# Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)

Source: https://onco.cc/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/  
OnCo record `paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Screening 914 patients identified 48 (5 percent) with HER2-positive tumours, of whom 27 were eligible and treated.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: The Lancet Oncology
- Year: 2016
- DOI: 10.1016/S1470-2045(16)00150-9
- Authors: Sartore-Bianchi A, Trusolino L, Martino C, et al.
- 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.
- What it means: 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.

## Sources

- Lancet Oncol 2016: https://doi.org/10.1016/S1470-2045(16)00150-9
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27108243/

## Connected records

- key papers: [Comprehensive molecular characterization of human colon and rectal cancer](https://onco.cc/key-papers/paper-tcga-colon-rectal-molecular-characterization-nature-2012/), [Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01)](https://onco.cc/key-papers/paper-siena-destiny-crc01-trastuzumab-deruxtecan-lancet-oncol-2021/), [Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER)](https://onco.cc/key-papers/paper-strickler-mountaineer-tucatinib-trastuzumab-lancet-oncol-2023/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [HER2-amplified colorectal cancer](https://onco.cc/cancers/her2-amplified-colorectal/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Lapatinib](https://onco.cc/drugs/lapatinib/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/)
- people: [Alberto Bardelli](https://onco.cc/people/alberto-bardelli/), [Salvatore Siena](https://onco.cc/people/salvatore-siena/)
- bottlenecks: [Lab models that fail to predict what happens in patients](https://onco.cc/bottlenecks/b-preclinical-models/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [Trials enrol too few, too slowly](https://onco.cc/bottlenecks/b-trial-enrolment/)
- journals: [The Lancet Oncology](https://onco.cc/journals/lancet-oncology/)
- 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/)

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