The neoadjuvant model is still the future for drug development in breast cancer

Angela De Michele, Douglas Yee, Donald A. Berry, Kathy S. Albain, Christopher C. Benz, Judy Boughey, Meredith Buxton, Stephen K. Chia, Amy J. Chien, Stephen (Steve) Chui, Amy Clark, Kirsten Edmiston, Anthony D. Elias, Andres Forero-Torres, Tufia C. Haddad, Barbara Haley, Paul Haluska, Nola M. Hylton, Claudine Isaacs, Henry KaplanLarissa Korde, Brian Leyland-Jones, Minetta C. Liu, Michelle Melisko, Susan E. Minton, Stacy L. Moulder, Rita Nanda, Olufunmilayo I. Olopade, Melissa Paoloni, John W. Park, Barbara A. Parker, Jane Perlmutter, Emanuel F. Petricoin, Hope Rugo, Fraser Symmans, Debasish Tripathy, Laura J. Van't Veer, Rebecca K. Viscusi, Anne Wallace, Denise Wolf, Christina Yau, Laura J. Esserman

    Research output: Contribution to journalArticle

    45 Citations (Scopus)

    Abstract

    The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.

    Original languageEnglish (US)
    Pages (from-to)2911-2915
    Number of pages5
    JournalClinical Cancer Research
    Volume21
    Issue number13
    DOIs
    StatePublished - Jul 1 2015

    Fingerprint

    Breast Neoplasms
    Meta-Analysis
    Clinical Trials
    Pharmaceutical Preparations
    Disease-Free Survival
    Drug Approval
    Drug Combinations
    Protein-Tyrosine Kinases
    Survival Rate
    Biomarkers
    Recurrence
    Drug Therapy
    lapatinib
    Therapeutics
    Trastuzumab

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    De Michele, A., Yee, D., Berry, D. A., Albain, K. S., Benz, C. C., Boughey, J., ... Esserman, L. J. (2015). The neoadjuvant model is still the future for drug development in breast cancer. Clinical Cancer Research, 21(13), 2911-2915. https://doi.org/10.1158/1078-0432.CCR-14-1760

    The neoadjuvant model is still the future for drug development in breast cancer. / De Michele, Angela; Yee, Douglas; Berry, Donald A.; Albain, Kathy S.; Benz, Christopher C.; Boughey, Judy; Buxton, Meredith; Chia, Stephen K.; Chien, Amy J.; Chui, Stephen (Steve); Clark, Amy; Edmiston, Kirsten; Elias, Anthony D.; Forero-Torres, Andres; Haddad, Tufia C.; Haley, Barbara; Haluska, Paul; Hylton, Nola M.; Isaacs, Claudine; Kaplan, Henry; Korde, Larissa; Leyland-Jones, Brian; Liu, Minetta C.; Melisko, Michelle; Minton, Susan E.; Moulder, Stacy L.; Nanda, Rita; Olopade, Olufunmilayo I.; Paoloni, Melissa; Park, John W.; Parker, Barbara A.; Perlmutter, Jane; Petricoin, Emanuel F.; Rugo, Hope; Symmans, Fraser; Tripathy, Debasish; Van't Veer, Laura J.; Viscusi, Rebecca K.; Wallace, Anne; Wolf, Denise; Yau, Christina; Esserman, Laura J.

    In: Clinical Cancer Research, Vol. 21, No. 13, 01.07.2015, p. 2911-2915.

    Research output: Contribution to journalArticle

    De Michele, A, Yee, D, Berry, DA, Albain, KS, Benz, CC, Boughey, J, Buxton, M, Chia, SK, Chien, AJ, Chui, SS, Clark, A, Edmiston, K, Elias, AD, Forero-Torres, A, Haddad, TC, Haley, B, Haluska, P, Hylton, NM, Isaacs, C, Kaplan, H, Korde, L, Leyland-Jones, B, Liu, MC, Melisko, M, Minton, SE, Moulder, SL, Nanda, R, Olopade, OI, Paoloni, M, Park, JW, Parker, BA, Perlmutter, J, Petricoin, EF, Rugo, H, Symmans, F, Tripathy, D, Van't Veer, LJ, Viscusi, RK, Wallace, A, Wolf, D, Yau, C & Esserman, LJ 2015, 'The neoadjuvant model is still the future for drug development in breast cancer', Clinical Cancer Research, vol. 21, no. 13, pp. 2911-2915. https://doi.org/10.1158/1078-0432.CCR-14-1760
    De Michele A, Yee D, Berry DA, Albain KS, Benz CC, Boughey J et al. The neoadjuvant model is still the future for drug development in breast cancer. Clinical Cancer Research. 2015 Jul 1;21(13):2911-2915. https://doi.org/10.1158/1078-0432.CCR-14-1760
    De Michele, Angela ; Yee, Douglas ; Berry, Donald A. ; Albain, Kathy S. ; Benz, Christopher C. ; Boughey, Judy ; Buxton, Meredith ; Chia, Stephen K. ; Chien, Amy J. ; Chui, Stephen (Steve) ; Clark, Amy ; Edmiston, Kirsten ; Elias, Anthony D. ; Forero-Torres, Andres ; Haddad, Tufia C. ; Haley, Barbara ; Haluska, Paul ; Hylton, Nola M. ; Isaacs, Claudine ; Kaplan, Henry ; Korde, Larissa ; Leyland-Jones, Brian ; Liu, Minetta C. ; Melisko, Michelle ; Minton, Susan E. ; Moulder, Stacy L. ; Nanda, Rita ; Olopade, Olufunmilayo I. ; Paoloni, Melissa ; Park, John W. ; Parker, Barbara A. ; Perlmutter, Jane ; Petricoin, Emanuel F. ; Rugo, Hope ; Symmans, Fraser ; Tripathy, Debasish ; Van't Veer, Laura J. ; Viscusi, Rebecca K. ; Wallace, Anne ; Wolf, Denise ; Yau, Christina ; Esserman, Laura J. / The neoadjuvant model is still the future for drug development in breast cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 13. pp. 2911-2915.
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    abstract = "The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.",
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