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

Journal Article (Journal Article)

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).

Full Text

Duke Authors

Cited Authors

  • Van Swearingen, AED; Siegel, MB; Deal, AM; Sambade, MJ; Hoyle, A; Hayes, DN; Jo, H; Little, P; Dees, EC; Muss, H; Jolly, T; Zagar, TM; Patel, N; Miller, CR; Parker, JS; Smith, JK; Fisher, J; Shah, N; Nabell, L; Nanda, R; Dillon, P; Abramson, V; Carey, LA; Anders, CK

Published Date

  • October 2018

Published In

Volume / Issue

  • 171 / 3

Start / End Page

  • 637 - 648

PubMed ID

  • 29938395

Pubmed Central ID

  • 29938395

Electronic International Standard Serial Number (EISSN)

  • 1573-7217

International Standard Serial Number (ISSN)

  • 0167-6806

Digital Object Identifier (DOI)

  • 10.1007/s10549-018-4852-5

Language

  • eng