A Phase Ib, Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non Small-Cell Lung Cancer

作者：Felip Enriqueta^*; Ranson Malcolm; Cedres Susana; Dean Emma; Brewster Mike; Martinez Pablo; McNally Virginia; Ross Graham; Galdermans Danny

来源：Clinical Lung Cancer, 2012, 13(6): 432-441.

DOI：10.1016/j.cllc.2012.03.004

• Epidermal growth factor tyrosine kinase inhibitor
• Human epidermal growth factor receptor 2
• Lung neoplasm
• Monoclonal antibody
• neu
• Pharmacokinetics

Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, has demonstrated pharmacodynamic activity in non-small-cell lung cancer. In a phase 1b study, 15 patients with stage IIIb/IV non-small-cell lung cancer who had failed chemotherapy received erlotinib followed by combination therapy that comprised erlotinib and pertuzumab. This combination had encouraging efficacy and did not affect the pharmacokinetics of erlotinib.
Background: Pertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non-small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers. Patients and Methods: Fifteen patients with stage IIIb/IV non-small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days -8 to -1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg). Results: No dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies. Conclusions: Combination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.

• 出版日期2012-11