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

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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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Data availability

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

Exelixis, Rosa’s Pursuit of Hope, and Global Giving Grant from Tripadvisor.

Author information

Authors and Affiliations

  1. Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    José Pablo Leone, Elizabeth Lawler, Eric P. Winer, Nancy U. Lin & Sara M. Tolaney

  2. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

    Dan G. Duda & Rakesh K. Jain

  3. Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA

    Jiani Hu, William T. Barry & Lorenzo Trippa

  4. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Elizabeth R. Gerstner

  5. Department of Internal Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Sally Tan

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  1. José Pablo Leone
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Corresponding author

Correspondence to Sara M. Tolaney.

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Conflict of interest

JPL receives institutional research funding from Merck and Kazia Therapeutics. SMT receives institutional research funding from Novartis, Genentech, Eli Lilly, Pfizer, Merck, Exelixis, Eisai, Bristol Meyers Squibb, AstraZeneca, Cyclacel, Immunomedics, Odenate, and Nektar. SMT has served as an advisor/consultant to Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics, Nektar, Tesaro, and Nanostring. RKJ received honorarium from Amgen and consultant fees from Chugai, Merck, Ophthotech, SPARC, SynDevRx, and XTuit. RKJ owns equity in Enlight, SPARC, and SynDevRx, and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. DGD received consultant fees from Bayer, Tilos, twoXAR, and BMS and has received research grants from Bayer, Merrimack, Leap, Exelixis, and BMS. WTB received institutional research funding from Pfizer. NUL receives institutional research funding from Genentech, Seattle Genetics, Novartis, and Pfizer. NUL has served as an advisor/consultant to Puma and Daiichi.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (include name of committee + reference number) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Leone, J.P., Duda, D.G., Hu, J. et al. A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases. Breast Cancer Res Treat 179, 113–123 (2020). https://doi.org/10.1007/s10549-019-05445-z

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  • DOI: https://doi.org/10.1007/s10549-019-05445-z

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