A Phase II Trial of the JAK-Inhibitor Ruxolitinib with Exemestane for Estrogen Receptor Positive, Aromatase Inhibitor Resistant, Advanced Breast Cancer

Abstract PURPOSE Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor outcomes and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. We investigated the safety and efficacy of ruxolitinib, an oral selective inhibitor of JAK1/2, given with exemestane in patients with HR + metastatic breast cancer (MBC) after progression on a non-steroidal AI (NSAI) and whether inflammatory biomarkers predict response. METHODS Participants had HR + MBC that relapsed on or within two years of adjuvant NSAI or progressed on NSAI for MBC. The trial was a phase II Simon two-stage design; primary objectives were safety and efficacy. Ruxolitinib, at a starting dose of 25mg twice daily, and exemestane, 25mg daily, were given continuously in the first stage; Grade 3/4 toxicity in < 5/15 participants enabled stage 2. Primary tumor and serial blood samples were collected. RESULTS Twenty-five subjects were enrolled. The combination of ruxolitinib and exemestane was safe and tolerable, though anemia requiring transfusion was a frequent adverse event at the 25 mg dose, leading to a reduction in the starting dose of 15 mg twice daily in stage 2. The clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4–45.1) with 6/25 patients demonstrating stable disease for ≥ 6 months. Median progression free survival was 2.8 months (95% CI 2.6–3.9). Exploratory biomarkers revealed a cohort with high levels of systemic inflammation: 60% harbored a high-risk IL-6 promoter genotype. Pharmacodynamic investigation demonstrated only a modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at the doses given. CONCLUSION Ruxolitinib combined with exemestane was feasible but lacked clinically meaningful efficacy, with only modest on-target inhibition in AI-resistant tumors when administered at a tolerable dose to a cohort of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in endocrine-resistant breast cancer.