Abstract OT1-1-16: LUX-Breast 1: Randomized, Phase III trial of afatinib (BIBW 2992) and vinorelbine vs. trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment*

Abstract

Abstract Background: Afatinib is a ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (non-small cell lung cancer [NSCLC]/head and neck squamous cell carcinoma) and HER2 (ErbB2)-driven (breast) malignancies, and has shown clinical efficacy in NSCLC patients with EGFR activating mutations.1,2 In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib. Afatinib monotherapy activity in this SUM190 model was increased by the addition of intravenous (i.v.) vinorelbine. Clinically, afatinib monotherapy demonstrated activity in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab, with a progression-free survival (PFS) of 15.1 weeks, an overall survival (OS) of 61.0 weeks and 10% objective response (OR).3 HER-reprogramming appears to play an important role in resistance4 and recent clinical trial results have indicated that targeting more than one ErbB Family member increases efficacy.5 Thus afatinib, as an ErbB Family Blocker, should add to the portfolio of drugs available to treat trastuzumab resistance in HER2-positive BC patients. This is currently being tested in the LUX-Breast 1 trial. Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/day oral) + vinorelbine (i.v. 25 mg/m2/week) or trastuzumab (i.v. 2 mg/kg/week after 4 mg/kg loading dose) + vinorelbine (i.v. 25 mg/m2/week). Patients receive continuous treatment in the absence of disease progression or unacceptable toxicity. Key eligibility criteria include histologically-confirmed HER2-positive MBC; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or <12 months after trastuzumab completion) or first-line (or <6 months after trastuzumab completion) setting; prior anthracycline and/or taxane chemotherapy and an ECOG score of 0 or 1. The primary endpoint is PFS and secondary endpoints include OR, OS and safety. Patients' quality of life will be evaluated alongside other endpoints. Biomarkers will be assessed on archival tissue, in serum and in voluntary fresh tissue biopsies. Analyses on fresh tissue biopsies include ErbB-receptor and ErbB-ligand reprogramming, putative resistance markers, and EGF response signature. Enrollment began in June 2010 and is ongoing, targeting >240 sites with a recruitment target of 780 patients. 1. Yang JCH. Lancet Oncol 2012;13:539–48. 2. Yang JCH. J Clin Oncol 2012;30(suppl; abstr LBA7500). 3. Lin NU, et al. Breast Cancer Res Treat 2012. DOI: 10.1007/s10549-012-2003-y. 4. Metro G, et al. Expert Opin Pharmacother 2008;9:2583–601. 5. Bischoff J and Ignatov A. Breast Care 2010;5:134–41. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-16.