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Anders, Carey K.; Deal, Allison Mary; Van Swearingen, Amanda Elyse Day; Siegel, Marni; Hayes, David N.; Jo, Heejoon; Little, Paul; Dees, Elizabeth Claire; Muss, Hyman B.; Jolly, Trevor Augustus; Zagar, Timothy; Smith, J Keith; Fisher, Julie Gottlieb; Shah, Nikita C.; Nabell, Lisle; Nanda, Rita; Dillon, Patrick Michael; Puhalla, Shannon; Abramson, Vandana Gupta; Carey, Lisa A.

LCCC 1025: Phase II study of everolimus, trastuzumab, and vinorelbine for HER2+ breast cancer brain metastases (BCBM)

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  • Media type: E-Article
  • Title: LCCC 1025: Phase II study of everolimus, trastuzumab, and vinorelbine for HER2+ breast cancer brain metastases (BCBM)
  • Contributor: Anders, Carey K.; Deal, Allison Mary; Van Swearingen, Amanda Elyse Day; Siegel, Marni; Hayes, David N.; Jo, Heejoon; Little, Paul; Dees, Elizabeth Claire; Muss, Hyman B.; Jolly, Trevor Augustus; Zagar, Timothy; Smith, J Keith; Fisher, Julie Gottlieb; Shah, Nikita C.; Nabell, Lisle; Nanda, Rita; Dillon, Patrick Michael; Puhalla, Shannon; Abramson, Vandana Gupta; Carey, Lisa A.
  • imprint: American Society of Clinical Oncology (ASCO), 2017
  • Published in: Journal of Clinical Oncology
  • Language: English
  • DOI: 10.1200/jco.2017.35.15_suppl.1011
  • ISSN: 1527-7755; 0732-183X
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:p> 1011 </jats:p><jats:p> Background: HER2+ BC is an aggressive subset of BC with high rates of BM and poor survival. Two-thirds of BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy (Rx). This phase II study evaluated everolimus (E), a brain permeable mTOR inhibitor, added to trastuzumab (T) and vinorelbine (V) in patients (pts) with HER2+ BCBM. Methods: Eligible pts had progressing HER2+ BCBM. Pts received E (5mg PO QD), T (2mg/kg IV weekly) and V (25mg/m<jats:sup>2</jats:sup> IV d1, 8 of 21d cycle). The primary endpoint was intracranial response rate (RR [CR+PR], modified RECIST); secondary objectives (CNS clinical benefit rate [CBR, CR+PR+SD], extracranial RR, time to progression (TTP), overall survival (OS), and correlative studies). Targeted DNA sequencing of 20 tissues from 18 pts was performed. We used a two-stage design to distinguish ORR of 5% vs 20%. Results: 32 pts were evaluable for toxicity; 26 for efficacy. Median age was 53 (28–70 yrs). 31/32 pts had prior radiation: 13 (42%) WBRT, 8 (26%) radiosurgery, 9 (29%) both. Median prior lines of metastatic Rx was 2 (0–7). 30 (94%) received anti-HER2 Rx: 91% T, 69% lapatinib, 38% pertuzumab, 25% TDM1. Intracranial RR was 4% (1 PR, 6 SD &gt; 6 mos, 10 SD &gt; 3 mos, 9 PD). CNS CBR (6 mos) was 27%; CNS CBR (3 mos) was 65%. Extracranial RR was 46%. Median TTP was 4 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%). DNA sequencing showed heterogeneous HER2 copy number amplification (CN amp): only 11/20 show HER2 CN amp (median 40X v 0.7X; 5/11 BC, 4/4 BCBM, 1/2 liver mets, 1/3 LN). BCBM exhibited high-level HER2 CN amp (median 49X) vs other sites (16X). While 11/20 show both HER2 CN amp and PI3K pathway mutation, this was not associated TTP; RAD21 CN amp was associated with TTP &lt; 3 mos. Lack of HER2 CN amp plus a HER2 Tyr-kinase domain mutation was seen in a pt with nonresponse and short OS. Conclusions: While intracranial RR to ETV was low in pts with HER2+ BCBM, a substantial proportion had CNS CBR; OS was 1 year for this pt population. No new toxicity signals were observed. Further evaluation of DNA heterogeneity, including degree of HER2 CN amp in HER2+ BCBM, and association with outcome is warranted. Clinical trial information: NCT01305941. </jats:p>
  • Access State: Open Access