Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases

Rachel A. Freedman, Rebecca S. Gelman, Jeffrey S. Wefel, Michelle E. Melisko, Kenneth R. Hess, Roisin M. Connolly, Catherine H. Van Poznak, Polly A. Niravath, Shannon L. Puhalla, Nuhad Ibrahim, Kimberly L. Blackwell, Beverly Moy, Christina Herold, Minetta C Liu, Alarice Lowe, Nathalie Y R Agar, Nicole Ryabin, Sarah Farooq, Elizabeth Lawler, Mothaffar F. RimawiIan E. Krop, Antonio C. Wolff, Eric P. Winer, Nancy U. Lin

Research output: Contribution to journalArticle

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Abstract

Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)- positive breast cancer inthe CNS are limited. Neratinib is anirreversible inhibitor oferbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods: Eligible patients were those with HER2-positive brain metastases (≤1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≤50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression - the threshold for success was five of 40 responders. Results: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≤3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

Original languageEnglish (US)
Pages (from-to)945-952
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number9
DOIs
StatePublished - Mar 20 2016

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Brain Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Research
Brain
Radiotherapy
N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
human ERBB2 protein
Loperamide
Radiosurgery
Central Nervous System Diseases
Neurologic Manifestations
Disease-Free Survival
Diarrhea
Adrenal Cortex Hormones
Quality of Life
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Translational breast cancer research consortium (TBCRC) 022 : A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. / Freedman, Rachel A.; Gelman, Rebecca S.; Wefel, Jeffrey S.; Melisko, Michelle E.; Hess, Kenneth R.; Connolly, Roisin M.; Van Poznak, Catherine H.; Niravath, Polly A.; Puhalla, Shannon L.; Ibrahim, Nuhad; Blackwell, Kimberly L.; Moy, Beverly; Herold, Christina; Liu, Minetta C; Lowe, Alarice; Agar, Nathalie Y R; Ryabin, Nicole; Farooq, Sarah; Lawler, Elizabeth; Rimawi, Mothaffar F.; Krop, Ian E.; Wolff, Antonio C.; Winer, Eric P.; Lin, Nancy U.

In: Journal of Clinical Oncology, Vol. 34, No. 9, 20.03.2016, p. 945-952.

Research output: Contribution to journalArticle

Freedman, RA, Gelman, RS, Wefel, JS, Melisko, ME, Hess, KR, Connolly, RM, Van Poznak, CH, Niravath, PA, Puhalla, SL, Ibrahim, N, Blackwell, KL, Moy, B, Herold, C, Liu, MC, Lowe, A, Agar, NYR, Ryabin, N, Farooq, S, Lawler, E, Rimawi, MF, Krop, IE, Wolff, AC, Winer, EP & Lin, NU 2016, 'Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases', Journal of Clinical Oncology, vol. 34, no. 9, pp. 945-952. https://doi.org/10.1200/JCO.2015.63.0343
Freedman, Rachel A. ; Gelman, Rebecca S. ; Wefel, Jeffrey S. ; Melisko, Michelle E. ; Hess, Kenneth R. ; Connolly, Roisin M. ; Van Poznak, Catherine H. ; Niravath, Polly A. ; Puhalla, Shannon L. ; Ibrahim, Nuhad ; Blackwell, Kimberly L. ; Moy, Beverly ; Herold, Christina ; Liu, Minetta C ; Lowe, Alarice ; Agar, Nathalie Y R ; Ryabin, Nicole ; Farooq, Sarah ; Lawler, Elizabeth ; Rimawi, Mothaffar F. ; Krop, Ian E. ; Wolff, Antonio C. ; Winer, Eric P. ; Lin, Nancy U. / Translational breast cancer research consortium (TBCRC) 022 : A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 9. pp. 945-952.
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title = "Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases",
abstract = "Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)- positive breast cancer inthe CNS are limited. Neratinib is anirreversible inhibitor oferbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods: Eligible patients were those with HER2-positive brain metastases (≤1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≤50{\%} reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression - the threshold for success was five of 40 responders. Results: Forty patients were enrolled between February 2012 and June 2013; 78{\%} of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8{\%}; 95{\%} CI, 2{\%} to 22{\%}). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≤3 event was diarrhea (occurring in 21{\%} of patients taking prespecified loperamide prophylaxis and 28{\%} of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion: Although neratinib had low activity and did not meet our threshold for success, 12.5{\%} of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.",
author = "Freedman, {Rachel A.} and Gelman, {Rebecca S.} and Wefel, {Jeffrey S.} and Melisko, {Michelle E.} and Hess, {Kenneth R.} and Connolly, {Roisin M.} and {Van Poznak}, {Catherine H.} and Niravath, {Polly A.} and Puhalla, {Shannon L.} and Nuhad Ibrahim and Blackwell, {Kimberly L.} and Beverly Moy and Christina Herold and Liu, {Minetta C} and Alarice Lowe and Agar, {Nathalie Y R} and Nicole Ryabin and Sarah Farooq and Elizabeth Lawler and Rimawi, {Mothaffar F.} and Krop, {Ian E.} and Wolff, {Antonio C.} and Winer, {Eric P.} and Lin, {Nancy U.}",
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TY - JOUR

T1 - Translational breast cancer research consortium (TBCRC) 022

T2 - A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases

AU - Freedman, Rachel A.

AU - Gelman, Rebecca S.

AU - Wefel, Jeffrey S.

AU - Melisko, Michelle E.

AU - Hess, Kenneth R.

AU - Connolly, Roisin M.

AU - Van Poznak, Catherine H.

AU - Niravath, Polly A.

AU - Puhalla, Shannon L.

AU - Ibrahim, Nuhad

AU - Blackwell, Kimberly L.

AU - Moy, Beverly

AU - Herold, Christina

AU - Liu, Minetta C

AU - Lowe, Alarice

AU - Agar, Nathalie Y R

AU - Ryabin, Nicole

AU - Farooq, Sarah

AU - Lawler, Elizabeth

AU - Rimawi, Mothaffar F.

AU - Krop, Ian E.

AU - Wolff, Antonio C.

AU - Winer, Eric P.

AU - Lin, Nancy U.

PY - 2016/3/20

Y1 - 2016/3/20

N2 - Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)- positive breast cancer inthe CNS are limited. Neratinib is anirreversible inhibitor oferbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods: Eligible patients were those with HER2-positive brain metastases (≤1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≤50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression - the threshold for success was five of 40 responders. Results: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≤3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

AB - Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)- positive breast cancer inthe CNS are limited. Neratinib is anirreversible inhibitor oferbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods: Eligible patients were those with HER2-positive brain metastases (≤1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≤50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression - the threshold for success was five of 40 responders. Results: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≤3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

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