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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/21705

Title: Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer
Authors: Michiels, Stefan
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, Marc
Piccart, M.
Issue Date: 2016
Citation: ANNALS OF ONCOLOGY, 27 (6), p. 1029-1034
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.
Notes: [Michiels, S.; Marguet, S.] Inst Gustave Roussy, Unit Biostat & Epidemiol, Rue Camille Desmoulins, F-94805 Villejuif, France. [Michiels, S.] Univ Paris 11, Univ Paris Saclay, UVSQ, CESP,INSERM, Villejuif, France. [Michiels, S.] Inst Gustave Roussy, Plateform Ligue Natl Canc Metaanal Oncol, Rue Camille Desmoulins, F-94805 Villejuif, France. [Michiels, S.; Pugliano, L.; Grun, D.; Piccart, M.] Univ Libre Bruxelles, Inst Jules Bordet, Brussels, Belgium. [Pugliano, L.; Piccart, M.] Breast Int Grp, Brussels, Belgium. [Barinoff, J.] Agaplesion Markus Krankenhaus, Frankfurt, Germany. [Cameron, D.] Univ Edinburgh, Dept Oncol, Edinburgh, Midlothian, Scotland. [Cobleigh, M.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Di Leo, A.] Hosp Prato, Med Oncol Unit, Ist Toscano Tumori, Prato, Italy. [Johnston, S.] Royal Marsden Hosp, Breast Unit, London SW3 6JJ, England. [Gasparini, G.] IRCCS Natl Canc Res Ctr Giovanni Paolo II, Sci Direct, Bari, Italy. [Kaufman, B.; Paluch-Shimon, S.] Chaim Sheba Med Ctr, Inst Breast Oncol, IL-52621 Tel Hashomer, Israel. [Marty, M.] St Louis Hosp, AP HP, Breast Canc Dis Unit, Paris, France. [Marty, M.] St Louis Hosp, AP HP, Dept Med Oncol, Paris, France. [Nekljudova, V.; von Minckwitz, G.] GBG Forsch GmbH, German Breast Grp, Neu Isenburg, Germany. [Penault-Llorca, F.] Univ Auvergne, EA 4233, Ctr Jean Perrin, Dept Pathol, Clermont Ferrand, France. [Slamon, D.] Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Vogel, C.] Univ Miami, Sch Med, Columbia Canc Res Network Florida, Comprehens Canc Res Grp Inc, Miami, FL USA. [Buyse, M.] Hasselt Univ, IDDI, Louvain La Neuve, Hasselt, Belgium.
URI: http://hdl.handle.net/1942/21705
DOI: 10.1093/annonc/mdw132
ISI #: 000377427900010
ISSN: 0923-7534
Category: A1
Type: Journal Contribution
Validation: ecoom, 2017
Appears in Collections: Research publications

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