Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases

Sarah Jenkins, Wei Zhang, Seth M. Steinberg, Darryl Nousome, Nicole Houston, Xiaolin Wu, Terri S. Armstrong, Eric Burton, Dee Dee Smart, Ritu Shah, Cody J. Peer, Brett Mozarsky, Oluwatobi Arisa, William D. Figg, Tito R. Mendoza, Elizabeth Vera, Priscilla Brastianos, Scott Carter, Mark R. Gilbert, Carey K. AndersRoisín M. Connolly, Carol Tweed, Karen L. Smith, Imran Khan, Stanley Lipkowitz, Patricia S. Steeg, Alexandra S. Zimmer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Purpose: Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer. Patients and Methods: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients' plasma and CSF. Results: Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis.NoDLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8-33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome. Conclusions: Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.

Original languageEnglish
Pages (from-to)1450-1459
Number of pages10
JournalClinical Cancer Research
Volume29
Issue number8
DOIs
StatePublished - 15 Apr 2023
Externally publishedYes

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