Efficacy and Safety of Single-Agent Pertuzumab, a Human Epidermal Receptor Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

• Published in: Clinical cancer research 2007-10, Vol.13 (20), p.6175-6181
• Main Authors: HERBST, Roy S, DAVIES, Angela M, DE VRIES, Daniel J, EBERHARD, David A, LYONS, Benjamin, LUTZKER, Stuart G, JOHNSON, Bruce E, NATALE, Ronald B, DANG, Thao P, SCHILLER, Joan H, GARLAND, Linda L, MILLER, Vincent A, MENDELSON, David, VAN DEN ABBEELE, Annick D, MELENEVSKY, Yulia
• Format: Article
• Language: English
• Subjects: Adult; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biopsy; carcinoma; Carcinoma, Non-Small-Cell Lung - drug therapy; Dimerization; EGFR; Female; Fluorodeoxyglucose F18 - pharmacology; HER2; Humans; Lung Neoplasms - drug therapy; Male; Medical sciences; Middle Aged; Mutation; non–small cell lung; pertuzumab; Pharmacology. Drug treatments; Pneumology; Positron-Emission Tomography - methods; Protein Structure, Tertiary; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - chemistry; Time Factors; Treatment Outcome; Tumors of the respiratory system and mediastinum
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0460

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.