Abstract OT1-01-06: A phase III randomized trial of atezolizumab in combination with nab-paclitaxel as first line therapy for patients with metastatic triple-negative breast cancer (mTNBC)
Authors: Emens L , Adams S , Loi S , Schmid P , Schneeweiss A , Rugo H , Chui S , Winer E 
Published: May 2016

Abstract
Background: The management of mTNBC is a therapeutic challenge, and chemotherapy remains the mainstay of treatment. Atezolizumab (atezo; MPDL3280A) is a humanized anti-PDL1 antibody that inhibits PD-L1 binding to PD-1 and B7.1 but leaves PD-L2/PD-1 binding intact. mTNBC has high levels of tumor-infiltrating immune cells (IC), increased PD-L1 expression and high mutation rates that may generate immunogenic neoantigens, making it an attractive candidate for PD-L1–targeted therapy with atezo. Accordingly, atezo monotherapy has demonstrated durable responses in mTNBC (Emens et al, AACR 2015). In addition, atezo combined with nab-paclitaxel has shown promising tolerability and activity in mTNBC (Adams et al, SABCS 2015; pending). Nab-paclitaxel has high anti-tumor activity that may favorably alter the immune microenvironment. Based on these preliminary results, a Phase III multicenter, randomized, double-blind, placebo-controlled trial (IMpassion130) was designed to evaluate the efficacy and safety of nab-paclitaxel combined with atezo as first-line therapy for mTNBC.
Methods: Patients are randomized 1:1 to receive atezo (840 mg) or placebo on days 1 and 15 plus nab-paclitaxel (100 mg/m2) on days 1, 8 and 15; all treatments are given on a 28-day cycle. Patients are stratified by the presence of liver metastases, prior taxane therapy and the PD-L1 status of IC (IC0 vs IC1/2/3). PD-L1 expression is centrally evaluated by immunohistochemistry using the SP142 assay. To capture pseudoprogression and delayed responses to atezo, patients with radiographic progression may continue to receive open-label atezo alone or with nab-paclitaxel until unacceptable toxicity or loss of clinical benefit.
Eligibility criteria: This study will enroll patients with histologically documented locally advanced or metastatic TNBC, no prior systemic therapy for advanced TNBC, ECOG PS 0-1 and measurable disease per RECIST v1.1. Patients with significant cardiovascular or CNS disease (except asymptomatic treated CNS metastases), autoimmune disease or prior immune checkpoint blockade therapy are excluded.
Endpoints: The co-primary efficacy endpoints are progression-free survival (PFS) in all patients and in PD-L1–selected patients. Secondary endpoints include overall survival, objective response rate, response duration, safety/tolerability, pharmacokinetics and health-related quality of life. Tumor biopsies are obtained at baseline and at progression to evaluate potential biomarkers associated with therapeutic response and resistance.
Statistical methods/target accrual: PFS will be compared between treatment arms (nab-paclitaxel vs. nab-paclitaxel plus atezo) using the stratified log-rank test. The hazard ratio for disease progression or death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm. About 350 patients will be enrolled at ≈ 120 sites globally.
Sponsor: Genentech, Inc. ClinicalTrials.gov identifier NCT02425891.
Citation Format: Emens L, Adams S, Loi S, Schmid P, Schneeweiss A, Rugo H, Chui S, Winer E. A phase III randomized trial of atezolizumab in combination with nab-paclitaxel as first line therapy for patients with metastatic triple-negative breast cancer (mTNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-06.