Journal Article

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

Dillon, Patrick, Abramson, Vandana, Jolly, Trevor, Carey, Lisa A, Deal, Allison M, Sambade, Maria J, Shah, Nikita, Patel, Nirali, Nabell, Lisle, Nanda, Rita, Zagar, Timothy M, Siegel, Marni B, Parker, Joel S, Dees, Elizabeth Claire, Muss, Hyman, Smith, J Keith, Heejoon Jo, Anders, Carey K, Little, Paul, C Ryan Miller, Amanda E D Van Swearingen, Hoyle, Alan, Fisher, Julie, Hayes, D Neil

2018

Overview

PurposeHER2 + 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 methodsEligible 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%.Results32 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.ConclusionWhile 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).

• Publisher: Springer Nature B.V
• Subject: 1-Phosphatidylinositol 3-kinase / Brain cancer / Breast cancer / Cancer research / Central nervous system / ErbB-2 protein / Immunotherapy / Inhibitor drugs / Metastases / Metastasis / Monoclonal antibodies / Mutation / Neutropenia / p53 Protein / Stomatitis / Targeted cancer therapy / TOR protein / Toxicity / Trastuzumab / Tumors / Vinorelbine