TBCRC 022

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

Rachel A. Freedman, Rebecca S. Gelman, Carey K. Anders, Michelle E. Melisko, Heather A. Parsons, Anne M. Cropp, Kelly Silvestri, Christine M. Cotter, Kathryn P. Componeschi, Juan M. Marte, Roisin Connolly, Beverly Moy, Catherine H. Van Poznak, Kimberly L. Blackwell, Shannon L. Puhalla, Rachel C. Jankowitz, Karen L. Smith, Nuhad Ibrahim, Timothy J. Moynihan, Ciara C. O'Sullivan & 10 others Julie Nangia, Polly Niravath, Nadine Tung, Paula R. Pohlmann, Robyn Burns, Mothaffar F. Rimawi, Ian E. Krop, Antonio C Wolff, Eric P. Winer, Nancy U. Lin

Research output: Contribution to journalArticle

Abstract

PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2- positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-näýve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

Original languageEnglish (US)
Pages (from-to)1081-1089
Number of pages9
JournalJournal of Clinical Oncology
Volume37
Issue number13
DOIs
StatePublished - Jan 1 2019

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Brain Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Diarrhea
Brain
Drug Combinations
Neurologic Manifestations
Disease-Free Survival
Cohort Studies
Radiotherapy
Steroids
N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
Capecitabine
human ERBB2 protein
Drug Therapy
Survival
lapatinib
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

TBCRC 022 : A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. / Freedman, Rachel A.; Gelman, Rebecca S.; Anders, Carey K.; Melisko, Michelle E.; Parsons, Heather A.; Cropp, Anne M.; Silvestri, Kelly; Cotter, Christine M.; Componeschi, Kathryn P.; Marte, Juan M.; Connolly, Roisin; Moy, Beverly; Van Poznak, Catherine H.; Blackwell, Kimberly L.; Puhalla, Shannon L.; Jankowitz, Rachel C.; Smith, Karen L.; Ibrahim, Nuhad; Moynihan, Timothy J.; O'Sullivan, Ciara C.; Nangia, Julie; Niravath, Polly; Tung, Nadine; Pohlmann, Paula R.; Burns, Robyn; Rimawi, Mothaffar F.; Krop, Ian E.; Wolff, Antonio C; Winer, Eric P.; Lin, Nancy U.

In: Journal of Clinical Oncology, Vol. 37, No. 13, 01.01.2019, p. 1081-1089.

Research output: Contribution to journalArticle

Freedman, RA, Gelman, RS, Anders, CK, Melisko, ME, Parsons, HA, Cropp, AM, Silvestri, K, Cotter, CM, Componeschi, KP, Marte, JM, Connolly, R, Moy, B, Van Poznak, CH, Blackwell, KL, Puhalla, SL, Jankowitz, RC, Smith, KL, Ibrahim, N, Moynihan, TJ, O'Sullivan, CC, Nangia, J, Niravath, P, Tung, N, Pohlmann, PR, Burns, R, Rimawi, MF, Krop, IE, Wolff, AC, Winer, EP & Lin, NU 2019, 'TBCRC 022: A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases', Journal of Clinical Oncology, vol. 37, no. 13, pp. 1081-1089. https://doi.org/10.1200/JCO.18.01511
Freedman, Rachel A. ; Gelman, Rebecca S. ; Anders, Carey K. ; Melisko, Michelle E. ; Parsons, Heather A. ; Cropp, Anne M. ; Silvestri, Kelly ; Cotter, Christine M. ; Componeschi, Kathryn P. ; Marte, Juan M. ; Connolly, Roisin ; Moy, Beverly ; Van Poznak, Catherine H. ; Blackwell, Kimberly L. ; Puhalla, Shannon L. ; Jankowitz, Rachel C. ; Smith, Karen L. ; Ibrahim, Nuhad ; Moynihan, Timothy J. ; O'Sullivan, Ciara C. ; Nangia, Julie ; Niravath, Polly ; Tung, Nadine ; Pohlmann, Paula R. ; Burns, Robyn ; Rimawi, Mothaffar F. ; Krop, Ian E. ; Wolff, Antonio C ; Winer, Eric P. ; Lin, Nancy U. / TBCRC 022 : A phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 13. pp. 1081-1089.
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title = "TBCRC 022: A phase II trial of neratinib and capecitabine 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 to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2- positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92{\%} after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-n{\"a}{\'y}ve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50{\%} or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49{\%} (95{\%} CI, 32{\%} to 66{\%}), and the CNS ORR in cohort 3B = 33{\%} (95{\%} CI, 10{\%} to 65{\%}). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29{\%} in cohorts 3A and 3B). CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.",
author = "Freedman, {Rachel A.} and Gelman, {Rebecca S.} and Anders, {Carey K.} and Melisko, {Michelle E.} and Parsons, {Heather A.} and Cropp, {Anne M.} and Kelly Silvestri and Cotter, {Christine M.} and Componeschi, {Kathryn P.} and Marte, {Juan M.} and Roisin Connolly and Beverly Moy and {Van Poznak}, {Catherine H.} and Blackwell, {Kimberly L.} and Puhalla, {Shannon L.} and Jankowitz, {Rachel C.} and Smith, {Karen L.} and Nuhad Ibrahim and Moynihan, {Timothy J.} and O'Sullivan, {Ciara C.} and Julie Nangia and Polly Niravath and Nadine Tung and Pohlmann, {Paula R.} and Robyn Burns 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 - TBCRC 022

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

AU - Freedman, Rachel A.

AU - Gelman, Rebecca S.

AU - Anders, Carey K.

AU - Melisko, Michelle E.

AU - Parsons, Heather A.

AU - Cropp, Anne M.

AU - Silvestri, Kelly

AU - Cotter, Christine M.

AU - Componeschi, Kathryn P.

AU - Marte, Juan M.

AU - Connolly, Roisin

AU - Moy, Beverly

AU - Van Poznak, Catherine H.

AU - Blackwell, Kimberly L.

AU - Puhalla, Shannon L.

AU - Jankowitz, Rachel C.

AU - Smith, Karen L.

AU - Ibrahim, Nuhad

AU - Moynihan, Timothy J.

AU - O'Sullivan, Ciara C.

AU - Nangia, Julie

AU - Niravath, Polly

AU - Tung, Nadine

AU - Pohlmann, Paula R.

AU - Burns, Robyn

AU - Rimawi, Mothaffar F.

AU - Krop, Ian E.

AU - Wolff, Antonio C

AU - Winer, Eric P.

AU - Lin, Nancy U.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2- positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-näýve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

AB - PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2- positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-näýve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

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U2 - 10.1200/JCO.18.01511

DO - 10.1200/JCO.18.01511

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SP - 1081

EP - 1089

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 13

ER -