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J Clin Oncol. 2016 Mar 20;34(9):945-52. doi: 10.1200/JCO.2015.63.0343. Epub 2016 Feb 1.

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

Author information

1
Rachel A. Freedman, Rebecca S. Gelman, Christina Herold, Nicole Ryabin, Sarah Farooq, Elizabeth Lawler, Ian E. Krop, Eric P. Winer, and Nancy U. Lin, Dana-Farber Cancer Institute; Beverly Moy, Massachusetts General Hospital; Alarice Lowe and Nathalie Y.R. Agar, Brigham and Women's Hospital, Boston, MA; Jeffrey S. Wefel, Kenneth R. Hess, and Nuhad Ibrahim, The University of Texas MD Anderson Cancer Center; Polly A. Niravath and Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; Michelle E. Melisko, University of California, San Francisco, San Francisco, CA; Roisin M. Connolly and Antonio C. Wolff, Johns Hopkins University, Baltimore, MD; Catherine H. Van Poznak, University of Michigan, Ann Arbor, MI; Shannon L. Puhalla, University of Pittsburgh Cancer Institute and Magee-Women's Hospital, Pittsburgh, PA; Kimberly L. Blackwell, Duke University Medical Center, Durham, NC; and Minetta C. Liu, Mayo Clinic, Rochester, MN. rafreedman@partners.org.
2
Rachel A. Freedman, Rebecca S. Gelman, Christina Herold, Nicole Ryabin, Sarah Farooq, Elizabeth Lawler, Ian E. Krop, Eric P. Winer, and Nancy U. Lin, Dana-Farber Cancer Institute; Beverly Moy, Massachusetts General Hospital; Alarice Lowe and Nathalie Y.R. Agar, Brigham and Women's Hospital, Boston, MA; Jeffrey S. Wefel, Kenneth R. Hess, and Nuhad Ibrahim, The University of Texas MD Anderson Cancer Center; Polly A. Niravath and Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; Michelle E. Melisko, University of California, San Francisco, San Francisco, CA; Roisin M. Connolly and Antonio C. Wolff, Johns Hopkins University, Baltimore, MD; Catherine H. Van Poznak, University of Michigan, Ann Arbor, MI; Shannon L. Puhalla, University of Pittsburgh Cancer Institute and Magee-Women's Hospital, Pittsburgh, PA; Kimberly L. Blackwell, Duke University Medical Center, Durham, NC; and Minetta C. Liu, Mayo Clinic, Rochester, MN.

Abstract

PURPOSE:

Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial.

PATIENTS AND METHODS:

Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders.

RESULTS:

Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time.

CONCLUSION:

Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01494662.

PMID:
26834058
PMCID:
PMC5070554
DOI:
10.1200/JCO.2015.63.0343
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

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