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

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

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)405-414
Number of pages10
JournalBreast Cancer Research and Treatment
Volume142
Issue number2
DOIs
StatePublished - Nov 2013

Fingerprint

Brain Neoplasms
Radiotherapy
Breast Neoplasms
Neoplasm Metastasis
Brain
Maximum Tolerated Dose
Exanthema
human ERBB2 protein
lapatinib
Mucositis
Embolism
Diarrhea
Confidence Intervals
Safety
Lung

Keywords

  • Brain metastases
  • Breast cancer
  • Lapatinib
  • Whole brain radiotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Lin, Nancy U.; Freedman, Rachel A.; Ramakrishna, Naren; Younger, Jerry; Storniolo, Anna Maria; Bellon, Jennifer R.; Come, Steven E.; Gelman, Rebecca S.; Harris, Gordon J.; Henderson, Mark A.; MacDonald, Shannon M.; Mahadevan, Anand; Eisenberg, Emily; Ligibel, Jennifer A.; Mayer, Erica L.; Moy, Beverly; Eichler, April F.; Winer, Eric P.

In: Breast Cancer Research and Treatment, Vol. 142, No. 2, 11.2013, p. 405-414.

Research output: Contribution to journalArticle

Lin, NU, Freedman, RA, Ramakrishna, N, Younger, J, Storniolo, AM, Bellon, JR, Come, SE, Gelman, RS, Harris, GJ, Henderson, MA, MacDonald, SM, Mahadevan, A, Eisenberg, E, Ligibel, JA, Mayer, EL, Moy, B, Eichler, AF & Winer, EP 2013, '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', Breast Cancer Research and Treatment, vol. 142, no. 2, pp. 405-414. https://doi.org/10.1007/s10549-013-2754-0
Lin, Nancy U. ; Freedman, Rachel A. ; Ramakrishna, Naren ; Younger, Jerry ; Storniolo, Anna Maria ; Bellon, Jennifer R. ; Come, Steven E. ; Gelman, Rebecca S. ; Harris, Gordon J. ; Henderson, Mark A. ; MacDonald, Shannon M. ; Mahadevan, Anand ; Eisenberg, Emily ; Ligibel, Jennifer A. ; Mayer, Erica L. ; Moy, Beverly ; Eichler, April F. ; Winer, Eric P. / 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. In: Breast Cancer Research and Treatment. 2013 ; Vol. 142, No. 2. pp. 405-414.
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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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