Preclinical and clinical studies suggest that trastuzumab resistance in HER2+ breast cancer is mediated by cross-activation of alternative signaling pathways, especially 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 breast cancer cell lines.1 These data provided the rationale for studying the efficacy of ruxolitinib and trastuzumab in a phase 1/2 clinical trial.
At SABCS 2019, results were presented from an investigator-initiated, multicenter, open-label phase 1/2 trial of ruxolitinib plus trastuzumab in patients with HER2+ metastatic breast cancer (MBC) who have progressed on >2 HER2-directed therapies in the metastatic setting (including trastuzumab, pertuzumab, and ado-trastuzumab emtansine [T-DM1]).2 The phase 1 portion of the trial is an adaptive design with 10 patients to determine the recommended phase 2 dose (25 mg orally twice daily).3 Phase 2 is a nonrandomized open-label trial of 30 patients treated with trastuzumab plus ruxolitinib to compare progression-free survival (PFS) against historical data with single-agent HER2-targeted therapy in HER+ MBC. Response was assessed by imaging every 9 weeks. Of 26 evaluable patients, 24 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 patients (88.5%) had received prior pertuzumab and 25 (96.1%) had received prior T-DM1. The median PFS was 8.29 weeks, with a 6-month PFS of 21%; 4 patients with hormone receptor–positive/HER2+ MBC experienced PFS longer than 52 weeks. One partial response was achieved.
The most common treatment-related adverse events (AEs) were hematologic (anemia, 50%; neutropenia, 38%; thrombocytopenia, 31%), fatigue (35%), aspartate aminotransferase increase (15%), and diarrhea (15%). The most common grade 3 AEs were anemia (27%) and neutropenia (23%). Grade ≥4 events were not observed.
The authors concluded that ruxolitinib plus trastuzumab was a well-tolerated regimen that does not include cytotoxic chemotherapy. Although the non–chemotherapy-containing combination did not achieve the primary phase 2 end point of improvement in PFS compared with historical controls, PFS of 6 months was 21% in this heavily pretreated HER2+ MBC population. Ongoing analyses will be done to determine factors that predict clinical benefit.
References
- Kalinsky K, et al. SABCS 2015. Abstract OT3-01-06.
- Kalinsky K, et al. SABCS 2019. Abstract P1-19-32.
- Mundi PS, et al. SABCS 2017. Abstract P4-21-37.