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Ann Oncol. 2016 Jun;27(6):1029-34. doi: 10.1093/annonc/mdw132. Epub 2016 Mar 8.

Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer.

Author information

1
Unit of Biostatistics and Epidemiology, Gustave Roussy, Villejuif University Paris-Sud, University Paris-Saclay, UVSQ, CESP, INSERM, Villejuif Plateform Ligue nationale contre le cancer for meta-analyses in oncology, Gustave Roussy, Villejuif, France Institut Jules Bordet, Université Libre de Bruxelles, Brussels stefan.michiels@gustaveroussy.fr.
2
Institut Jules Bordet, Université Libre de Bruxelles, Brussels Breast International Group (BIG), Brussels, Belgium.
3
Unit of Biostatistics and Epidemiology, Gustave Roussy, Villejuif.
4
Institut Jules Bordet, Université Libre de Bruxelles, Brussels.
5
Agaplesion Markus Krankenhaus, Frankfurt am Main, Germany.
6
Department of Oncology, University of Edinburgh, Edinburgh, UK.
7
Rush University Medical Center, Chicago, USA.
8
Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
9
Breast Unit, Royal Marsden Hospital, London, UK.
10
Scientific Direction, IRCCS National Cancer Research Centre "Giovanni Paolo II," Bari, Italy.
11
The Institute of Breast Oncology, Sheba Medical Center, Tel Hashomer, Israel.
12
Breast Cancer Diseases Unit and Department of Medical Oncology, Saint Louis Hospital, APHP, Paris, France.
13
German Breast Group, GBG ForschungsGmbH, Neu-Isenburg, Germany.
14
Department of Pathology, Centre Jean Perrin, EA 4233, University of Auvergne, Clermont-Ferrand, France.
15
Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles.
16
University of Miami School of Medicine, Comprehensive Cancer Research Group Inc, Columbia Cancer Research Network of Florida, Miami, USA.
17
IDDI, Louvain-la-Neuve, Hasselt University, Hasselt, Belgium.

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.

METHODS:

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.

RESULTS:

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 ρ = 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).

CONCLUSIONS:

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.

KEYWORDS:

HER2; lapatinib; metastatic breast cancer; progression-free survival; surrogate; trastuzumab

PMID:
26961151
DOI:
10.1093/annonc/mdw132
[Indexed for MEDLINE]

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