Michiels, S., Pugliano, L., Marguet, S., Grun, D., Barinoff, J., Cameron, D., Cobleigh, M., Di Leo, A., Johnston, S., Gasparini, G., Kaufman, B., Marty, M., Nekljudova, V., Paluch-Shimon, S., Penault-Llorca, F., Slamon, D., Vogel, C., von Minckwitz, G., Buyse, M., Piccart, M. (2016) Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer. ANNALS OF ONCOLOGY, 27 (6). pp. 1029-1034. ISSN 0923-7534

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Abstract

Background: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC. Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy. We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to rho = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R-2 = 0.51 (95% CI 0.22-0.81). In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting.

Item Type:	Article
Authors (ICR Faculty only):	johnston, stephen
All Authors:	Michiels, S., Pugliano, L., Marguet, S., Grun, D., Barinoff, J., Cameron, D., Cobleigh, M., Di Leo, A., Johnston, S., Gasparini, G., Kaufman, B., Marty, M., Nekljudova, V., Paluch-Shimon, S., Penault-Llorca, F., Slamon, D., Vogel, C., von Minckwitz, G., Buyse, M., Piccart, M.
Additional Information:	ISI Document Delivery No.: DN9VD Times Cited: 0 Cited Reference Count: 42 Michiels, S. Pugliano, L. Marguet, S. Grun, D. Barinoff, J. Cameron, D. Cobleigh, M. Di Leo, A. Johnston, S. Gasparini, G. Kaufman, B. Marty, M. Nekljudova, V. Paluch-Shimon, S. Penault-Llorca, F. Slamon, D. Vogel, C. von Minckwitz, G. Buyse, M. Piccart, M. Ligue Nationale Contre le Cancer Ligue Nationale Contre le Cancer (no grant numbers apply). 0 OXFORD UNIV PRESS OXFORD ANN ONCOL
Uncontrolled Keywords:	surrogate progression-free survival HER2 metastatic breast cancer trastuzumab lapatinib RANDOMIZED CONTROLLED-TRIALS ADVANCED COLORECTAL-CANCER DISEASE-FREE SURVIVAL PHASE-II TRIAL 1ST-LINE TREATMENT TRASTUZUMAB EMTANSINE ADJUVANT CHEMOTHERAPY GASTRIC-CANCER DOUBLE-BLIND METAANALYSIS
Research teams:	Clinical Units > Breast Unit
Depositing User:	Barry Jenkins
Date Deposited:	05 Jul 2016 12:33
Last Modified:	07 Jul 2016 09:40
URI:	http://publications.icr.ac.uk/id/eprint/15165

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