{"entity":{"id":"paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","kind":"paper","name":"Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)","aka":[],"tldr":"A trial designed from mouse avatars: screening 914 patients found 48 with HER2-amplified bowel cancer, and blocking HER2 two ways shrank tumours in 30 percent of the 27 who were treated.","summary":"Sartore-Bianchi, Trusolino, Martino and colleagues ran HERACLES as a proof-of-concept, multicentre, open-label phase 2 trial at four Italian academic cancer centres, after finding that dual HER2 blockade inhibited tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. Adults with KRAS exon 2 wild-type, HER2-positive metastatic colorectal cancer refractory to standard of care including cetuximab or panitumumab received intravenous trastuzumab and oral lapatinib 1,000 mg daily until progression. HER2 positivity used colorectal-specific immunohistochemistry and fluorescence in-situ hybridisation criteria the group had validated. The primary endpoint was objective response by independent central review.\n\nScreening 914 patients identified 48 (5 percent) with HER2-positive tumours, of whom 27 were eligible and treated.","asOf":"2026-09-24","links":[{"label":"Lancet Oncol 2016","url":"https://doi.org/10.1016/S1470-2045(16)00150-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27108243/"}],"tags":["colorectal-evidence"],"related":["paper-tcga-colon-rectal-molecular-characterization-nature-2012","paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023"],"cancers":["colorectal","her2-amplified-colorectal"],"sections":["targeted-therapy"],"technologies":["monoclonal-antibody","kinase-inhibitors"],"targets":["her2","kras"],"drugs":["trastuzumab","lapatinib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":["salvatore-siena","alberto-bardelli"],"bottlenecks":["b-rare-cancers","b-trial-enrolment","b-preclinical-models"],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2016,"doi":"10.1016/S1470-2045(16)00150-9","pmid":"27108243","authors":"Sartore-Bianchi A, Trusolino L, Martino C, et al.","paperType":"rct","findings":["914 KRAS exon 2 wild-type patients screened; 48 (5 percent) HER2-positive; 27 eligible and treated.","Objective response in 8 of 27 (30 percent, 95 percent CI 14 to 50): one complete and seven partial responses; 12 (44 percent) had stable disease.","Median follow-up 94 weeks (IQR 51 to 127).","Grade 3 adverse events in 6 of 27 (22 percent); no grade 4 or 5 events and no drug-related serious adverse events."],"whatItMeans":"The first demonstration that HER2 is actionable in colorectal cancer, and the trial that defined the colorectal-specific HER2 scoring criteria every later trial has used.","caveats":["Twenty-seven patients in a single-arm phase 2 at four centres.","Screening 914 patients to treat 27 shows the practical problem: the biomarker is rare and testing has to be universal for the trial to be feasible.","Trastuzumab with lapatinib has since been superseded by tucatinib with trastuzumab and by trastuzumab deruxtecan."],"changedPractice":true,"participants":27},"route":"/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/","neighbours":{"paper":[{"id":"paper-tcga-colon-rectal-molecular-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","route":"/key-papers/paper-tcga-colon-rectal-molecular-characterization-nature-2012/"},{"id":"paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021","kind":"paper","name":"Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01)","route":"/key-papers/paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021/"},{"id":"paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023","kind":"paper","name":"Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)","route":"/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","route":"/cancers/her2-amplified-colorectal/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"lapatinib","kind":"drug","name":"Lapatinib","route":"/drugs/lapatinib/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"}],"person":[{"id":"alberto-bardelli","kind":"person","name":"Alberto Bardelli","route":"/people/alberto-bardelli/"},{"id":"salvatore-siena","kind":"person","name":"Salvatore Siena","route":"/people/salvatore-siena/"}],"bottleneck":[{"id":"b-preclinical-models","kind":"bottleneck","name":"Lab models that fail to predict what happens in patients","route":"/bottlenecks/b-preclinical-models/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-trial-enrolment","kind":"bottleneck","name":"Trials enrol too few, too slowly","route":"/bottlenecks/b-trial-enrolment/"}],"journal":[{"id":"lancet-oncology","kind":"journal","name":"The Lancet Oncology","route":"/journals/lancet-oncology/"}],"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/"}]}}