Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

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 e cacy 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.

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

“…However, the combination of the JAK2 inhibitor ruxolitinib with trastuzumab for the treatment of patients with pretreated metastatic disease was studied in a phase 1/2 clinical trial and showed no improvement of outcomes, compared to historical controls. Additional research is needed to determine if there is a role for other JAK/STAT targeting agents, and the optimal setting [ 82 ].…”

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer

“…These data suggest that the currently approved doses of ruxolitinib may be insufficient to achieve the potent inhibition of the IL-6/JAK/STAT pathway necessary to induce clinically meaningful responses, and that either novel drug-to-target delivery mechanisms are needed to bypass systemic toxicity (thus allowing higher doses to be given safely), or more specific JAK inhibitors need to be tested to minimize off-target toxicity while maximizing on-target suppression. Our results add to the growing body of evidence that utilizing ruxolitinib in different MBC settings (ER+ 15 , HER2+ 17 , and triple negative 14 , 16 ) is not effective, which may be explained in part by sub-optimal suppression of the JAK/STAT pathway.…”

“…Despite strong pre-clinical rationale for IL-6/STAT3 blockade, early phase studies utilizing ruxolitinib (INCB018424), an orally available selective JAK1/2 inhibitor currently approved by the Food and Drug Administration (FDA) for use in myelofibrosis, polycythemia vera, and graft-versus-host disease 13 have failed to show clinically meaningful responses in metastatic breast cancer as a single agent 14 or in combination with chemotherapy 15 , 16 or trastuzumab 17 . However, no studies to date have examined its feasibility and activity in combination with endocrine therapy in the ET-resistant metastatic setting.…”

Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer

“…This type of response is also consistent the lack of efficacy of ruxolitinib as a single agent in solid tumors [ 27 , 28 ]. A recent study demonstrates that addition of ruxolitinib to trastuzumab did not improve response in heavily pretreated patients [ 29 ]. These clinical findings are consistent with the notion that the TG2:NF-κB:IL6:STAT3 loop is operant during acquisition of resistance, and targeting this pathway is incapable of re-sensitizing tumors that have already bypassed HER2 signaling via alternative growth factor pathways.…”