Abstract P2-08-03: Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer
Authors: DeMichele AM , Clark AS , Holmes R , Volpe M , Medrano C , Troxel A , Fox K , Domchek S , Matro J , Bradbury A , Shih N , Feldman M , Hexner E , Bromberg J 
Published: March 2017

Abstract
Background: In vitro mechanisms link IL-6 to poor outcome in breast cancer via inflammatory pathways, activated JAK/STAT tumor signaling and upregulation of aromatase, leading to an aggressive tumor phenotype. Epidemiological data from our group and others support these mechanisms in women with ER-positive (+) disease. We therefore hypothesized that the JAK inhibitor, ruxolitinib (RUX, INCB018424; Incyte), would enhance activity of exemestane (EXE) in women with ER+ breast cancer who relapsed after non-steroidal aromatase inhibitor therapy, particularly among carriers of a germ-line polymorphism in IL-6, conferring elevated levels of IL-6 in the tumor microenvironment.
Methods: The “JAKEE trial” is a phase II trial to determine the safety and efficacy of RUX + EXE in postmenopausal women with relapsed, ER+ advanced breast cancer. Eligible patients were required to have progressed on a non-steroidal AI and either measureable or bone-only disease. CRP, a putative biomarker of tumor microenvironment inflammation, was measured at baseline and serially during treatment. Using a Simon 2-stage design, we treated 15 patients with RUX at 25 mg BID and EXE at 25mg daily on a continuous 28-day schedule. First stage results were previously presented (AACR, 2014). Accrual proceeded to second stage after no patient met the pre-defined stopping rule of grade (G) 3/4 toxicity requiring discontinuation from the study within the first treatment cycle. Due to the substantial rate of anemia requiring dose reductions, however, RUX dose was reduced to 15 mg BID in second stage.
Results: A total of 25 patients were enrolled; 24/25 had progressed on AI in metastatic setting; 1 relapsed on adjuvant AI. RUX+EXE was well-tolerated overall, with only 2 G4 events (creatinine elevation, hepatic failure); both were due to disease progression. 16% had G3 fatigue, anemia or hypertension; 12% had G3 neutropenia or depression. Other lower grade toxicities in &gt;20% included musculoskeletal pain, increased ALT, and headache. Overall, patients stayed on therapy for a median of 3 cycles (range 2 – 21). There were no CR or PR, but 6/25 (24%) had prolonged disease control (SD&gt; 6 months). Median CRP at study entry was 6.4 (range 0.3-38.9), with 8/25 (32%) having CRP&gt;10. Achieving SD&gt;6 months was not associated with baseline CRP (CRP&gt;10 in 32% with vs. 33% without SD&gt;6 months, p(exact)=1.0). A novel pharmacodynamic assay to assess STAT3 phosphorylation in peripheral blood mononuclear cells after RUX exposure demonstrated differential effects in patients with response.
Conclusions: Targeting JAK/STAT signaling in AI-resistant breast cancer with RUX+EXE was safe and well-tolerated. 24% of patients had prolonged SD, but baseline CRP level did not predict response. Correlative studies to determine whether host and/or tumor biomarkers predict response to therapy, including germline IL-6 genotype, immune profiles, p-STAT3 and estradiol levels, are currently underway.
Citation Format: DeMichele AM, Clark AS, Holmes R, Volpe M, Medrano C, Troxel A, Fox K, Domchek S, Matro J, Bradbury A, Shih N, Feldman M, Hexner E, Bromberg J. Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer [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 P2-08-03.