{"entity":{"id":"paper-karapetis-kras-cetuximab-colorectal-nejm-2008","kind":"paper","name":"K-ras mutations and benefit from cetuximab in advanced colorectal cancer","aka":[],"tldr":"The first randomised proof that a mutation can say a drug will not work: in a trial of cetuximab against supportive care alone, only patients whose tumours had a normal K-ras gene lived longer.","summary":"Tumour samples from 394 of 572 patients (68.9%) with colorectal cancer randomly assigned to cetuximab plus best supportive care or best supportive care alone were analysed for activating mutations in exon 2 of the K-ras gene. Of the tumours evaluated, 42.3% had at least one such mutation. The effectiveness of cetuximab was significantly associated with K-ras mutation status (interaction p = 0.01 for overall survival and p less than 0.001 for progression-free survival). In patients with wild-type tumours, cetuximab improved median overall survival from 4.8 to 9.5 months (hazard ratio 0.55) and progression-free survival from 1.9 to 3.7 months (hazard ratio 0.40). Among patients with mutated tumours there was no difference in overall survival (hazard ratio 0.98) or progression-free survival (hazard ratio 0.99). K-ras status was not associated with survival in the supportive-care group, so it is predictive rather than prognostic in this setting.","asOf":"2026-09-24","links":[{"label":"Karapetis et al., N Engl J Med 2008: K-ras mutation and benefit from cetuximab (CO.17, 394 tumours)","url":"https://doi.org/10.1056/NEJMoa0804385"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/18946061/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["kras","egfr"],"drugs":["cetuximab"],"companies":[],"institutions":[],"pathways":["ras-mapk"],"terms":["wild-type","driver-mutation"],"trials":[],"people":["christos-karapetis"],"bottlenecks":[],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2008,"doi":"10.1056/NEJMoa0804385","pmid":"18946061","authors":"Karapetis CS, Khambata-Ford S, Jonker DJ, et al.","paperType":"rct","findings":["K-ras exon 2 mutation in 42.3% of 394 evaluable tumours.","Wild-type: overall survival 9.5 against 4.8 months with cetuximab (hazard ratio 0.55).","Mutant: no benefit (overall survival hazard ratio 0.98)."],"whatItMeans":"It created the negative predictive biomarker in solid tumour oncology and, with the panitumumab analysis of the same year, restricted EGFR antibodies to RAS wild-type disease worldwide.","caveats":["Retrospective biomarker analysis of a randomised trial, with tissue for 69% of patients.","Exon 2 only; the other RAS codons came five years later (Douillard 2013).","Sidedness had not yet been recognised, so the wild-type group mixed left and right."],"changedPractice":true,"participants":572},"route":"/key-papers/paper-karapetis-kras-cetuximab-colorectal-nejm-2008/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"therascreen-cdx","kind":"drug","name":"therascreen companion diagnostic kits (KRAS, EGFR, PIK3CA, FGFR, BRAF)","route":"/drugs/therascreen-cdx/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"wild-type","kind":"term","name":"Wild-type (WT)","route":"/terms/wild-type/"}],"person":[{"id":"christos-karapetis","kind":"person","name":"Christos Karapetis","route":"/people/christos-karapetis/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"biomarker":[{"id":"kras-g12d","kind":"biomarker","name":"KRAS G12D (and other non-G12C KRAS mutations)","route":"/biomarkers/kras-g12d/"}]}}