title: 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.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Rubinson
authors.forename: Howard S
authors.initials: HS
authors.lastname: Hochster
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Nadine Jackson
authors.initials: NJ
authors.lastname: McCleary
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Abrams
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Syma
authors.initials: S
authors.lastname: Iqbal
authors.forename: Heinz J
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Dean
authors.initials: D
authors.lastname: Lim
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rose
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020794:Receptor Protein-Tyrosine Kinases; C485206:pertuzumab; D000068818:Cetuximab