Abstract 4705: CTLA4 blockade with HER2-directed therapy (H) yields clinical benefit in women undergoing radiation therapy (RT) for HER2-positive (HER2+) breast cancer brain metastases (BCBM)
Authors: McArthur Heather , Beal Kathryn , Halpenny Darragh , Henrich Micaela , Modi Shanu , Patil Sujata , Young Robert , Kaley Thomas , Merghoub Taha , Barker Christopher , Wong Phillip , Hamilton Nicola , Hudis Clifford , Wolchok Jedd , Norton Larry 
Published: July 2017

Abstract
Introduction: BCBM is a devastating complication of breast cancer and women with specific subtypes (i.e. HER2+ disease) are at increased risk. Conventional systemic and local therapies have demonstrated limited effectiveness in preventing and treating BCBM. However, preclinical and clinical data indicate that the local effects of RT may be augmented by immune therapy and that abscopal effects (distant benefits outside of the RT field) may be achieved when combined with CTLA4-blockade. Thus, a pilot study of standard-of-care brain RT with tremelimumab, a CTLA4-directed monoclonal antibody, was undertaken to evaluate the impact on distant (non-CNS) disease control in women with HER2-normal (HER2-) disease and to confirm safety when administered with H in women with HER2+ disease.
Methods: Eligible women were age ≥18y, ECOG 0-2, with radiologically confirmed BCBM of any histology requiring whole brain RT (WBRT) or stereotactic radiosurgery (SRS), and non-CNS progression of disease (PD). Twenty women with HER2- disease were enrolled in an efficacy cohort with a primary endpoint of 12-week non-CNS disease control by RECIST v1.1. Six women with HER2+ disease were enrolled in a safety cohort and received concurrent H every 3 weeks. Tremelimumab (10mg/kg) was administered within 5 days prior to or 3 days after the first fraction of RT, then monthly for 6 months, and then every 3 months. Radiographic responses by irRC criteria were explored.
Results: Of the 6 women with HER2+ disease: 6 (100%) received WBRT, 1 had a non-CNS partial response (PR) at 12 weeks (-56.9% by RECIST, -86.2% by irRC) after 5 lines of palliative H-chemotherapy that was durable at 6 months; 1 had non-CNS stable disease at 12 weeks that was durable at 6 months; 2 had non-CNS PD at 12 weeks; 1 came off study for non-CNS PD prior to 12 weeks; and 1 died at 5 weeks. Among the 20 women with HER2- disease the best response was non-CNS SD (2 had SD, 9 had PD, 9 came off study due to PD and/or died prior to 12 weeks). The regimen was well tolerated with 15 grade 3 and no grade 4 attributable toxicity events reported. The most common treatment related AEs were diarrhea (12.9%), fatigue (9.7%), and colitis (6.5%).
Conclusions: BCBM RT plus tremelimumab with or without H was generally well tolerated. This is a poor prognosis population with 11/26 (42%) women coming off study due to death or rapid PD within 12 weeks of initiating brain RT. Although only modest activity was observed at 12 weeks in the HER2- cohort, durable clinical benefit was observed with concurrent H in 2 women with HER2+ disease. This is the first report of clinical responses to checkpoint blockade with H in breast cancer. The contribution of an abscopal effect due to RT is not known and thus, studies of immune therapy with H +/- RT are underway.
Citation Format: Heather McArthur, Kathryn Beal, Darragh Halpenny, Micaela Henrich, Shanu Modi, Sujata Patil, Robert Young, Thomas Kaley, Taha Merghoub, Christopher Barker, Phillip Wong, Nicola Hamilton, Clifford Hudis, Jedd Wolchok, Larry Norton. CTLA4 blockade with HER2-directed therapy (H) yields clinical benefit in women undergoing radiation therapy (RT) for HER2-positive (HER2+) breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4705. doi:10.1158/1538-7445.AM2017-4705