Adaptive randomization of neratinib in early breast cancer

John W. Park, Minetta C. Liu, Douglas Yee, Christina Yau, Laura J. Van't Veer, W. Fraser Symmans, Melissa Paoloni, Jane Perlmutter, Nola M. Hylton, Michael Hogarth, Angela DeMichele, Meredith B. Buxton, A. Jo Chien, Anne M. Wallace, Judy C. Boughey, Tufia C. Haddad, Stephen Y. Chui, Kathleen A. Kemmer, Henry G. Kaplan, Claudine Isaacs & 23 others Rita Nanda, Debasish Tripathy, Kathy S. Albain, Kirsten K. Edmiston, Anthony D. Elias, Donald W. Northfelt, Lajos Pusztai, Stacy L. Moulder, Julie E. Lang, Rebecca K. Viscusi, David M. Euhus, Barbara B. Haley, Qamar J. Khan, William C. Wood, Michelle Melisko, Richard Schwab, Teresa Helsten, Julia Lyandres, Sarah E. Davis, Gillian L. Hirst, Ashish Sanil, Laura J. Esserman, Donald A. Berry

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

BACKGROUND The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for highrisk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Original languageEnglish (US)
Pages (from-to)11-22
Number of pages12
JournalNew England Journal of Medicine
Volume375
Issue number1
DOIs
StatePublished - Jul 7 2016

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Random Allocation
Breast Neoplasms
Biomarkers
Hormones
Neoadjuvant Therapy
Drug Therapy
Medical Futility
Residual Neoplasm
Protein-Tyrosine Kinases
Multicenter Studies
N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
Therapeutics
Lymph Nodes
Magnetic Resonance Imaging
Delivery of Health Care
human ERBB2 protein
Genes
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Park, J. W., Liu, M. C., Yee, D., Yau, C., Van't Veer, L. J., Symmans, W. F., ... Berry, D. A. (2016). Adaptive randomization of neratinib in early breast cancer. New England Journal of Medicine, 375(1), 11-22. https://doi.org/10.1056/NEJMoa1513750

Adaptive randomization of neratinib in early breast cancer. / Park, John W.; Liu, Minetta C.; Yee, Douglas; Yau, Christina; Van't Veer, Laura J.; Symmans, W. Fraser; Paoloni, Melissa; Perlmutter, Jane; Hylton, Nola M.; Hogarth, Michael; DeMichele, Angela; Buxton, Meredith B.; Chien, A. Jo; Wallace, Anne M.; Boughey, Judy C.; Haddad, Tufia C.; Chui, Stephen Y.; Kemmer, Kathleen A.; Kaplan, Henry G.; Isaacs, Claudine; Nanda, Rita; Tripathy, Debasish; Albain, Kathy S.; Edmiston, Kirsten K.; Elias, Anthony D.; Northfelt, Donald W.; Pusztai, Lajos; Moulder, Stacy L.; Lang, Julie E.; Viscusi, Rebecca K.; Euhus, David M.; Haley, Barbara B.; Khan, Qamar J.; Wood, William C.; Melisko, Michelle; Schwab, Richard; Helsten, Teresa; Lyandres, Julia; Davis, Sarah E.; Hirst, Gillian L.; Sanil, Ashish; Esserman, Laura J.; Berry, Donald A.

In: New England Journal of Medicine, Vol. 375, No. 1, 07.07.2016, p. 11-22.

