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Background: Preclinical and clinical studies suggest that trastuzumab resistance in HER2+ BC is mediated by cross-activation of alternative signaling pathways. Computational analysis and pooled whole-genome RNAi screens in HER2 transformed BC cell lines identified the IL6/JAK2/STAT3 axis as a master regulator pathway. The combination of trastuzumab plus ruxolitinib, a JAK1/JAK2 inhibitor, demonstrated synergistic tumor growth inhibition in mouse xenografts of HER2 transformed BC cell lines. These data provide the rationale for studying the efficacy of ruxolitinib and trastuzumab in a phase I/II trial. Design: This is an investigator-initiated, multi-center, open-label, phase I/II trial of ruxolitinib plus trastuzumab in patients (pts) with HER2+ MBC who have progressed on >2 HER2-directed therapies in the metastatic setting (including trastuzumab, pertuzumab and T-DM1, unless pt refusal). The phase I is an adaptive design with 10 pts to determine the recommended phase II dose (RP2D: 25 mg po BID, SABCS 2017). Phase II is a non-randomized open-label trial of 30 pts with trastuzumab plus ruxolitinib to compare progression free survival (PFS) against historical data with single-agent HER2-targeted therapy in HER+ MBC (Blackwell JCO 2010). The study was powered to detect a difference in median PFS of 8 weeks versus 13 weeks. Response was assessed by imaging every 9 weeks. Results: We accrued 28 pts from 10/14-8/18 and stopped early due to slow accrual. Of the 27 evaluable pts, 11 were in the phase I, of which 10 pts received 25 mg po BID (RP2D). Thus, 26 pts are included in the phase 2 study (pre-specified). Of the evaluable pts, the median age was 56 (range 32 - 77). Of these, 24 pts were postmenopausal (92%), 15 (58%) were estrogen receptor positive, and 24 (92%) had measurable disease, including 8 (33%) in lung and 4 (15%) in liver. The median number of prior lines of therapy in the metastatic setting was 4 (range: 2-9). Twenty-three pts (88.5%) received prior pertuzumab and 25 (96.1%) received prior T-DM1. As of 6/24/19, 2 pts remain on therapy at 46 and 72 weeks of follow-up. Twenty evaluable pts came off study due to progression, 3 due to death from disease, and 1 for adverse events. The median PFS was 10.7 weeks (95% CI: 7.1-15.1). The 6-month PFS is 21% (7%, 40%). The most common treatment-related adverse events (AEs) were hematologic [anemia 13 (50%), neutropenia 10 (38%), thrombocytopenia 8 (31%)], fatigue 9 (35%), aspartate aminotransferase increase 4 (15%) and diarrhea 4 (15%). The most common grade 3 AEs were anemia 7 (27%), and neutropenia 6 (23%). Grade 4 or higher events were not observed. Response data in pts with measurable disease will be presented at SABCS. Conclusion: Ruxolitinib plus trastuzumab was a well-tolerated regimen that does not include cytotoxic chemotherapy. While the combination did not achieve the primary endpoint (median PFS), there was 6-month PFS of 21% in this heavily pre-treated HER2+ MBC population. Ongoing analyses will be done to determine factors that predict clinical benefit. Citation Format: Kevin Kalinsky, Shing Lee, Amy Tiersten, Della F Makower, Tessa Cigler, Lauren Franks, Prabhjot Mundi, Dow-Chung Chi, Lauren Blumberg, Naomi Sender, Magdalena Galazyn, Kristina Hosi, Anupama Goel, Paula Klein, Eleni Andreopoulou, Joseph Sparano, Katherine D Crew, Andrea Califano, Jose Silva, Dawn L Hershman. Phase I/II trial of ruxolitinib in combination with trastuzumab in HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-32.