The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer Journal Article

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Authors: DeMichele, A; Yee, D; Berry, D. A.; Albain, K. S.; Benz, C. C.; Boughey, J.; Buxton, M.; Chia, S. K.; Chien, A. J.; Chui, S. Y.; Clark, A; Edmiston, K.; Elias, A; Forero-Torres, A; Haddad, T. C.; Haley, B.; Haluska, P.; Hylton, N. M.; Isaacs, C; Kaplan, H.; Korde, L. A.; Leyland-Jones, B; Liu, M. C.; Melisko, M.; Minton, S. E.; Moulder, S.; Nanda, R; Olopade, O. I.; Paoloni, M; Park, J. W.; Parker, B. A.; Perlmutter, J; Petricoin, E., 3rd; Rugo, H. S.; Symmans, W. F.; Tripathy, D; van 't Veer, L. J.; Viscusi, R. K.; Wallace, A.; Wolf, D; Yau, C; Esserman, L. J.
Article Title: The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer
Abstract: Purpose: 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. Experimental Design: 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 This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval.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 non-significant 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. Results: 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 hazard ratio in ALTTO. Conclusions: This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.
Journal Title: Clinical cancer research : an official journal of the American Association for Cancer Research
Volume: 21
Issue: 13
ISSN: 1078-0432; 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015
Start Page: 2911
End Page: 2915
Language: ENG
DOI/URL:

clincanres.1760.2014
Notes: LR: 20150226; CI: Copyright (c) 2015; JID: 9502500; aheadofprint