Abstract OT1-1-17: LUX-Breast 2: Phase II, open-label study of oral afatinib in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) who progressed on prior trastuzumab and/or lapatinib*

Background: Management of HER2-overexpressing MBC has improved over the past decade. However, pts still develop resistance to currently available HER2-targeted therapies and novel effective treatments are increasingly required as dual targeted combinations are given in early treatment lines already. Current therapies focus on targeting HER2 and do not inhibit all relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical studies have demonstrated efficacy in trastuzumab-sensitive, and trastuzumab-resistant human BC xenograft models dependent on ErbB signaling. Efficacy of afatinib in a trastuzumab-resistant SUM190 xenograft model has been shown to be increased by addition of intravenous (i.v.) vinorelbine. Afatinib monotherapy has shown promising clinical benefit in 46% of HER2-overexpressing MBC pts who progressed on prior trastuzumab, with 10% of pts achieving a partial response. 1 Methods: This open-label Phase II trial (NCT01271725) investigates efficacy and safety of afatinib alone (40 mg/day) followed by afatinib ‘beyond progression’ in combination with chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed on prior neoadjuvant and/or adjuvant trastuzumab and/or lapatinib. Pts who progress on afatinib monotherapy receive afatinib + either weekly paclitaxel 80 mg/m 2 or vinorelbine i.v. 25 mg/m 2 . Eligible pts have confirmed HER2-overexpressing BC, Stage IV disease measurable by RECIST 1.1, progressed on trastuzumab and/or lapatinib therapy in either neoadjuvant and/or adjuvant setting, are eligible for retreatment with paclitaxel (i.e. should not have been pretreated with paclitaxel within the past 12 months), or are eligible for treatment with vinorelbine (i.e. should not have been pretreated with vinorelbine). Exclusion criteria include inadequate cardiac, renal, hepatic and hematological function, pre-existing gastrointestinal dysfunction, rapidly progressing visceral MBC, interstitial lung disease, and active brain metastases. The primary endpoint is objective response (OR) and secondary endpoints include best overall response, duration of OR, progression-free survival (PFS) and safety. PFS and safety will be assessed separately for afatinib mono- and combination therapy. An early stopping rule was deployed to minimize the number of pts treated should afatinib be ineffective; once 20 evaluable pts (according to RECIST 1.1) completed at least two courses of afatinib (or progressed during the first course), a meeting was held to evaluate the objective tumor response rate and to decide whether to proceed with the trial or stop due to futility. If at least one unconfirmed OR had been witnessed from all available information at the time, then the trial was to continue to full accrual. This early stopping rule for futility has been passed and the trial will continue to full accrual. Pt enrollment began in May 2011 in ∼40 sites and five countries. 1. Lin NU, et al. Breast Cancer Res Treat 2012. DOI: 10.1007/s10549-012-2003-y. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-17.