Abstract OT2-01-14: Triple-negative first-line study: Neoadjuvant trial of nab-paclitaxel and atezolizumab, a PD-L1 inhibitor, in patients with triple negative breast cancer (TNBC) (NCT02530489)
Authors: Litton JK , Moulder S , Helgason T , Clayborn AR , Rauch GM , Gilcrease M , Adrada BE , Huo L , Hess KR , Symmans WF , Thompson A , Tripathy D , Mittendorf EA 
Published: March 2017

Abstract
BACKGROUND: TNBC has an especially poor prognosis in patients (pts) whose tumor does not respond to anthracycline and taxane-based chemotherapy. Approximately 50% will have chemo-insensitive disease (CID) resulting in extensive residual disease at the time of surgery. 40-80% of these pts will recur &lt; 3 years. Recently developed molecular profiling techniques to identify TNBC subsets detect distinct molecular hallmarks. We designed a clinical trial to identify and characterize CID (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival). Treatment naïve pts with localized TNBC undergo a pretreatment biopsy followed by anthracycline-based chemotherapy (AC). During AC the molecular profile is determined; these results along with the response assessment (clinical exam/diagnostic imaging) will identify CID and guide the second phase of neoadjuvant chemotherapy. Tumor-infiltrating lymphocytes (TIL) have been identified as having prognostic and predictive significance in TNBC pts leading to higher pCR rates post NACT. However, the tumor microenvironment also contains regulatory T cells and myeloid-derived suppressor cells that are immunosuppressive. Programmed death ligand 1 (PD-L1) is expressed in 20% TNBC. Targeting this may lead to a more durable response as compared to chemotherapy alone.
PRIMARY OBJECTIVE: Evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden (RCB)-I responses in TNBC pts, determined to have CID after anthracycline-based chemotherapy, then treat with atezolizumab + nab-paclitaxel preoperatively.
TRIAL DESIGN AND STATISITCAL METHODS: Pts deemed to have CID on the ARTEMIS trial can enter this non-randomized phase II study. Pts without response to their initial chemotherapy cycles have a low likelihood (5%) of achieving pCR with additional cycles of chemotherapy. It would be clinically meaningful for pCR to improve to 20%. Counting pCR (RCB-0) or RCB-I as response given similar survival outcomes, a two-stage Gehan-type design will be employed with 14 pts in the first stage. If at least one pt responds, 23 more will be added. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% if the true rate is 0.15 and 4% if the true rate is 0.20. If accrual continues to the second stage, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35.
BRIEF ELIGIBILITY CRITERIA: Inclusion: localized TNBC enrolled onto ARTEMIS and determined to have CID at the time of response assessment after anthracycline chemotherapy, adequate organ, bone marrow and cardiac parameters. Exclusion: prior immunotherapy, IBC, history of autoimmune disease, HIV, Hep-B, Hep-C, active tuberculosis, pregnant.
CORRELATIVE SCIENCE: Evaluate the presence and phenotype of TIL and other immune cell populations in tumor tissue pre/post treatment; determine changes in expression of co-stimulatory and co-inhibitory molecules on tumor cells and immune cells in the microenvironment; evaluate the immune repertoire and cytokine responses in serially collected peripheral blood mononuclear cells and serum respectively.
Citation Format: Litton JK, Moulder S, Helgason T, Clayborn AR, Rauch GM, Gilcrease M, Adrada BE, Huo L, Hess KR, Symmans WF, Thompson A, Tripathy D, Mittendorf EA. Triple-negative first-line study: Neoadjuvant trial of nab-paclitaxel and atezolizumab, a PD-L1 inhibitor, in patients with triple negative breast cancer (TNBC) (NCT02530489) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-14.