Multidrug inhibition of the HER pathway in metast

Authors: 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 BekaiiSaab Helen X Chen Charles S Fuchs Kimmie Ng

Publish Date: 2013/04/09

Volume: 32, Issue: 1, Pages: 113-122

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Abstract

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 heterodimerization thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance Patients and methods This singlearm openlabel multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximabresistant 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 doselimiting 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 21 months 95  CI 15–49 and median overall survival was 37 months 95  CI 16–79 Conclusion Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity however the combination was not tolerable due to overlapping toxicitiesPertuzumab 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 studyDr Hochster has received support from Genentech and BristolMyers 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 BekaiiSaab has served as a consultant for Bristol MyersSquibb and Genentech Dr Fuchs has received support from Genentech Metamark Genetics Sanofi Amgen Momenta Pharmaceuticals Celgene and Bayer

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