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

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 (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.

Evaluation of Circulating Tumor Cells and Circulating Tumor DNA in Non–Small Cell Lung Cancer: Association with Clinical Endpoints in a Phase II Clinical Trial of Pertuzumab and Erlotinib

“…Pertuzumab is a humanized monoclonal antibody directed against HER2 that is designed to inhibit dimerization of HER2 with other HER family receptors including EGFR, HER3, and HER4 (5)(6)(7). Previous phase II studies in NSCLC have shown signs of pharmacodynamic activity in response to single-agent pertuzumab therapy in patients with advanced or recurrent NSCLC, though no partial or complete responses were observed (8,9). Pertuzumab and erlotinib inhibit overlapping but distinct aspects of HER family signaling, and other studies have suggested that development of acquired resistance to EGFR inhibitors is associated with upregulation and increased dependency on other HER family members such as HER3 (10), providing a strong rationale for studying the safety and efficacy of the combination of these agents in advanced NSCLC.…”

Changes in 18F-Fluorodeoxyglucose and 18F-Fluorodeoxythymidine Positron Emission Tomography Imaging in Patients with Non–Small Cell Lung Cancer Treated with Erlotinib

“…For molecularly targeted therapies, several small studies in selected NSCLC patients have evaluated FDG-or FLT-PET changes (20)(21)(22)(23)(24)(25). However, for molecularly targeted therapies, it has not yet been established whether these imaging approaches provide a clinically meaningful assessment of therapeutic activity in NSCLC, particularly in the absence of tumor shrinkage.…”

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

“…A phase I clinical trial in which 43 NSCLC chemonaïve patients were treated with pertuzumab i.v. every 3 weeks found 9.3% grade ≥ 3 adverse events and no response [136]. Lastly, a phase II clinical trial assesses the response to F-18-fluorodeoxyglucose positron emission tomography of the combination of erlotinib and pertuzumab and results are pending [137].…”