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 M.
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 A.
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.
N1 - Funding Information:
Supported by Puma Biotechnology, the Translational Breast Cancer Research Consortium’s foundation partners (AVON Foundation, the Breast Cancer Research Foundation, Susan G. Komen for the Cure), the American Cancer Society (125912-MRSG-14-240-01-CPPB to R.A.F.), Susan G. Komen for the Cure (CCR14298143 to R.A.F.), the Breast Cancer Research Foundation (N.U.L. and E.P.W.), the Dana-Farber Women’s Cancer Program Executive Council Personalized Medicine
Funding Information:
Kimberly L. Blackwell, Rachel C. Jankowitz, Karen L. Smith, Nuhad Ibrahim, Ciara C. O’Sullivan, Polly Niravath, Nadine Tung, Paula R. Pohlmann, Mothaffar F. Rimawi, Antonio C. Wolff, Nancy U. Lin Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors ACKNOWLEDGMENT We are grateful to all the patients who generously volunteered to participate in this study. We thank the Translational Breast Cancer Research Consortium (TBCRC) investigators, research nurses, and study coordinators for their efforts on behalf of the patients. We are appreciative of the funding support provided by Puma Biotechnology and to the TBCRC by its three foundation partners: the AVON Foundation, the Breast Cancer Research Foundation, and Susan G. Komen for the Cure. We are also appreciative of additional funding support provided by the American Cancer Society and Susan G. Komen, the Breast Cancer Research Foundation, the Dana-Farber Women’s Cancer Program Executive Council, and the Dana-Farber/Harvard Cancer Center. We thank Kaitlyn Bifolck for her assistance with preparation of our submission.
Publisher Copyright:
© 2019 American Society of Clinical Oncology. All rights reserved.
PY - 2019
Y1 - 2019
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
M3 - Article
C2 - 30860945
AN - SCOPUS:85063793782
SN - 0732-183X
VL - 37
SP - 1081
EP - 1089
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 13
ER -