@article{7df62a1e6a3c465b91897283886c12fe,
title = "Brain radiotherapy, tremelimumab-mediated CTLA-4-directed blockade +/− trastuzumab in patients with breast cancer brain metastases",
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.",
author = "Page, {David B.} and Kathryn Beal and Linch, {Stefanie N.} and Spinelli, {Kateri J.} and Micaela Rodine and Darragh Halpenny and Shanu Modi and Sujata Patil and Young, {Robert J.} and Thomas Kaley and Taha Merghoub and David Redmond and Phillip Wong and Barker, {Christopher A.} and Adi Diab and Larry Norton and McArthur, {Heather L.}",
note = "Funding Information: The study was supported by MedImmune/AstraZeneca, the Terri Brodeur Breast Cancer Research Foundation (DBP), the Memorial Sloan Kettering Cancer Center Translational and Integrative Medicine Research Fund (HLM), the NIH/NCI Cancer Center Support Grant P30 CA008748, the Ludwig Center for Cancer Immunotherapy, and Breast Cancer Research Foundation (HLM). Funding Information: D.B.P. has served on the advisory board for Merck, Syndax, Peregrine, Bristol-Myers Squibb, Puma, and Nanostring; has received research support from Bristol-Myers Squibb, Merck, and Brooklyn ImmunoTherapeutics; and has served on the speaker{\textquoteright}s bureau for Genentech and Novartis. K.B., K.J.S., M.R., D.H., S.P., T.K., D.R., and C.A.B. have no disclosures. S.N.L. has received patent royalties from Galectin Therapeutics. R.J.Y. has consulted for Agios, Puma, ICON plc and NordicNeuroLab; has received research support from Agios. S.M. has research funding from Genentech, Daiichi Sankyo, Novartis, AstraZeneca, and Seattle Genetics; she has received speaking fees from Genentech, Daiichi Sankyo, AstraZeneca, and Seattle Genetics; she has consulted for Genentech, Daiichi Sankyo, AstraZeneca, Macrogenics, and Seattle Genetics. T.M. is a cofounder and holds an equity in IMVAQ Therapeutics. He is a consultant of Immunos Therapeutics and Pfizer. He has research support from Bristol-Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. He has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neo antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. P.W. has consulted for Sellas Life Sciences and Leap Therapeutics. A.D. has consultaed for Bristol-Myers Squibb, NEKTAR therapeutics, Pfizer, and Apexigen and has received research support from Bristol-Myers Squibb, Nektar therapeutics, Idera, and Merck. H.L.M. has consulted for Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi Sankyo, Seattle Genetics, AstraZeneca and TapImmune; and has received research support from Bristol-Myers Squibb; MedImmune, LLC/AstraZeneca; BTG; and Merck. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41523-022-00404-2",
language = "English (US)",
volume = "8",
journal = "npj Breast Cancer",
issn = "2374-4677",
publisher = "Nature Publishing Group",
number = "1",
}