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

• DOI: 10.1158/1078-0432.c.6533213.v2
• Publication Date: 2023-04-14T11:21:46Z
• Authors: 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. Anders; Roisín M. Connolly; Carol Tweed; Karen L. Smith; Imran Khan; Stanley Lipkowitz; Patricia S. Steeg; Alexandra S. Zimmer

<div>AbstractPurpose:<p>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.</p>Patients and Methods:<p>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.</p>Results:<p>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 <i>Pneumocystis jirovecii</i> pneumonia prophylaxis. No DLT 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.</p>Conclusions:<p>Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2⁺ brain metastases.</p></div>