Abstract
Purpose:Preclinical data demonstrate STAT3 as an important regular 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 25mg twice daily was the recommended phase II dose with no 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.
Highlights
HER2 is a transmembrane receptor tyrosine kinase which plays an important role in cellular proliferation, differentiation and survival [1]
While well-tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in progression free survival (PFS) compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer
One patient had a partial response to the combination of ruxolitinib and trastuzumab and 4 patients had a best response of stable disease among those with measurable disease
Summary
HER2 is a transmembrane receptor tyrosine kinase which plays an important role in cellular proliferation, differentiation and survival [1]. Since the approval of trastuzumab, a variety of agents currently have FDA approval for the treatment of HER2 + metastatic breast cancer, including pertuzumab, lapatinib, neratinib, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, tucatinib, and margetuximab. Despite these therapeutic improvements, most patients with metastatic HER2 + disease have tumors that progress on currently approved HER2 directed agents. As such, identifying treatment strategies with novel agents complementary to HER2 directed therapy would present an important non-chemotherapy option to patients whose tumors progress on standard therapy
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