Safety and Efficacy of Neratinib (HKI-272) in Combination with Vinorelbine in ErbB2+ Metastatic Breast Cancer.
Authors: Awada A. , Dirix L. , Beck J. , Luu T. , Dieras V. , Llombart A. , Manso L. , Limentani S. , Binlich F. , Germa C. , Abbas R. , Agrapart V. , Powell C. , Hershman D. 
Published: December 2010

Abstract
Background: The irreversible pan-ErbB tyrosine kinase inhibitor neratinib (HKI-272) potently blocks downstream signaling of the ErbB1, -2, and -4 receptors and has demonstrated antitumor activity in patients with ErbB2+ breast cancer (BC). Vinorelbine has shown synergistic antitumor activity in combination with the ErbB2-specific monoclonal antibody trastuzumab. The objective of this ongoing phase 1/2 study is to evaluate the safety and efficacy of neratinib in combination with vinorelbine in patients with solid tumors and ErbB2+ metastatic BC.Material and Methods: This open-label, 2-part, phase 1/2 study enrolled patients with solid tumors (part 1) to evaluate safety and determine the maximum tolerated dose (MTD) of neratinib administered as ascending multiple daily oral doses (160 mg, 240 mg) in combination with IV vinorelbine 25 mg/m2 (days 1 and 8 every 3 weeks). In part 2, the clinical activity, safety, and pharmacokinetics (PK) of the combination will be assessed in patients ≥18 years of age with ErbB2+ metastatic BC (Eastern Cooperative Oncology Group status of 0 to 2) who had received ≤2 prior treatments with a trastuzumab-containing regimen for ≥6 weeks, with or without prior lapatinib exposure. The primary endpoint is objective response rate. Tumor responses are assessed by modified RECIST criteria every 6 weeks.Results: In part 1 (n = 12), no dose-limiting toxicities were observed in the neratinib 240-mg–vinorelbine 25-mg/m2 cohort (full standard doses; defined as the MTD). Two patients withdrew from the study because of adverse events (1 case each of neuropathy and progression of non-small cell lung cancer). As of the 1 May 2009 data cutoff, 1 patient with gastric cancer had received treatment with neratinib 160 mg plus vinorelbine for 183 days and 1 patient with BC had received treatment with neratinib 240 mg plus vinorelbine for 259 days. In part 2, as of 1 May 2009, 14 patients with ErbB2+ metastatic BC were enrolled and treated at the MTD (including 11 in the no prior lapatinib exposure cohort and 3 in the prior lapatinib exposure cohort; 100% were female). The median duration of treatment with neratinib was 5.9 weeks (range, 0-26). The most common drug-related treatment-emergent adverse events (all grades, ≥10% of patients) included diarrhea (86%), vomiting (36%), nausea (29%), fatigue (29%), headache (14%), and neutropenia (14%). No cases of rash were observed. The most common adverse events leading to dose reductions were diarrhea (n = 2) and vomiting (n = 1). One patient withdrew from the study because of diarrhea. Six patients from part 2 are evaluable for efficacy, all in the no prior lapatinib cohort. Among these 6 patients, best overall responses (based on investigator-assessed radiographic and clinical data) included 1 partial response and 4 cases of stable disease &lt;24 weeks.Discussion: Preliminary results of this study show that the combination of neratinib and vinorelbine is tolerable and demonstrates promising antitumor activity in patients with ErbB2+ metastatic BC. Updated efficacy and safety data are forthcoming, as well as PK results.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5095.