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 Ng

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)113-122
Number of pages10
JournalInvestigational New Drugs
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Colorectal Neoplasms
Pharmaceutical Preparations
Monoclonal Antibodies
Stomatitis
Mucositis
Growth Factor Receptors
Cetuximab
pertuzumab
Dimerization
Dermatitis
Exanthema
Disease-Free Survival
Diarrhea
Myocardial Infarction
Safety
Survival

Keywords

  • Cetuximab
  • Colorectal Cancer
  • Pertuzumab
  • Phase I
  • Phase II

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

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

In: Investigational New Drugs, Vol. 32, No. 1, 01.01.2014, p. 113-122.

Research output: Contribution to journalArticle

Rubinson, DA, Hochster, HS, Ryan, DP, Wolpin, BM, McCleary, NJ, Abrams, TA, Chan, JA, Iqbal, S, Lenz, HJ, Lim, D, Rose, J, Bekaii-Saab, T, Chen, HX, Fuchs, CS & Ng, K 2014, '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', Investigational New Drugs, vol. 32, no. 1, pp. 113-122. https://doi.org/10.1007/s10637-013-9956-5
Rubinson, Douglas A. ; Hochster, Howard S. ; Ryan, David P. ; Wolpin, Brian M. ; McCleary, Nadine Jackson ; Abrams, Thomas A. ; Chan, Jennifer A. ; Iqbal, Syma ; Lenz, Heinz J. ; Lim, Dean ; Rose, Jeffrey ; Bekaii-Saab, Tanios ; Chen, Helen X. ; Fuchs, Charles S. ; Ng, Kimmie. / 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. In: Investigational New Drugs. 2014 ; Vol. 32, No. 1. pp. 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 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.",
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T2 - Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients

AU - Rubinson, Douglas A.

AU - Hochster, Howard S.

AU - Ryan, David P.

AU - Wolpin, Brian M.

AU - McCleary, Nadine Jackson

AU - Abrams, Thomas A.

AU - Chan, Jennifer A.

AU - Iqbal, Syma

AU - Lenz, Heinz J.

AU - Lim, Dean

AU - Rose, Jeffrey

AU - Bekaii-Saab, Tanios

AU - Chen, Helen X.

AU - Fuchs, Charles S.

AU - Ng, Kimmie

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N2 - 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.

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