Research output: Contribution to journalArticle

Park, JW, Liu, MC, Yee, D, Yau, C, Van't Veer, LJ, Symmans, WF, Paoloni, M, Perlmutter, J, Hylton, NM, Hogarth, M, DeMichele, A, Buxton, MB, Chien, AJ, Wallace, AM, Boughey, JC, Haddad, TC, Chui, SY, Kemmer, KA, Kaplan, HG, Isaacs, C, Nanda, R, Tripathy, D, Albain, KS, Edmiston, KK, Elias, AD, Northfelt, DW, Pusztai, L, Moulder, SL, Lang, JE, Viscusi, RK, Euhus, DM, Haley, BB, Khan, QJ, Wood, WC, Melisko, M, Schwab, R, Helsten, T, Lyandres, J, Davis, SE, Hirst, GL, Sanil, A, Esserman, LJ & Berry, DA 2016, 'Adaptive randomization of neratinib in early breast cancer', New England Journal of Medicine, vol. 375, no. 1, pp. 11-22. https://doi.org/10.1056/NEJMoa1513750
Park JW, Liu MC, Yee D, Yau C, Van't Veer LJ, Symmans WF et al. Adaptive randomization of neratinib in early breast cancer. New England Journal of Medicine. 2016 Jul 7;375(1):11-22. https://doi.org/10.1056/NEJMoa1513750
Park, John W. ; Liu, Minetta C. ; Yee, Douglas ; Yau, Christina ; Van't Veer, Laura J. ; Symmans, W. Fraser ; Paoloni, Melissa ; Perlmutter, Jane ; Hylton, Nola M. ; Hogarth, Michael ; DeMichele, Angela ; Buxton, Meredith B. ; Chien, A. Jo ; Wallace, Anne M. ; Boughey, Judy C. ; Haddad, Tufia C. ; Chui, Stephen Y. ; Kemmer, Kathleen A. ; Kaplan, Henry G. ; Isaacs, Claudine ; Nanda, Rita ; Tripathy, Debasish ; Albain, Kathy S. ; Edmiston, Kirsten K. ; Elias, Anthony D. ; Northfelt, Donald W. ; Pusztai, Lajos ; Moulder, Stacy L. ; Lang, Julie E. ; Viscusi, Rebecca K. ; Euhus, David M. ; Haley, Barbara B. ; Khan, Qamar J. ; Wood, William C. ; Melisko, Michelle ; Schwab, Richard ; Helsten, Teresa ; Lyandres, Julia ; Davis, Sarah E. ; Hirst, Gillian L. ; Sanil, Ashish ; Esserman, Laura J. ; Berry, Donald A. / Adaptive randomization of neratinib in early breast cancer. In: New England Journal of Medicine. 2016 ; Vol. 375, No. 1. pp. 11-22.
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T1 - Adaptive randomization of neratinib in early breast cancer

AU - Park, John W.

AU - Liu, Minetta C.

AU - Yee, Douglas

AU - Yau, Christina

AU - Van't Veer, Laura J.

AU - Symmans, W. Fraser

AU - Paoloni, Melissa

AU - Perlmutter, Jane

AU - Hylton, Nola M.

AU - Hogarth, Michael

AU - DeMichele, Angela

AU - Buxton, Meredith B.

AU - Chien, A. Jo

AU - Wallace, Anne M.

AU - Boughey, Judy C.

AU - Haddad, Tufia C.

AU - Chui, Stephen Y.

AU - Kemmer, Kathleen A.

AU - Kaplan, Henry G.

AU - Isaacs, Claudine

AU - Nanda, Rita

AU - Tripathy, Debasish

AU - Albain, Kathy S.

AU - Edmiston, Kirsten K.

AU - Elias, Anthony D.

AU - Northfelt, Donald W.

AU - Pusztai, Lajos

AU - Moulder, Stacy L.

AU - Lang, Julie E.

AU - Viscusi, Rebecca K.

AU - Euhus, David M.

AU - Haley, Barbara B.

AU - Khan, Qamar J.

AU - Wood, William C.

AU - Melisko, Michelle

AU - Schwab, Richard

AU - Helsten, Teresa

AU - Lyandres, Julia

AU - Davis, Sarah E.

AU - Hirst, Gillian L.

AU - Sanil, Ashish

AU - Esserman, Laura J.

AU - Berry, Donald A.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - BACKGROUND The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for highrisk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

AB - BACKGROUND The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for highrisk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

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