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LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases

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Abstract

Purpose

HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM.

Patients and methods

Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%.

Results

32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2–5). OS was 12.2 mos (95% CI 0.6–20.2). Grade 3–4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS.

Conclusion

While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. Clinical Trial: (NCT01305941).

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Data Availability

The datasets generated during and/or analyzed during the current study will be made available in the dbGAP repository.

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Acknowledgements

The authors thank the patients and their families who participated in this trial. We also thank the following cores and groups at UNC-Chapel Hill for their assistance with this correlative study: Tissue Procurement Facility, Translational Pathology Laboratory, Translational Genomics Laboratory, and Lineberger Bioinformatics Group. We also appreciate Erin Laurie’s administrative support.

Funding

This study was funded by the Novartis Pharmaceuticals, Damon Runyon Research Foundation (CKA), National Institute of Health K23 (CKA), National Institute of Health F30-CA200345 (MBS), and University of North Carolina Network Group Integrated Translational Science Center award (NCI 5U10CA181009).

Author information

Author notes

  1. D. Neil Hayes

    Present address: West Cancer Center, University of Tennessee, Knoxville, USA

  2. Amanda E. D. Van Swearingen and Marni B. Siegel are co-first authors.

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 170 Manning Drive, CB #7305, Chapel Hill, NC, 27599-7305, USA

    Amanda E. D. Van Swearingen, Marni B. Siegel, Allison M. Deal, Maria J. Sambade, Alan Hoyle, D. Neil Hayes, Heejoon Jo, Paul Little, Elizabeth Claire Dees, Hyman Muss, Trevor Jolly, Timothy M. Zagar, Nirali Patel, C. Ryan Miller, Joel S. Parker, J. Keith Smith, Lisa A. Carey & Carey K. Anders

  2. Carolinas Medical Center, Charlotte, NC, USA

    Julie Fisher

  3. MD Anderson Orlando, Orlando, FL, USA

    Nikita Shah

  4. University of Alabama, Birmingham, AL, USA

    Lisle Nabell

  5. University of Chicago, Chicago, IL, USA

    Rita Nanda

  6. University of Virginia, Charlottesville, VA, USA

    Patrick Dillon

  7. Vanderbilt University, Nashville, TN, USA

    Vandana Abramson

Authors
  1. Amanda E. D. Van Swearingen
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  2. Marni B. Siegel
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  6. D. Neil Hayes
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  9. Elizabeth Claire Dees
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  24. Carey K. Anders
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Contributions

Conception and design: Amanda E. D. Van Swearingen, PhD, Marni B. Siegel, PhD, Allison M Deal, Carey K. Anders, Lisa A. Carey. Financial support: Carey K. Anders (Novartis, Damon Runyon Cancer Foundation). Administrative support: Carey K. Anders. Provision of study materials or patients: Elizabeth Claire Dees, Hyman Muss, Trevor Jolly, Timothy M. Zagar, Julie Fisher, Nikita Shah, Lisle Nabell, Rita Nanda, Patrick Dillon, Vandana Abramson, Lisa (A) Carey, Carey K. Anders, Collection and assembly of data: Amanda E. D. Van Swearingen, Marni (B) Siegel, Allison M. Deal, Maria J. Sambade, Alan Hoyle, D. Neil Hayes, Heejoon Jo, Paul Little, Nirali Patel, (C) Ryan Miller, Joel S. Parker, J. Keith Smith, Carey K. Anders. Data analysis and interpretation: Marni B. Siegel, Amanda E. (D) Van Swearingen, Allison Mary Deal, D. Neil Hayes, Joel S. Parker, Carey K. Anders. Manuscript writing: Amanda (E) D. Van Swearingen, Marni B. Siegel, Allison Mary Deal, Carey K. Anders. Final approval of manuscript: All authors.

Corresponding author

Correspondence to Carey K. Anders.

Ethics declarations

Conflict of interest

Carey K. Anders is an uncompensated consultant/advisory board member for Novartis, Sanofi, toBBB, Angiochem, Merrimack, Lily, Genentech, Nektar, and Kadmon, receives unrelated research funding from Novartis, Sanofi, toBBB, Angiochem, Merrimack, PUMA, Lily, Merck, Oncothyreon, Cascadian, Nektar, and Tesaro, and receives honoraria for UptoDate and Jones and Bartlett Publishing. Rita Nanda is a consultant/advisory board member for AstraZeneca, Celgene, Genentech, Merck, Pfizer, Puma, and Syndax. Nikita Shah is a consultant for Novartis. The other authors declare they have no conflicts of interest.

Ethical approval

This manuscript complies with all current laws of the country in which they were performed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

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

Research involving human and animal participants

This article does not contain any studies with animals performed by any of the authors.

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Van Swearingen, A.E.D., Siegel, M.B., Deal, A.M. et al. LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases. Breast Cancer Res Treat 171, 637–648 (2018). https://doi.org/10.1007/s10549-018-4852-5

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