Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC).

Abstract

TPS650 Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene amplification (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.