Abstract OT1-1-07: Human epidermal growth factor receptor 2 (HER2) suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (LTP112515)
Authors: Lin N , Danso MA , David AK , Muscato J , Rayson D , Houck WA , Ellis C , DeSilvio M , Garofalo A , Nagarwala Y , Winer E 
Published: August 2014

Abstract
Background: The combination of lapatinib (L) with trastuzumab (T) results in enhanced antitumor activity in preclinical models of HER2-positive breast cancer (BC), due to the complementary mechanisms of action of the two agents. In patients with prior T-treated HER2-positive metastatic BC (MBC), treatment with T plus L was associated with longer progression-free survival (PFS) and overall survival (OS) compared with L alone. The combination also had an acceptable safety and tolerability profile. In patients with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. Current common clinical practice for most patients experiencing clinical benefit from first-line treatment with T plus chemotherapy is to continue T as maintenance therapy after completion of the recommended number of chemotherapy cycles. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy.
Methods: In this open-label, Phase III study, 280 patients will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]), or T (6 mg/kg q3w) alone. Patients will receive study treatment until disease progression, death, discontinuation due to adverse events, or patient withdrawal. The primary endpoint is PFS; secondary endpoints are; OS, clinical benefit rate, and safety.
Key eligibility criteria include females, age ≥18 years with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Patients with stable brain metastases are eligible if entering the study on second-line treatment.
Efficacy endpoints will be analyzed in the intent-to-treat population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.667) from 18 weeks (T alone) to 27 weeks (L plus T). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. One interim analysis is planned for futility when approximately 97 PFS events (50% of the required events) have been observed. Safety endpoints will be analyzed in all randomized patients who receive ≥1 dose of study medication.
The trial is currently open for accrual in the United States and Canada.
ClinicalTrials.gov - NCT00968968
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-07.