{"entity":{"id":"adagrasib","kind":"drug","name":"Adagrasib","aka":[],"tldr":"Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer.","summary":"Adagrasib is a covalent KRAS G12C inhibitor with a 24-hour half-life and brain penetration, dosed at 600 mg twice daily to keep the target continuously occupied. It was approved in 2022 (accelerated) for previously treated KRAS G12C NSCLC on KRYSTAL-1, with KRYSTAL-12 as the randomised follow-on, and in 2024 with cetuximab for KRAS G12C colorectal cancer on the KRYSTAL-1 combination cohort. Mirati developed it and was acquired by Bristol Myers Squibb in 2024. Gastrointestinal toxicity is frequent (diarrhoea 70%, nausea 69%), with hepatotoxicity (37%) and QT prolongation (20%) also needing monitoring. Activity in brain metastases is the main argument for choosing it over sotorasib, but resistance still develops within months. For a newcomer: the second KRAS G12C pill, distinguished by its long action and brain reach.","status":"approved","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Adagrasib","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Adagrasib"},{"label":"Bekaii-Saab et al., adagrasib in KRAS G12C solid tumours, KRYSTAL-1 (JCO 2023)","url":"https://doi.org/10.1200/JCO.23.00434"},{"label":"Krazati label (openFDA): indications","url":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22KRAZATI%22"},{"label":"FDA oncology approval notifications","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications"}],"tags":[],"related":["kras-g12c"],"cancers":["nsclc","colorectal","pancreatic","kras-g12c-colorectal","kras-g12c-nsclc","kras-g12c-pdac"],"sections":[],"technologies":["kras-inhibitors"],"targets":["kras"],"drugs":[],"companies":["bms"],"institutions":[],"pathways":[],"terms":[],"trials":["nct04613596","nct05853575","nct05609578","nct07415031","nct06875310","nct03785249"],"people":[],"bottlenecks":[],"keyPapers":["paper-krystal-12-plain-language-summary-future-oncol-2026","paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","paper-schirripa-kras-g12c-metastatic-colorectal-clin-colorectal-cancer-2020"],"journals":[],"dependsOn":[],"notes":["Pancreatic cancer: the Krazati label (effective 25 March 2026) covers KRAS G12C lung and colorectal cancer only; the KRYSTAL-1 phase 2 cohort of other solid tumours reported responses in 7 of 21 pancreatic cancers (33.3 percent), a median duration of response of 5.3 months and progression-free survival of 7.4 months across the cohort (JCO 2023), which is the basis of the NCCN listing. No NICE or EMA pancreatic indication.","Pancreatic ductal adenocarcinoma: KRYSTAL-1's solid-tumour cohort gave 7 responses among 21 KRAS G12C pancreatic patients (33.3%), with a median duration of response of 5.3 months across tumour types (Bekaii-Saab 2023).","Colorectal cancer biomarkers: KRAS G12C, with cetuximab rather than alone, for the same adaptive EGFR reactivation reason (KRYSTAL-1)."],"brand":"Krazati","modality":"Small-molecule inhibitor (KRAS G12C)","mechanism":"Covalent KRAS G12C inhibitor, 24-hour half-life.","approvals":[{"region":"US","year":2022,"indication":"KRAS G12C NSCLC (accelerated)"},{"region":"US","year":2024,"indication":"KRAS G12C colorectal cancer with cetuximab"},{"region":"EU","year":2024,"indication":"KRAS G12C NSCLC after ≥1 line; 5 Jan 2024 (conditional)","note":"Conditional marketing authorisation"},{"region":"US","year":2024,"indication":"KRAS G12C-mutated locally advanced or metastatic colorectal cancer after fluoropyrimidine, oxaliplatin and irinotecan chemotherapy, with cetuximab","note":"Accelerated approval on 21 June 2024 on the KRYSTAL-1 colorectal cohort; KRYSTAL-10 is the confirmatory randomised trial. No NICE recommendation for colorectal cancer at September 2026."}],"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 inhibitor with a 24-hour half-life and CNS penetration","Oncogene-addicted cells arrest and undergo apoptosis"],"dosing":{"route":"Oral","schedule":"600 mg twice daily; with cetuximab in colorectal cancer","modifications":"Reduce to 400 mg BID then 600 mg once daily for GI, hepatic, or QTc toxicity","monitoring":"LFTs monthly for 3 months; ECG and electrolytes; renal function","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01"},"toxicity":[{"event":"Diarrhoea","anyGradePct":70,"grade3PlusPct":0.9,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Nausea","anyGradePct":69,"grade3PlusPct":4.3,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Fatigue","anyGradePct":59,"grade3PlusPct":7,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Vomiting","anyGradePct":56,"grade3PlusPct":0.9,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Musculoskeletal pain","anyGradePct":41,"grade3PlusPct":7,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Hepatotoxicity","anyGradePct":37,"grade3PlusPct":10,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Renal impairment","anyGradePct":36,"grade3PlusPct":6,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Dyspnoea","anyGradePct":35,"grade3PlusPct":10,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"Oedema","anyGradePct":32,"grade3PlusPct":0,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"},{"event":"QT