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

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).

Keywords: Brain metastases; Breast cancer; Metastases; PI3K, MEK; Targeted therapy.

Conflict of interest statement

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.

Figures

Fig. 1

Consort diagram of LCCC 1025: vinorelbine, trastuzumab, and everolimus in HER2 + breast cancer brain metastases

Fig. 2

Clinical outcomes and survival. a Most prevalent toxicities (All grades) in response to everolimus, vinorelbine, trastuzumab therapy. Grade 1 and 2 toxicities are presented in blue; Grade 3–5 toxicities are presented in red. b Waterfall plot of intracranial objective response rates by modified RECIST criteria. c Median time toprogression (TTP) and d median overall survival (OS) in response to everolimus, vinorelbine, trastuzumab among patients with progressive or new brain metastases arising from HER2 positive breast cancer

Fig. 3

Targeted DNA sequencing mutations and copy number alterations. a Significantly mutated genes (SMGs) across all available tissues, b mutations in the PI3K/mTOR pathway, c HER2 Copy Number Variations (CNVs) versus Intracranial Time to Progression in brain metastases, d HER2 CNVs versus Overall Survival across all available tissues. Dotted line is the correlation based on the primary tumors only. Horizontal lines indicate tissues from matched pairs (n = 2)