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25.06.2018 | Clinical trial

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

verfasst von: 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, Julie Fisher, Nikita Shah, Lisle Nabell, Rita Nanda, Patrick Dillon, Vandana Abramson, Lisa A. Carey, Carey K. Anders

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 3/2018

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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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Titel: LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases
verfasst von: 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
Julie Fisher
Nikita Shah
Lisle Nabell
Rita Nanda
Patrick Dillon
Vandana Abramson
Lisa A. Carey
Carey K. Anders
Publikationsdatum: 25.06.2018
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 3/2018
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4852-5

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