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.

Conflict of interest statement

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’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.

© 2022. The Author(s).

Figures

Fig. 1. Trial schema and overall survival.

A Trial design showing Simon two-stage design for the HER2− cohort and the safety evaluation for the HER2+ cohort. Three or more DCR responses in 17 patients at the end of the study for the treatment to be considered meritorious for further investigation. However, three additional subjects enrolled in the HER2− cohort to expand sample size for estimation of DCR at week 12. These subjects were not included in the pre-specified primary efficacy determination. B Median OS for HER2− cohort = 4.9 months, median OS for HER2+ cohort = 7.98 months. C Median OS for patients with PD = 4.47 months, median OS for patients with SD or PR = 14.58 months.

Fig. 2. Swimmer’s plot.

The Swimmer’s plot illustrates time on treatment in blue and green for the HER2+ and HER2- cohorts, respectively. Time of death is indicated by the red diamonds.

Fig. 3. HER2+ responder treatment schedule and radiological response.

A Prior therapies. B Treatment timeline and blood draws (red) for the patient who responded to tremelimumab (blue) and WBRT (black rectangle) with trastuzumab (gold), showing when she responded (green) to when she relapsed (pink). C Baseline (left) and week 12 (right) PET/CT demonstrating a non-CNS PR in a woman treated with concurrent tremelimumab and WBRT with HER2-directed therapy that was durable at 6 months. H trastuzumab, P pertuzumab, cape capecitabine, T-DM1 trastuzumab emtansine, T paclitaxel, treme tremelimumab, RTradiotherapy.

Fig. 4. Immunologic correlates in the blood of a HER2+ responder.

Peripheral blood mononuclear cells were stained for various markers and analyzed using flow cytometry at weeks 0, 2, 4, 24, and 60 post-treatment initiation (n = 2, technical replicates). A Expression of CD8 (red), FoxP3−CD4 conventional T cells (Tconv; light blue), and FoxP3+CD4 regulatory T cells (Treg; dark blue) out of total CD3+ live cells. B CD8:Treg ratio. (C-F) CD8 (red triangles), CD4 Tconv (light blue circles), and Treg (dark blue squares) were analyzed for expression of (C) Ki-67, (D) ICOS, (E) CTLA-4, and (F) PD-1. G Tim-3 expression on PD-1+ compared to PD-1− CD8 T cells. H Percentage of CD14+ and HLA-DRlo monocytes over time.