Abstract OT1-1-04: ALTERNATIVE: safety and efficacy of lapatinib (L), trastuzumab (T), or both in combination with an aromatase inhibitor (AI) for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer

Abstract

Abstract 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 HER2+ patients, ∼50% are also hormone receptor-positive (HR+). For patients who are both HER2+ and HR+, combining the AI letrozole with the dual tyrosine kinase inhibitor L has been shown to improve outcomes compared with letrozole alone. The combination of L and 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 versus T/AI alone. 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+ metastatic breast cancer (MBC) who have received neo/adjuvant T and endocrine therapy, are treatment naïve for MBC, 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 4-year recruitment is anticipated. More than 200 centers across 37 countries are planned; approximately 110 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 28.5 months) versus T/AI (median 20 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 249. Secondary comparisons are not powered and will be based on the intent-to-treat population. Present and target accrual: Twenty-six (26) of 525 patients have been randomized. Patients who have participated in previous neo-/adjuvant trials including a T regimen are eligible, provided they meet all other inclusion criteria. The study is currently recruiting patients, with an anticipated target accrual of 525 patients by March 2016. Clinical trial registry number: NCT01160211 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-04.