Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non-small cell lung cancer

Roy S. Herbst, Angela M. Davies, Ronald B. Natale, Thao P. Dang, Joan H. Schiller, Linda L Garland, Vincent A. Miller, David Mendelson, Annick D. Van Den Abbeele, Yulia Melenevsky, Daniel J. De Vries, David A. Eberhard, Benjamin Lyons, Stuart G. Lutzker, Bruce E. Johnson

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Abstract

Purpose: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER2's dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non - small cell lung cancer (NSCLC). Experimental Design: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUVmax) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. Results: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUVmax. These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. Conclusions: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC.

Original languageEnglish (US)
Pages (from-to)6175-6181
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number20
DOIs
StatePublished - Oct 15 2007

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Dimerization
Non-Small Cell Lung Carcinoma
Safety
Disease-Free Survival
Survival Rate
Fluorodeoxyglucose F18
Positron-Emission Tomography
Confidence Intervals
pertuzumab
Pharmaceutical Preparations
Neoplasms
Research Design
Biopsy
Glucose
Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non-small cell lung cancer. / Herbst, Roy S.; Davies, Angela M.; Natale, Ronald B.; Dang, Thao P.; Schiller, Joan H.; Garland, Linda L; Miller, Vincent A.; Mendelson, David; Van Den Abbeele, Annick D.; Melenevsky, Yulia; De Vries, Daniel J.; Eberhard, David A.; Lyons, Benjamin; Lutzker, Stuart G.; Johnson, Bruce E.

In: Clinical Cancer Research, Vol. 13, No. 20, 15.10.2007, p. 6175-6181.

Research output: Contribution to journalArticle

Herbst, RS, Davies, AM, Natale, RB, Dang, TP, Schiller, JH, Garland, LL, Miller, VA, Mendelson, D, Van Den Abbeele, AD, Melenevsky, Y, De Vries, DJ, Eberhard, DA, Lyons, B, Lutzker, SG & Johnson, BE 2007, 'Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non-small cell lung cancer', Clinical Cancer Research, vol. 13, no. 20, pp. 6175-6181. https://doi.org/10.1158/1078-0432.CCR-07-0460
Herbst, Roy S. ; Davies, Angela M. ; Natale, Ronald B. ; Dang, Thao P. ; Schiller, Joan H. ; Garland, Linda L ; Miller, Vincent A. ; Mendelson, David ; Van Den Abbeele, Annick D. ; Melenevsky, Yulia ; De Vries, Daniel J. ; Eberhard, David A. ; Lyons, Benjamin ; Lutzker, Stuart G. ; Johnson, Bruce E. / Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non-small cell lung cancer. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 20. pp. 6175-6181.
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T1 - Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non-small cell lung cancer

AU - Herbst, Roy S.

AU - Davies, Angela M.

AU - Natale, Ronald B.

AU - Dang, Thao P.

AU - Schiller, Joan H.

AU - Garland, Linda L

AU - Miller, Vincent A.

AU - Mendelson, David

AU - Van Den Abbeele, Annick D.

AU - Melenevsky, Yulia

AU - De Vries, Daniel J.

AU - Eberhard, David A.

AU - Lyons, Benjamin

AU - Lutzker, Stuart G.

AU - Johnson, Bruce E.

PY - 2007/10/15

Y1 - 2007/10/15

N2 - Purpose: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER2's dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non - small cell lung cancer (NSCLC). Experimental Design: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUVmax) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. Results: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUVmax. These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. Conclusions: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC.

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