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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

Authors' Affiliations: ¹ The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ² UC Davis Cancer Center, Sacramento, California; ³ Cedars-Sinai Cancer Center, Los Angeles, California; ⁴ Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; ⁵ University of Wisconsin, Madison, Wisconsin; ⁶ Arizona Cancer Center, Tucson, Arizona; ⁷ Memorial-Sloan Kettering Cancer Center, New York, New York; ⁸ Premiere Oncology of Arizona, Scottsdale, Arizona; ⁹ Dana-Farber Cancer Institute, Boston, Massachusetts; and ¹⁰ Genentech, Inc., South San Francisco, California

Requests for reprints: Bruce E. Johnson, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1234, Boston, MA 02115. Phone: 617-632-4790; Fax: 617-632-5786; E-mail: bruce_johnson{at}dfci.harvard.edu.

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 (SUV_max) 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 SUV_max. 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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