Abstract OT1-1-14: Open-label, Phase II trial of afatinib, with or without vinorelbine, for the treatment of HER2-overexpressing inflammatory breast cancer (IBC)*

Abstract

Abstract Background: IBC is a rare but aggressive form of BC accounting for 1–5% of all BC. Despite recent treatment advances, prognosis remains poor, with 3-year survival rate of 40% vs. 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbor HER2 gene amplification (∼40%), and EGFR overexpression (∼30%) that are associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab naïve/resistant HER2-positive IBC. Afatinib is an oral irreversible ErbB Family Blocker that blocks signaling through activated EGFR (ErbB1), HER2 (ErbB2), ErbB4 receptors, and transphosphorylation of ErbB3. Afatinib demonstrated preclinical activity in trastuzumab-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pretreated, HER2-positive metastatic BC patients (pts) who progressed after trastuzumab, with a partial response in 10% and a clinical benefit in 46% of pts. The combination of afatinib and vinorelbine has been shown to be more effective than either compound alone in reducing tumor volume in the SUM190 xenograft model. The purpose of this biomarker-driven trial is to investigate the efficacy and safety of afatinib alone and in combination with vinorelbine following progression on afatinib monotherapy and the genomic changes that occur during treatment in pts with trastuzumab pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in two parallel cohorts of 20 pts each – trastuzumab-naïve and trastuzumab failure cohorts. Key eligibility criteria: Histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and edema (peau d'orange) – dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except trastuzumab in the trastuzumab failure cohort; no prior vinorelbine; ECOG performance status 0–2; disease must be biopsiable. All pts start afatinib monotherapy (40 mg/day oral) in 4-week cycles (Part A). Following disease progression, pts may receive afatinib (40 mg/day) + vinorelbine (i.v. 25 mg/m2/week) (Part B). Primary endpoint: Clinical benefit defined as stable disease (for ≥6 months), partial response or complete response (RECIST 1.1). Secondary endpoints: Objective response, duration of objective response and progression-free survival. Other endpoints include overall survival and safety. Endpoints are assessed separately for Part A and Part B. In Part A (afatinib monotherapy) fresh tumor biopsies are taken pretreatment and following progressive disease, and blood samples are taken pretreatment to explore predictive markers of response/resistance to afatinib, to describe the IBC population that may benefit most and for tumor DNA next-generation sequencing and proteomic analysis. This is one of the first prospective clinical trials to integrate deep exome sequencing into trial design to assess proof of principle of a personalized cancer medicine approach to improve individualized pt treatment. The trial is planned to accrue 40 pts worldwide and recruitment is ongoing since August 2011. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-14.