Abstract OT1-1-09: ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV) and endocrine therapy
Authors: Gradishar W , Wroblewski S , Huang Y , Harvey C , Franklin N , Johnston S 
Published: August 2014

Abstract
On behalf of the ALTERNATIVE (EGF114299) Steering Committee.
Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) gene in breast cancer is associated with an aggressive phenotype, poor prognosis, and resistance to endocrine therapies. Of HER-positive (+) patients, ∼50% are also hormone receptor (HR)+. For patients who are both HER+ and HR+, combining the aromatase inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L) has been shown to improve outcomes compared with letrozole alone. The combination of L and trastuzumab (T), a humanized monoclonal antibody-targeting HER2, has been shown to improve outcomes compared with L alone.
Trial Design: The ALTERNATIVE study is a Phase III, randomized, open-label, multicenter trial which will examine the efficacy of L/T/AI in combination vs T/AI alone as first- or second-line therapy in metastatic breast cancer (MBC). Patients will be randomized to 1 of 3 treatment arms: L 1000 mg po QD plus T (loading dose of 8 mg/kg followed by maintenance with 6 mg/kg IV q3w plus an AI po QD); T plus an AI; or L 1500 mg po QD plus an AI. Choices of AI include letrozole, anastrozole, or exemestane.
Eligibility Criteria: Postmenopausal female patients with HER2+/HR+ MBC who have received prior T and endocrine therapies and are not candidates for chemotherapy.
Specific Aims: The primary efficacy endpoint is overall survival (OS), defined as the time from randomization until death due to any cause, for L/T/AI compared with T/AI alone. Secondary efficacy objectives include comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI in addition to comparisons of progression-free survival, overall response rate, time to response, and duration of response. The safety objective is to evaluate the safety and tolerability for all 3 treatment groups.
A 5.75-year recruitment is anticipated. Around 200 centers across 36 countries are planned; approximately 182 centers are currently open for enrollment.
Statistical Methods: The study is powered to detect a 42% reduction in risk of death (hazard ratio = 0.70) in patients who receive L/T/AI (median 34.3 months) vs T/AI (median 24 months) using a 1-sided test for superiority with α = 0.025. The required number of total events to achieve a power of 80% is 247. Secondary comparisons are not powered and all analyses will be based on the intent-to-treat population.
Present and Target Accrual: Eighty (80) of 525 patients have been randomized.
The original study population included only first-line patients. The study has recently undergone a protocol amendment to expand the eligible patient population to include both first- and second-line patients. The study is currently recruiting, with an anticipated target accrual of 525 patients by 2017.
Contact Info: Susan Wroblewski (susan.l.wroblewski@gsk.com).
Clinical trial registry number: NCT01160211
Funding: GlaxoSmithKline.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-09.