Abstract OT1-1-06: A phase III randomized study of Paclitaxel and Trastuzumab versus Paclitaxel, Trastuzumab and Lapatinib in first line treatment of HER2 positive metastatic breast cancer.
Authors: Crown JP , Moulton B , O'Donovan N 
Published: August 2014

Abstract
Background: Preclinical studies have shown that dual targeting of the extracellular domain and the kinase domain of HER2 using trastuzumab (H) and lapatinib (L) produces greater growth inhibition than single agent treatment. The combination of trastuzumab and lapatinib has shown improved clinical outcome compared to lapatinib alone in the pre-treated metastatic setting (EGF104900), and compared to trastuzumab in the neo-adjuvant setting (Neo-Altto). This international phase III randomised trial will compare the efficacy of trastuzumab and paclitaxel (T) with trastuzumab, paclitaxel and lapatinib in first line treatment of HER2 positive metastatic breast cancer, and will examine potential predictive biomarkers of response to trastuzumab and/or lapatinib.
Study Design and Eligibility: Six hundred patients with invasive HER2 positive (3+ or FISH positive) metastatic breast cancer (measurable disease per RECIST 1.1), who have not received prior systemic therapy for metastatic disease, will be randomised to receive (A) weekly paclitaxel (80 mg/m2, for 3 weeks of a 4 week cycle) plus trastuzumab (8 mg/kg loading dose day 1 and 4mg/kg every 2 weeks) or (B) weekly paclitaxel (80 mg/m2, for 3 weeks of a 4 week cycle) plus trastuzumab (8 mg/kg loading dose day 1 and 4 mg/kg every 2 weeks) plus lapatinib (1,000 mg daily), until disease progression, unacceptable toxicity or consent withdrawal.
Objectives: The primary objective of the study is to compare the efficacy of THL versus TH in first line treatment of metastatic HER2 positive breast cancer. Secondary objectives include: (i) examining the objective tumour response rate and overall survival; (ii) assessing the safety and tolerability of lapatinib when administrated with both paclitaxel and trastuzumab; (iii) examining the effects of the TH regimen versus the THL regimen on health-related quality of life (FACT-B); (iv) examining potential biomarkers in tumour tissue and serum samples; (v) determining if prophylactic loperamide significantly reduces the number of diarrhoea-related adverse events.
Statistical Methods: The expected median progression free survival time for the control arm is 6.9 months based on the trastuzumab plus paclitaxel arm of the phase III trastuzumab plus chemotherapy trial. A total of 600 evaluable patients (and 485 observed events) would be sufficient to detect an increase to 8.9 months in median PFS time for the THL combination, with 80% power and a two sided significance level of 0.05. Progression-free survival will be analysed at nine months after enrolment ends and overall survival will be analysed at 30 months after the end of enrolment. Objective response will be defined as the proportion of patients who receive a complete or partial response as defined by RECIST 1.1.
Accrual: This study will accrue six hundred patients across forty International centres. Countries signed up to participate include Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Netherlands, Norway, Poland, Portugal, Switzerland and Spain. The study opened to accrual in Ireland Feb 12 and six patients have been accrued to date.
Funding: Trial supported by GlaxoSmithKline. Lapatinib kindly supplied by GlaxoSmithKline.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-06.