Abstract P3-14-05: Safety and Efficacy of Neratinib (HKI-272) Plus Vinorelbine in the Treatment of Patients with ErbB2+ Metastatic Breast Cancer Pretreated with Anti-HER2 Therapy
Authors: Staroslawska E , Dirix L , Luu T , Diéras V , Manso L , Xu B , Yang J , Abbas R , Strahs A , Vo Van M-L , Berkenblit A , Agrapart V , Powell C , Awada A. 
Published: April 2011

Abstract
Background: Neratinib (HKI-272) is an irreversible pan-ErbB tyrosine kinase inhibitor that blocks downstream signaling of the ErbB1, -2, and -4 receptors and has shown antitumor activity in patients with ErbB2+ breast cancer. Vinorelbine has shown synergistic antitumor activity in combination with trastuzumab, an ErbB2-specific monoclonal antibody. We report updated safety and efficacy data from this ongoing phase 1/2 study evaluating the combination of neratinib and vinorelbine in patients with solid tumors and ErbB2+ metastatic breast cancer. Material and Methods: In part 1 of this open-label, phase 1/2 study, patients with solid tumors underwent safety evaluations; the maximum tolerated dose (MTD) of oral neratinib administered as ascending multiple daily doses (160 mg, 240 mg) in combination with IV vinorelbine 25 mg/m2 (Days 1 and 8 every 3 weeks) was determined. In part 2, the clinical activity, safety, and pharmacokinetics of the combination was assessed in patients ≥18 years of age with ErbB2+ metastatic breast cancer (ECOG status of 0-2) who had received ≥1 prior treatment with a trastuzumab-containing regimen for ≥6 weeks for metastatic disease or relapse during adjuvant treatment, with or without prior lapatinib exposure. The primary endpoint is objective response rate (ORR). Tumor responses were assessed based on modified RECIST 1.0 criteria every 6 weeks.
Results: In part 1 (n = 12), there were no dose-limiting toxicities observed in the neratinib 240-mg plus vinorelbine 25-mg/m2 cohort (full standard doses; defined as the MTD). In part 2, as of April 26, 2010, 77 patients with ErbB2+ metastatic breast cancer were enrolled and treated at the MTD (including 62 in the no prior lapatinib exposure cohort and 15 in the prior lapatinib exposure cohort). At the time of the data snapshot, 56.2% of patients treated at the MTD were still receiving neratinib. The most common drug-related treatment-emergent adverse events (TEAEs; all grades, ≥20% of patients) at the MTD were diarrhea (97.4%), nausea (48.1%), neutropenia (45.5%), vomiting (36.4%), fatigue (26.0%), decreased appetite (28.6%), leukopenia (26.0%), and abdominal pain (23.4%). Common drug-related grade ≥3 TEAEs (≥5% of patients) included neutropenia (36.0%), diarrhea (25.8%), and leukopenia (11.2%). One patient withdrew from the study at the MTD because of grade 3 diarrhea. Fifty-five patients from part 2 were evaluable for efficacy in the no prior lapatinib (n = 43) and prior lapatinib (n = 12) cohorts. ORR (based on investigator-assessed radiographic and clinical data) was 51% in the no prior lapatinib cohort and 42% in the prior lapatinib cohort.
Discussion: The results of this study to date indicate that neratinib in combination with vinorelbine is tolerable and shows interesting antitumor activity in patients with ErbB2+ metastatic breast cancer pretreated with trastuzumab and lapatinib.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-05.