Brain radiotherapy, tremelimumab-mediated CTLA-4-directed blockade +/− trastuzumab in patients with breast cancer brain metastases

David B. Page, Kathryn Beal, Stefanie N. Linch, Kateri J. Spinelli, Micaela Rodine, Darragh Halpenny, Shanu Modi, Sujata Patil, Robert J. Young, Thomas Kaley, Taha Merghoub, David Redmond, Phillip Wong, Christopher A. Barker, Adi Diab, Larry Norton, Heather L. McArthur

Research output: Contribution to journalArticlepeer-review

Abstract

Breast cancer brain metastases (BCBM) are a common and devastating complication of metastatic breast cancer with conventional systemic therapies demonstrating limited effectiveness. Consequently, radiotherapy (RT) ± surgery remains the cornerstone of BCBM management. Because preclinical and clinical evidence indicate that immune checkpoint blockade (ICB) may synergize with RT to promote systemic tumor regression, we explored the safety and efficacy of RT and concurrent tremelimumab-mediated cytotoxic T-lymphocyte associated protein 4 (CTLA-4) ICB with tremelimumab ± HER2-directed therapy with trastuzumab for BCBM. Eligible patients had BCBM indicated for brain RT. A Simon two-stage design was adopted to evaluate the efficacy of tremelimumab and RT in 20 patients with human epidermal growth factor receptor normal (HER2−) BCBM. The safety of concurrent RT, tremelimumab, and trastuzumab was evaluated in a cohort of 6 HER2+ patients. The primary endpoint was 12-week non-central nervous system (CNS) disease control rate (DCR). Secondary endpoints included safety, survival, and CNS response. Exploratory correlatives included characterization of peripheral blood immune responses among exceptional responders. Tremelimumab plus RT ± trastuzumab was tolerated with no treatment-related grade 4 adverse events reported. The 12-week non-CNS DCR was 10% (2/20) in the HER2− cohort and 33% (2/6) in the HER2+ cohort. One patient with HER2+ disease experienced a durable partial response with evidence of peripheral T-cell activation. Thus, tremelimumab and RT ± trastuzumab was tolerated. Although modest clinical activity was observed in the HER2- efficacy cohort, encouraging responses were observed in the HER2+ safety cohort. Consequently, a trial to determine efficacy in HER2+ BCBM is planned. Clinical Trial Registration Number: NCT02563925.

Original languageEnglish (US)
Article number50
Journalnpj Breast Cancer
Volume8
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Brain radiotherapy, tremelimumab-mediated CTLA-4-directed blockade +/− trastuzumab in patients with breast cancer brain metastases'. Together they form a unique fingerprint.

Cite this