# 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-heracles-trastuzumab-lapatinib-her2-colorectal-lancet-oncol-2016/  
OnCo record `paper-heracles-trastuzumab-lapatinib-her2-colorectal-lancet-oncol-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The first trial to treat bowel cancer as a HER2 disease. Screening 914 patients to find 48 with extra HER2, it produced lasting responses in nearly a third of those treated, after every standard drug had failed.

## Summary

HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial at four Italian academic cancer centres. Adults with KRAS exon 2 wild-type, HER2-positive metastatic colorectal cancer refractory to standard of care including an EGFR antibody received intravenous trastuzumab and oral lapatinib until progression, with HER2 positivity defined by the previously validated colorectal-specific criteria. Between August 2012 and May 2015, 914 KRAS exon 2 wild-type patients were screened and 48 (5%) had HER2-positive tumours; 27 were eligible and treated. At data cutoff with a median follow-up of 94 weeks, 8 of 27 (30%) had achieved an objective response, 1 complete and 7 partial, and 12 (44%) had stable disease. Six of 27 patients had grade 3 adverse events and there were no grade 4 or 5 events.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Lancet Oncology
- Year: 2016
- DOI: 10.1016/S1470-2045(16)00150-9
- Authors: Sartore-Bianchi A, Trusolino L, Martino C, et al.
- Findings: 48 of 914 KRAS exon 2 wild-type patients (5%) were HER2-positive.; Objective response in 8 of 27 (30%), one complete; stable disease in 12 (44%).; No grade 4 or 5 adverse events.
- What it means: It established HER2 amplification as an actionable colorectal genotype and set the screening arithmetic every later HER2 trial has faced: you must test about 20 wild-type patients to find one eligible patient.
- Caveats: 27 patients, single-arm, no randomised comparison.; KRAS exon 2 only; extended RAS was not required.; Trastuzumab plus lapatinib has since been superseded by tucatinib plus trastuzumab and by trastuzumab deruxtecan.

## Sources

- Sartore-Bianchi et al., Lancet Oncol 2016: HERACLES, trastuzumab plus lapatinib in HER2-positive metastatic colorectal cancer: https://doi.org/10.1016/S1470-2045(16)00150-9
- PubMed: https://pubmed.ncbi.nlm.nih.gov/27108243/

## Connected records

- biomarkers: [HER2 ISH amplified (ERBB2 gene amplification)](https://onco.cc/biomarkers/her2-ish-amplified/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- 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/)
- institutions: [Istituto di Candiolo IRCCS (FPO)](https://onco.cc/institutions/candiolo/), [Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda](https://onco.cc/institutions/niguarda-cancer-center/)
- pathways: [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- trials: [HERACLES](https://onco.cc/trials/heracles/)
- people: [Andrea Sartore-Bianchi](https://onco.cc/people/andrea-sartore-bianchi/), [Salvatore Siena](https://onco.cc/people/salvatore-siena/)
- journals: [The Lancet Oncology](https://onco.cc/journals/lancet-oncology/)

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