Abstract OT3-05-04: Phase II study of atezolizumab, cobimetinib, and eribulin in patients with recurrent or metastatic inflammatory breast cancer (IBC)
Authors: Alexander A , Marx AN , Reddy SM , Reuben JM , Le-Petross HC , Lane D , Huang ML , Krishnamurthy S , Gong Y , Gombos DS , Patel N , Tung CI , Allen RC , Kandl TJ , Wu J , Liu S , Patel AB , Futreal A , Wistuba I , Layman RM , Valero V , Tripathy D , Ueno NT , Lim B 
Published: May 2019

Abstract
Background: IBCs that do not completely respond to chemotherapy often have dysregulated immune pathways, and novel therapies are needed to improve outcomes in recurrent/metastatic disease. One-third of IBCs express the atezolizumab target PD-L1, and cobimetinib increases PD-L1 expression; thus, we hypothesize that atezolizumab and cobimetinib may act synergistically in IBC. The FDA-approved agent eribulin is active in IBC and has anti-stem cell activity and can reverse the IBC phenotype of epithelial-to-mesenchymal transition. Hence the use of eribulin as a chemotherapy backbone in combination with other novel agents is well justified.
Trial Design: This single-arm, open-label trial is enrolling patients with recurrent IBC or de novo metastatic IBC that has progressed on at least 1 line of standard chemotherapy. During a 4-week pharmacodynamic window, patients have an upfront biopsy, receive atezolizumab and cobimetinib treatment for 4 weeks, and have a second biopsy. Triple-combination treatment then commences, with standard eribulin dosing. After 4 cycles of eribulin, patients receive maintenance targeted therapy until disease progression or intolerable toxicity.
Eligibility Criteria: Patients with metastatic IBC of any molecular subtype must have measurable disease (per RECIST 1.1) amenable to biopsy. Patients with HER2+ disease must have received both pertuzumab and T-DM1. Patients with treated stable brain metastases are allowed. Patients must have recovered from the acute effects of any prior therapies and have adequate hematologic, organ, and cardiac function. Patients with autoimmune diseases or a history of pneumonitis are ineligible.
Specific Aims: The primary objective is to determine the overall response rate (ORR) of the combination therapy. Secondary objectives include determining the safety and tolerability, clinical benefit rate, response duration, progression-free survival, 2-year overall survival rate and predictive biomarker analyses.
Statistical Methods: The trial will enroll up to 9 patients in its phase I/safety lead-in portion and up to 33 patients total. A Bayesian optimal interval design is used to efficiently determine the maximum tolerated cobimetinib dose in phase I. Patients start cobimetinib at the FDA-approved dose of 60 mg/day with a target toxicity rate is 0.3. Phase II will enroll 24 patients to determine the efficacy of the triple-combination therapy. The historical ORR in metastatic IBC is 10%; our sample size provides 80% power to detect an ORR improvement to 25%.
Accrual: The trial has enrolled 7 patients since its start in August 2017.
Citation Format: Alexander A, Marx AN, Reddy SM, Reuben JM, Le-Petross HC, Lane D, Huang ML, Krishnamurthy S, Gong Y, Gombos DS, Patel N, Tung CI, Allen RC, Kandl TJ, Wu J, Liu S, Patel AB, Futreal A, Wistuba I, Layman RM, Valero V, Tripathy D, Ueno NT, Lim B. Phase II study of atezolizumab, cobimetinib, and eribulin in patients with recurrent or metastatic inflammatory breast cancer (IBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-05-04.