prolongation","anyGradePct":20,"grade3PlusPct":6,"source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b8bf078-34c2-4f45-9012-38a8ac082b01","note":"KRYSTAL-1 NSCLC"}],"access":[{"country":"US","reimbursement":"Medicare Part D (oral); commercial plans per formulary, often with prior authorisation","assistance":"https://www.bmsaccesssupport.com","source":"https://www.cms.gov/medicare/payment/part-b-drugs/asp-pricing-files","asOf":"2026-09-06"},{"country":"UK","reimbursement":"NICE: appraisal for KRAS G12C NSCLC (2025)","source":"https://www.nice.org.uk/guidance/published?ngt=Technology%20appraisal%20guidance","asOf":"2026-09-06"}],"regulatoryEvents":[{"date":"2021-06","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":"2022-12-12","type":"accelerated-approval","region":"US","note":"Accelerated approval, KRAS G12C NSCLC after ≥1 therapy The confirmatory requirement was still open 3.8 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":"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":"2024-06-01","type":"accelerated-approval","region":"US","note":"Accelerated approval on a surrogate endpoint, with a confirmatory trial required.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer","indication":"In combination with cetuximab for the treatment of adult patients with KRAS G12C mutated locally advanced or metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy."},{"date":"2024-06-21","type":"approval","region":"US","note":"KRAS G12C colorectal cancer with cetuximab (accelerated)","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2025-06","type":"approval","region":"US","note":"Full approval in NSCLC (KRYSTAL-12)","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},{"date":"2026-09-01","type":"withdrawal","region":"US","note":"Withdrawn: the indication came off the label 2.3 years after its accelerated approval.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer","indication":"In combination with cetuximab for the treatment of adult patients with KRAS G12C mutated locally advanced or metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy."}]},"route":"/drugs/adagrasib/","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":"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":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"trial":[{"id":"nct06412198","kind":"trial","name":"A Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations","route":"/trials/nct06412198/"},{"id":"nct07415031","kind":"trial","name":"A Solid Tumor Study for Long Term Treatment of Cancer Patients Who Participated in Adagrasib Studies","route":"/trials/nct07415031/"},{"id":"nct06875310","kind":"trial","name":"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)","route":"/trials/nct06875310/"},{"id":"nct06248606","kind":"trial","name":"Adagrasib + SRS for Patients With Metastatic KRAS G12C-mutated NSCLC With Untreated Brain Metastases","route":"/trials/nct06248606/"},{"id":"nct05609578","kind":"trial","name":"Combination Therapies With Adagrasib in Patients With Advanced NSCLC With KRAS G12C Mutation","route":"/trials/nct05609578/"},{"id":"krascendo-1","kind":"trial","name":"Krascendo 1","route":"/trials/krascendo-1/"},{"id":"krystal-12","kind":"trial","name":"KRYSTAL-12","route":"/trials/krystal-12/"},{"id":"nct03785249","kind":"trial","name":"Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1","route":"/trials/nct03785249/"},{"id":"nct04613596","kind":"trial","name":"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","route":"/trials/nct04613596/"},{"id":"nct05853575","kind":"trial","name":"Trial of Two Adagrasib Dosing Regimens in NSCLC With KRAS G12C Mutation (KRYSTAL 21)","route":"/trials/nct05853575/"}],"paper":[{"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-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-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023","kind":"paper","name":"KRYSTAL-1: adagrasib in advanced solid tumours harbouring a KRAS G12C mutation, including pancreatic cancer","route":"/key-papers/paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023/"},{"id":"paper-krystal-1-crc-yaeger-nejm-2023","kind":"paper","name":"KRYSTAL-1: adagrasib with or without cetuximab in KRAS G12C-mutated colorectal cancer","route":"/key-papers/paper-krystal-1-crc-yaeger-nejm-2023/"},{"id":"paper-krystal-12-plain-language-summary-future-oncol-2026","kind":"paper","name":"KRYSTAL-12 plain language summary: adagrasib for non-small-cell lung cancer with KRAS G12C mutations","route":"/key-papers/paper-krystal-12-plain-language-summary-future-oncol-2026/"},{"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":"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":"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/"}],"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/"},{"id":"pasi-janne","kind":"person","name":"Pasi A. Jänne","route":"/people/pasi-janne/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"idea":[{"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/"}],"term":[{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"}],"drug":[{"id":"resolution-ctdx-first","kind":"drug","name":"Resolution ctDx FIRST","route":"/drugs/resolution-ctdx-first/"}]}}