Abstract OT1-03-07: Single arm, phase IIA clinical trial assessing the safety and activity of atezolizumab in combination with paclitaxel, trastuzumab, and pertuzumab in patients with metastatic HER-2 positive breast cancer (mHER2+BC)
Authors: Goldstein LJ , Obeid E 
Published: February 2018

Abstract
Background:HER2+BC is a subtype of breast cancer where tumor cells overexpress the HER2-receptor tyrosine kinase or have over-amplification of HER2/neu gene and comprises 25-30% of all BC. Pertuzumab and trastuzumab, are monoclonal antibodies that target HER2 signaling, and synergize to improve outcomes when added to a taxane regimen in mHER2+BC [CLEOPATRA trial]. Significant challenges persist as 15% of patients would relapse due to resistance to HER2-targeted therapy. Trastuzumab has an immune-mediated activity to sensitize HER2-overexpressing tumors to the killing by cytotoxic T lymphocytes (CTLs). A positive correlation between T-cell infiltration (TILs) and outcomes in HER2+BC has been reported. Atezolizumab is a humanized IgG1 monoclonal antibody targeting human programmed death ligand 1 (PD-L1) and inhibits its interaction with its receptor PD-1. Atezolizumab also blocks binding of PD-L1 to B7.1, an interaction conferring additional inhibitory signals to T cells. Certain chemotherapeutic drugs, such as taxanes, mediate their anticancer activity not only by direct cytotoxic effects, but also by activation of CD8+ T-cell responses.Here we propose a single arm, Phase IIA clinical trial to study the safety and efficacy of atezolizumab in combination with a standard regimen of paclitaxel, trastuzumab and pertuzumab in patients with mHER2+BC, in comparison with a historic cohort of the same regimen without atezolizumab.
Methods: A total of 50 subjects will be enrolled. Premedication systemic corticosteroids are usually administered with taxane therapy to avoid hypersensitivity reactions. With concerns over a negative immune effect from corticosteroids on atezolizumab activity, this protocol's subjects will receive premedication with dexamethasone only for weeks 1 and 2 of weekly paclitaxel, and then discontinued if there is no hypersensitivity reaction. The primary endpoint is safety and efficacy (overall response rate) by evaluation for acute toxicity and of tumor response using RECIST v1.1. Other endpoints include clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Tumor biopsies and peripheral blood collection at baseline and just prior cycle 4 are mandatory for correlative studies. PD-L1 expression will be evaluated in exploratory analysis with a planned assessment of response based on PD-L1 status as well as by hormone receptor status. NCT03125928 www.clinicaltrials.gov
Citation Format: Goldstein LJ, Obeid E. Single arm, phase IIA clinical trial assessing the safety and activity of atezolizumab in combination with paclitaxel, trastuzumab, and pertuzumab in patients with metastatic HER-2 positive breast cancer (mHER2+BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-07.