Abstract P1-21-06: Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy
Authors: Zimmer Alexandra S , Steinberg Seth , Gilbert Mark , Armstrong Terri , Burton Eric , Houston Nicole , Smart Dee Dee , Biassou Nadia , Butman John , Brastianos Priscilla K , Anders Carey K , Lipkowitz Stanley , Steeg Patricia S 
Published: March 2022

Abstract
Background: The incidence of breast cancer brain metastases is rising, and, these lesions in the central nervous system (CNS) and their treatments cause physical and neurocognitive impairment. Only modest incremental advances in progression free survival have been achieved with drugs to treat CNS lesions, while nearly half of the patients who receive SRS will develop new brain metastases within 1 year. In murine models of breast cancer, we demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion significantly prevented development of brain metastases. No effect, however, was seen in established brain metastases or systemic breast cancer metastases. We hypothesize that low dose, metronomic TMZ will prevent the outgrowth of brain lesions in HER2+ patients, when added to an active anti-HER2 treatment. We present here the results of the phase I trial combining T-DM1 to TMZ for the prevention of additional brain metastases after their first occurrence and local treatment. Methods: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of local brain metastases therapy (WBRT, SRS and or surgery), with PS 0-2 and adequate end organ function. Standard doses of T-DM1 were administered IV every 21 days (3.6 mg/kg) and TMZ was given PO daily in a 3+3 design at 30, 40 or 50 mg/m2, continuously. The DLT period was one 21d cycle. Safety was assessed by CTCAEv4.0 and response by RECISTv1.1 and RANO-BM. Brain MRI and systemic CT scans were performed every 6 weeks. Blood samples for correlatives evaluation were collected at baseline and every cycle while on trial. CSF was collected at baseline and C3D1 for all patients. Questionnaires (MDASI-BT and PROMIS®) for evaluation of symptoms and quality of life were completed every 6 weeks. Results: Twelve women with median age 55.5yr (44-67) were enrolled. Only 3 (25%) patients had HR+/HER2+ tumors at initial diagnosis. Nine (75%) patients presented stages II and III disease at initial diagnosis, and developed brain metastases at the diagnosis of first recurrence. Nine (75%) patients received SRS therapy and 3 (25%) received WBRT prior to trial enrollment. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12) and decreased CD4 (6/12), requiring pentamidine for PCP prophylaxis. No DLT was observed. Four patients underwent dose reductions (thrombocytopenia, fatigue and peripheral neuropathy), all of them enrolled on the highest TMZ dose. Median follow-up on study is now 9.6m (1.2-32) and no patient developed new parenchymal brain metastases. Five patients remain on study, while 7 are off study due to progression at previously irradiated CNS lesion (2), progression of systemic disease (2), focal leptomeningeal involvement (1), new cancer (1) and persistent thrombocytopenia (1). Completion rates for the questionnaires were 99% by Cycle 15 (81 completed out of expected 82) and 90% by Cycle 41 (123/137), and will be reported at presentation. Conclusion: Metronomic TMZ in combination with standard dose T-DM1 is tolerable and shows promising activity in secondary prevention of HER2+ brain metastases. Systematic longitudinal symptom assessments in breast cancer patients with brain metastasis are feasible. A randomized phase II expansion of this trial with T-DM1 or T-Dxd +/- TMZ is planned.
Citation Format: Alexandra S Zimmer, Seth Steinberg, Mark Gilbert, Terri Armstrong, Eric Burton, Nicole Houston, Dee Dee Smart, Nadia Biassou, John Butman, Priscilla K Brastianos, Carey K Anders, Stanley Lipkowitz, Patricia S Steeg. Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-06.