first-line therapy; daraxonrasib, approved for all previously treated metastatic pancreatic adenocarcinoma, covers G12C as well.","Pancreatic ductal adenocarcinoma: CodeBreaK 100 gave 8 confirmed responses among 38 previously treated KRAS G12C patients (21%), with progression-free survival 4.0 months and overall survival 6.9 months; G12C is only 1 to 2% of pancreatic cancers (Strickler 2023).","Colorectal cancer biomarkers: KRAS G12C, about 3% of colorectal cancers, and only in combination with panitumumab, because blocking G12C alone triggers adaptive EGFR reactivation in this tissue (CodeBreaK 300). G12C patients present more often with lung and liver metastases and have shorter survival than other KRAS-mutant patients (Schirripa 2020)."],"brand":"Lumakras","modality":"Small-molecule inhibitor (KRAS G12C)","mechanism":"Covalent binder to cysteine-12 in the switch-II pocket, locking KRAS G12C in the inactive GDP state.","approvals":[{"region":"US","year":2021,"indication":"KRAS G12C NSCLC, previously treated (accelerated)"},{"region":"US","year":2025,"indication":"KRAS G12C colorectal cancer with panitumumab"},{"region":"EU","year":2022,"indication":"EU brand Lumykras","note":"Conditional marketing authorisation"},{"region":"US","year":2025,"indication":"KRAS G12C-mutated metastatic colorectal cancer after fluoropyrimidine, oxaliplatin and irinotecan chemotherapy, with panitumumab","note":"Approved 16 January 2025 on CodeBreaK 300. CodeBreaK 301 is testing the first-line combination. No NICE recommendation for colorectal cancer at September 2026."},{"region":"England (NICE)","year":2022,"indication":"KRAS G12C mutation-positive locally advanced or metastatic non-small-cell lung cancer that has progressed on, or after intolerance of, platinum-based chemotherapy or PD-1/PD-L1 immunotherapy","note":"TA781, published 30 March 2022, recommends sotorasib for use within the Cancer Drugs Fund only, under a managed access agreement, because the clinical evidence was uncertain."}],"mechanismSteps":["Oral drug is absorbed and reaches the tumour","Binds the ATP pocket (or allosteric site) of KRAS G12C","Phosphorylation of downstream substrates stops","Covalent bond to the mutant cysteine locks KRAS in the inactive GDP-bound state","Oncogene-addicted cells arrest and undergo apoptosis"],"dosing":{"route":"Oral","schedule":"960 mg once daily (240 mg daily is the label-optional lower dose in NSCLC); with panitumumab in colorectal cancer","modifications":"Hold for grade ≥3 hepatotoxicity; discontinue for ILD","monitoring":"LFTs every 3 weeks for 3 months then monthly; respiratory symptoms","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1"},"toxicity":[{"event":"Diarrhoea","anyGradePct":42,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Musculoskeletal pain","anyGradePct":35,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Nausea","anyGradePct":26,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Fatigue","anyGradePct":26,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Hepatotoxicity","anyGradePct":25,"grade3PlusPct":12,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Cough","anyGradePct":20,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Vomiting","anyGradePct":17,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"},{"event":"Interstitial lung disease","anyGradePct":2.2,"grade3PlusPct":1.1,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1","note":"CodeBreaK 100"}],"access":[{"country":"US","reimbursement":"Medicare Part D (oral); commercial plans per formulary, often with prior authorisation","assistance":"https://www.amgensupportplus.com","source":"https://www.cms.gov/medicare/payment/part-b-drugs/asp-pricing-files","asOf":"2026-09-06"},{"country":"UK","reimbursement":"NICE: recommended via Cancer Drugs Fund for KRAS G12C NSCLC after platinum (TA781); later terminated then re-appraised","source":"https://www.nice.org.uk/guidance/published?ngt=Technology%20appraisal%20guidance","asOf":"2026-09-06"}],"regulatoryEvents":[{"date":"2020-12","type":"designation","region":"US","note":"Breakthrough Therapy designation","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2021-05-28","type":"accelerated-approval","region":"US","note":"Accelerated approval, KRAS G12C NSCLC after ≥1 therapy: first KRAS inhibitor The confirmatory requirement was still open 5.3 years later, when the FDA's table was read.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","indication":"Treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy."},{"date":"2023-12","type":"crl","region":"US","note":"FDA declines full approval based on CodeBreaK 200; postmarketing dose study required","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2025-01-16","type":"approval","region":"US","note":"KRAS G12C colorectal cancer with panitumumab (CodeBreaK 300)","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"}]},"route":"/drugs/sotorasib/","neighbours":{"biomarker":[{"id":"kras-g12c","kind":"biomarker","name":"KRAS G12C","route":"/biomarkers/kras-g12c/"},{"id":"ras-wild-type","kind":"biomarker","name":"RAS wild-type (extended KRAS and NRAS testing)","route":"/biomarkers/ras-wild-type/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"early-onset-colorectal","kind":"cancer","name":"Early-onset colorectal cancer (under 50)","route":"/cancers/early-onset-colorectal/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"kras-g12c-colorectal","kind":"cancer","name":"KRAS G12C-mutant colorectal