Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer: Results from the drug rediscovery protocol (DRUP)

Ilse A C Spiekman, Laurien J Zeverijn, Birgit S Geurts, Karlijn Verkerk, Soemeya F Haj Mohammad, Vincent van der Noort, Paul Roepman, Wendy W J de Leng, Anne M L Jansen, Elske C Gootjes, Derk-Jan A de Groot, Emile D Kerver, Theo van Voorthuizen, Jeanine M L Roodhart, Liselot B J Valkenburg-van Iersel, Hans Gelderblom, Emile E Voest, Henk M W Verheul*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


BACKGROUND: In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'.

METHODS: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies.

RESULTS: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available.

CONCLUSIONS: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.

Original languageEnglish
Article number113988
JournalEuropean Journal of Cancer
Early online date7 Mar 2024
Publication statusPublished - May 2024


  • Colorectal cancer
  • DRUP-trial
  • HER2amplification
  • Precision medicine
  • Trastuzumab plus pertuzumab


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