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01-01-2020 | Metastasis | Clinical trial

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases

Authors: José Pablo Leone, Dan G. Duda, Jiani Hu, William T. Barry, Lorenzo Trippa, Elizabeth R. Gerstner, Rakesh K. Jain, Sally Tan, Elizabeth Lawler, Eric P. Winer, Nancy U. Lin, Sara M. Tolaney

Published in: Breast Cancer Research and Treatment | Issue 1/2020

Abstract

Purpose

To analyze the efficacy and tolerability of cabozantinib—a small molecule inhibitor of MET and VEGFR2—alone or with trastuzumab in patients with breast cancer brain metastases (BCBM).

Methods

This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective.

Results

Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1–9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume.

Conclusions

Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia.

Trial registration

Clinicaltrial.gov registration: NCT02260531.

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Title: A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases
Authors: José Pablo Leone
Dan G. Duda
Jiani Hu
William T. Barry
Lorenzo Trippa
Elizabeth R. Gerstner
Rakesh K. Jain
Sally Tan
Elizabeth Lawler
Eric P. Winer
Nancy U. Lin
Sara M. Tolaney
Publication date: 01-01-2020
Publisher: Springer US
Keywords: Metastasis
Breast Cancer
CNS Metastasis
Breast Cancer
Cabozantinib
Trastuzumab
Biomarkers
Published in: Breast Cancer Research and Treatment / Issue 1/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05445-z

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Abstract

Purpose

Methods

Results

Conclusions

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