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

Page, David B, Beal, Kathryn, Linch, Stefanie N, Spinelli, Kateri J, Rodine, Micaela, Halpenny, Darragh, Modi, Shanu, Patil, Sujata, Young, Robert J, Kaley, Thomas, Merghoub, Taha, Redmond, David, Wong, Phillip, Barker, Christopher A, Diab, Adi, Norton, Larry, McArthur, Heather L (April 2022) Brain radiotherapy, tremelimumab-mediated CTLA-4-directed blockade +/- trastuzumab in patients with breast cancer brain metastases. npj Breast Cancer, 8 (1). p. 50. ISSN 2374-4677

PDF 2022.Page.brain_metastases.pdf Available under License Creative Commons Attribution. Download (1MB)

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > metastasis diseases & disorders > cancer > drugs and therapies > patient outcomes diseases & disorders > cancer > cancer types
CSHL Authors:	Norton, Larry
Communities:	CSHL labs > Wigler lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	19 April 2022
Date Deposited:	02 May 2022 14:12
Last Modified:	16 Jan 2024 21:00
PMCID:	PMC9018738
URI:	https://repository.cshl.edu/id/eprint/40597

Actions (login required)

Administrator's edit/view item