Abstract OT1-1-15: LUX-Breast 3: Randomized Phase II trial of afatinib (BIBW 2992) alone or with vinorelbine versus investigator's choice of treatment in patients (pts) with HER2-positive breast cancer (BC) with progressive brain metastases after trastuzumab and/or lapatinib-based therapy* (2012)

Abstract Background: BC is one of the most common causes of central nervous system (CNS) metastases and approximately a third of pts with HER2-positive, advanced BC will develop brain metastases with a poor prognosis. Efficacy of systemic therapies is limited since few drugs can readily cross the blood-brain barrier. BC brain metastases represent a high unmet medical need for which novel therapies are needed. Afatinib is an oral irreversible ErbB Family Blocker that blocks signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorlyation of ErbB3. Afatinib has shown preclinical activity in trastuzumab-resistant cell lines and HER2-positive tumor xenografts. Its clinical efficacy has been demonstrated in pts with heavily pretreated, HER2-positive metastatic BC (MBC), who progressed after trastuzumab therapy, with partial responses (PRs) in 10% and clinical benefit in 46% of pts. In a Phase I afatinib trial, a sustained PR was observed in a non-small cell lung cancer (NSCLC) pt with brain metastasis and in a Phase II trial in NSCLC, pts with or without brain metastases achieved comparable objective response on afatinib. The purpose of this trial (NCT01441596) is to investigate whether afatinib alone or in combination with vinorelbine has any effect on HER2-positive BC with brain metastases after prior trastuzumab and/or lapatinib therapy. Methods: Key eligibility criteria: Histologically confirmed HER2-positive BC; recurrent/progressive brain metastases during/after prior trastuzumab and/or lapatinib therapy; at least one measurable and progressive lesion in the CNS (≥10 mm on T1-weighted, gadolinium-enhanced MRI) after prior systemic and/or radiation therapy; extra-CNS lesions allowed; prior surgery, whole brain radiotherapy or stereotactic radiosurgery allowed; ECOG performance status (PS) 0–2; no prior treatment with HER2-tyrosine kinase inhibitor other than lapatinib. Eligible pts are stratified by: ECOG PS score 0–1 vs. 2; number of brain metastases ≤3 vs. &amp;gt;3; prior lapatinib therapy. Pts are randomized to (n = 40/arm): Arm A: Afatinib (40 mg/day oral); Arm B: Afatinib (40 mg/day oral) + vinorelbine (25 mg/m2/ week); Arm C: Investigator's choice of medical treatment approved for MBC. All treatments are administered in a 3-weekly course. Primary endpoint: Pt benefit at 12 weeks (i.e. absence of CNS/extra CNS disease progression as per RECIST 1.1 and no tumor-related worsening of neurological signs/symptoms or increase in steroid dosage). Secondary and other endpoints: Progression-free survival, overall survival, safety and afatinib concentration in plasma and cerebrospinal fluid in ≥12 pts who consent to participate in the PK study. The trial is planned to accrue 120 pts worldwide. When 20 pts in each treatment arm have been treated for at least 12 weeks (or progressed before Week 12), a Data Monitoring Committee will evaluate the benefit–risk ratio to decide whether to proceed with the trial or stop one of the treatment arms for futility. The study began in October 2011 and enrollment is ongoing. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-15.