A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases |
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Authors: | Nancy U. Lin Rachel A. Freedman Naren Ramakrishna Jerry Younger Anna Maria Storniolo Jennifer R. Bellon Steven E. Come Rebecca S. Gelman Gordon J. Harris Mark A. Henderson Shannon M. MacDonald Anand Mahadevan Emily Eisenberg Jennifer A. Ligibel Erica L. Mayer Beverly Moy April F. Eichler Eric P. Winer |
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Affiliation: | 1. Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA 2. M.D. Anderson Cancer Center Orlando, Orlando, FL, USA 3. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA 4. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA 5. Dana-Farber Cancer Institute and Brigham and Women’s Hospital, 450 Brookline Avenue, Boston, MA, 02215, USA 6. Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02115, USA 7. Massachusetts General Hospital, 25 New Chardon St, Suite 400C, Boston, MA, 02114, USA 8. Massachusetts General Hospital Cancer Center, Yawkey 112, 55 Fruit Street, Boston, MA, 02114, USA 9. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Finard Basement, Boston, MA, 02215, USA
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Abstract: | Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1–8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59–92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring. |
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