cancer","route":"/cancers/kras-g12c-colorectal/"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","route":"/cancers/kras-g12c-pdac/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"company":[{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/"}],"term":[{"id":"cancer-drugs-fund","kind":"term","name":"Cancer Drugs Fund (England)","route":"/terms/cancer-drugs-fund/"},{"id":"inhibitor","kind":"term","name":"Inhibitor","route":"/terms/inhibitor/"},{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"},{"id":"lung-uk-drug-access","kind":"term","name":"Lung cancer drugs in England: what NICE has recommended","route":"/terms/lung-uk-drug-access/"},{"id":"pancreatic-cancer-uk-drug-access","kind":"term","name":"Pancreatic cancer drugs in England: NICE appraisals and the Cancer Drugs Fund (September 2026)","route":"/terms/pancreatic-cancer-uk-drug-access/"},{"id":"project-optimus","kind":"term","name":"Project Optimus","route":"/terms/project-optimus/"}],"trial":[{"id":"nct07563738","kind":"trial","name":"A 2-part Phase 1/2 Open-label Trial on ODM-212","route":"/trials/nct07563738/"},{"id":"nct07172919","kind":"trial","name":"A Rollover Study Evaluating Sotorasib With or Without Panitumumab in Participants With KRAS p.G12C Mutation","route":"/trials/nct07172919/"},{"id":"nct05920356","kind":"trial","name":"A Study Evaluating Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Participants Wi","route":"/trials/nct05920356/"},{"id":"codebreak-100","kind":"trial","name":"CodeBreaK 100 (pancreatic cancer cohort)","route":"/trials/codebreak-100/"},{"id":"codebreak-200","kind":"trial","name":"CodeBreaK 200","route":"/trials/codebreak-200/"},{"id":"codebreak-300","kind":"trial","name":"CodeBreaK 300","route":"/trials/codebreak-300/"},{"id":"krascendo-1","kind":"trial","name":"Krascendo 1","route":"/trials/krascendo-1/"},{"id":"nct05074810","kind":"trial","name":"Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients","route":"/trials/nct05074810/"},{"id":"nct05845450","kind":"trial","name":"Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN)","route":"/trials/nct05845450/"},{"id":"nct06252649","kind":"trial","name":"Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal","route":"/trials/nct06252649/"}],"paper":[{"id":"paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023","kind":"paper","name":"CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer","route":"/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/"},{"id":"paper-codebreak-200-lancet-2023","kind":"paper","name":"CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug","route":"/key-papers/paper-codebreak-200-lancet-2023/"},{"id":"paper-codebreak-300-nejm-2023","kind":"paper","name":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer","route":"/key-papers/paper-codebreak-300-nejm-2023/"},{"id":"paper-drug-dosing-conundrum-nejm-2021","kind":"paper","name":"FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high","route":"/key-papers/paper-drug-dosing-conundrum-nejm-2021/"},{"id":"paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020","kind":"paper","name":"KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population","route":"/key-papers/paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020/"},{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/colorectal-roadmap/"},{"id":"drug-discovery-roadmap","kind":"roadmap","name":"Drug discovery roadmap: screening in mice → maps of dependency → designing in silico","route":"/roadmaps/drug-discovery-roadmap/"},{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/"},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}],"pathway":[{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","route":"/pathways/oncogene-activation-two-hit/"},{"id":"micrornas-in-cancer","kind":"pathway","name":"MicroRNAs in cancer","route":"/pathways/micrornas-in-cancer/"},{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"pairing":[{"id":"kras-plus-egfr-crc","kind":"pairing","name":"KRAS G12C inhibitor + anti-EGFR antibody (colorectal)","route":"/pairings/kras-plus-egfr-crc/"}],"person":[{"id":"ferdinandos-skoulidis","kind":"person","name":"Ferdinandos Skoulidis","route":"/people/ferdinandos-skoulidis/"},{"id":"kevan-shokat","kind":"person","name":"Kevan M. Shokat","route":"/people/kevan-shokat/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"idea":[{"id":"idea-bio1-upfront-bypass-combination","kind":"idea","name":"Add the second drug on day one when the escape route is predictable","route":"/ideas/idea-bio1-upfront-bypass-combination/"},{"id":"idea-bio1-pan-ras-covalent-g12d","kind":"idea","name":"Covalent chemistry for the RAS mutations that still have no drug","route":"/ideas/idea-bio1-pan-ras-covalent-g12d/"},{"id":"idea-bio1-evolution-forecasting","kind":"idea","name":"Forecast the next resistance mutation like the weather","route":"/ideas/idea-bio1-evolution-forecasting/"},{"id":"idea-reg-global-dose-optimisation-guideline","kind":"idea","name":"Make pre-approval dose optimisation an ICH standard so it is done once worldwide","route":"/ideas/idea-reg-global-dose-optimisation-guideline/"},{"id":"idea-tr1-randomised-dose-comparison-before-pivotal","kind":"idea","name":"Randomise at least two doses in phase 2 before any pivotal trial","route":"/ideas/idea-tr1-randomised-dose-comparison-before-pivotal/"},{"id":"idea-moon-post-approval-dose-deescalation","kind":"idea","name":"Randomised lower-dose trials for approved drugs with quality of life as the primary endpoint","route":"/ideas/idea-moon-post-approval-dose-deescalation/"}],"drug":[{"id":"guardant360-cdx","kind":"drug","name":"Guardant360 CDx","route":"/drugs/guardant360-cdx/"}]}}