Abstract B42: Ibrutinib in combination with durvalumab (MEDI4736) in patients with relapsed or refractory HER2-positive or triple-negative breast cancer: A phase 1b/2 multicenter study
Authors: Rasco Drew W. , Borazanci Erkut , Guiterrez Martin , Hong David , Tawashi Ahmed , Lin Jennifer , Dimery Isaiah W. , Fosdale Mark 
Published: May 2016

Abstract
Purpose: HER2+ and triple-negative (TN) breast cancers (BC) are associated with an aggressive course and poor prognosis, with currently available treatments yielding low response rates and decreased progression-free survival (PFS) due to a high relapse rate, rapid disease progression, and development of resistance. Hence, novel agents with efficacy and a tolerable safety profile are needed for this challenging patient (pt) population. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase (BTK), which is a crucial signaling molecule in the B-cell receptor pathway. It has demonstrated robust clinical activity in B-cell malignancies. In preclinical studies, ibrutinib inhibited tyrosine phosphorylation of ErbB and ErbB2 in HER2- positive BC cell lines, thereby suppressing AKT and MAPK signaling (Elias, 2013; Grabinski, 2014). Programmed death-ligand 1 (PD-L1) is a molecule associated with inhibition of antitumor T cell immunity (Zou, 2008; Keir, 2008), and is highly expressed in TNBC (Tessari, 2014; Mittendorf, 2014). Durvalumab (MEDI4736) is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 (IC50 of 0.1nM) and CD80/B7.1 (IC50 of 0.04 nM) (Ibrahim, 2015). Durvalumab has shown promising clinical activity with an acceptable safety profile across multiple solid tumors (Fury, 2014; Segal, 2014; Antonia, 2014). The combination of an anti–PD-L1 antibody and ibrutinib suppressed tumor growth in mouse models of solid tumors, and led to enhanced antitumor T-cell immune responses (Sagiv-Barfi, 2015). Based on these encouraging preclinical data, the PCYC-1135 trial (NCT02403271) was initiated to test the safety and efficacy of ibrutinib plus durvalumab in pts with relapsed/refractory (R/R) Stage III/IV BC (both HER2+ and TNBC), as well as non-small cell lung cancer (NSCLC), and pancreatic cancer. This abstract focuses on the BC cohort enrolling in the trial.
Methods: A total of 130–160 pts (BC, NSCLC, and pancreatic) will be enrolled in this Phase 1b/2 study. Key eligibility criteria for the BC cohort include pathologically confirmed BC (HER2+ or TN), R/R disease (Stage III or IV) failing at least 2 prior therapies, measurable lesion by RECIST 1.1, and adequate hematologic, hepatic, and renal function. Key exclusion criteria include central nervous system involvement, antitumor therapy within 21 days of study initiation, prior treatment with ibrutinib or other BTK inhibitors, and/or anti-PD1, anti–PD-L1, anti–PD-L2, anti–CD137 or anti–CTLA-4 antibody, a history of allogeneic organ transplant, or treatment with a strong cytochrome P4503A inhibitor. The primary objectives are safety, tolerability, and efficacy as assessed by overall response rate. Secondary endpoints are disease control rate, duration of response, PFS, overall survival, and pharmacokinetics and pharmacodynamic assessments of the combination.
The Phase 1b will assess dose-limiting toxicities (DLTs) and will determine the recommended phase 2 dose (RP2D) of ibrutinib plus durvalumab. The starting dose level of ibrutinib is 560 mg daily, with the potential for subsequent dose level reductions if DLTs occur, in combination with durvalumab 10 mg/kg IV every 2 weeks in 28-day cycles until DLT or disease progression. Enrollment in phase 2 will commence at the RP2D, accruing a total of 130–160 pts (Phase 1b + Phase 2). Ibrutinib and durvalumab will be administered until unacceptable toxicity or disease progression. Enrollment began in March 2015.
Citation Format: Drew W. Rasco, Erkut Borazanci, Martin Guiterrez, David Hong, Ahmed Tawashi, Jennifer Lin, Isaiah W. Dimery, Mark Fosdale. Ibrutinib in combination with durvalumab (MEDI4736) in patients with relapsed or refractory HER2-positive or triple-negative breast cancer: A phase 1b/2 multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B42.