Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer
M Kearney, L Franks, S Lee, A Tiersten… - Breast cancer research …, 2021 - Springer
M Kearney, L Franks, S Lee, A Tiersten, DF Makower, T Cigler, P Mundi, DC Chi, A Goel…
Breast cancer research and treatment, 2021•SpringerPurpose Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors,
and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+
cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a
phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and
ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. Methods
Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2 …
and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+
cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a
phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and
ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. Methods
Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2 …
Purpose
Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer.
Methods
Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control.
Results
Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25 mg twice daily was the recommended phase II dose with no dose limiting toxicities (DLTs). Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic.
Conclusion
While well tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer.
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