Investigational New Drugs

, Volume 32, Issue 1, pp 113–122 | Cite as

Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients

  • Douglas A. Rubinson
  • Howard S. Hochster
  • David P. Ryan
  • Brian M. Wolpin
  • Nadine Jackson McCleary
  • Thomas A. Abrams
  • Jennifer A. Chan
  • Syma Iqbal
  • Heinz J. Lenz
  • Dean Lim
  • Jeffrey Rose
  • Tanios Bekaii-Saab
  • Helen X. Chen
  • Charles S. Fuchs
  • Kimmie NgEmail author


Purpose Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. Patients and methods This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. Results Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5–4.9) and median overall survival was 3.7 months (95 % CI, 1.6–7.9). Conclusion Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.


Pertuzumab Cetuximab Phase I Phase II Colorectal Cancer 



Pertuzumab was supplied by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) in Bethesda, MD. The trial was conducted under a Phase 2 Consortium contract with the NCI. Genentech also provided supplementary funding for the study.

Conflicts of interest

Dr. Hochster has received support from Genentech and Bristol-Myers Squibb. Dr. Wolpin has received support from Agensys/Astellas, Momenta Pharmaceuticals, Merrimack Pharmaceuticals, and Genentech. Dr. Lenz has served on Advisory Boards and received honoraria for lectures from Genentech. Dr. Bekaii-Saab has served as a consultant for Bristol Myers-Squibb and Genentech. Dr. Fuchs has received support from Genentech, Metamark Genetics, Sanofi, Amgen, Momenta Pharmaceuticals, Celgene, and Bayer.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Douglas A. Rubinson
    • 1
  • Howard S. Hochster
    • 2
  • David P. Ryan
    • 3
  • Brian M. Wolpin
    • 1
  • Nadine Jackson McCleary
    • 1
  • Thomas A. Abrams
    • 1
  • Jennifer A. Chan
    • 1
  • Syma Iqbal
    • 4
  • Heinz J. Lenz
    • 4
  • Dean Lim
    • 5
  • Jeffrey Rose
    • 6
  • Tanios Bekaii-Saab
    • 7
  • Helen X. Chen
    • 8
  • Charles S. Fuchs
    • 1
  • Kimmie Ng
    • 1
    Email author
  1. 1.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  2. 2.Department of Medical OncologyYale Cancer CenterNew HavenUSA
  3. 3.Massachusetts General Hospital Cancer CenterMassachusetts General HospitalBostonUSA
  4. 4.Division of Medical Oncology, Sharon A. Carpenter Laboratory, Keck School of MedicineUniversity of Southern California/Norris Comprehensive Cancer CenterLos AngelesUSA
  5. 5.Division of Medical Oncology and Therapeutics ResearchCity of Hope National Medical CenterDuarteUSA
  6. 6.Lowcountry Hematology and OncologyMount PleasantUSA
  7. 7.Department of Pharmacology, College of MedicineThe Ohio State UniversityColumbusUSA
  8. 8.Cancer Therapy Evaluation ProgramNational Cancer InstituteBethesdaUSA

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