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

S. Michiels, L. Pugliano, S. Marguet, D. Grun, J. Barinoff, D. Cameron, M. Cobleigh, A. Di Leo, S. Johnston, G. Gasparini, B. Kaufman, M. Marty, V. Nekljudova, S. Paluch-Shimon, F. Penault-Llorca, D. Slamon, C. Vogel, G. von Minckwitz, M. Buyse, M. Piccart

Research output: Contribution to journalArticle

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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. 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 R2 = 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.

Original languageEnglish
Article numbermdw132
Pages (from-to)1029-1034
Number of pages6
JournalAnnals of Oncology
Volume27
Issue number6
DOIs
Publication statusPublished - Jun 18 2016

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Disease-Free Survival
Biomarkers
Clinical Trials
Breast Neoplasms
Survival
Confidence Intervals
Therapeutics
Randomized Controlled Trials
Research Personnel
Mortality

Keywords

  • HER2
  • Lapatinib
  • Metastatic breast cancer
  • Progression-free survival
  • Surrogate
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

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

In: Annals of Oncology, Vol. 27, No. 6, mdw132, 18.06.2016, p. 1029-1034.

Research output: Contribution to journalArticle

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, vol. 27, no. 6, mdw132, pp. 1029-1034. https://doi.org/10.1093/annonc/mdw132
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. / Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer. In: Annals of Oncology. 2016 ; Vol. 27, No. 6. pp. 1029-1034.
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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. 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 R2 = 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.",
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AU - Michiels, S.

AU - Pugliano, L.

AU - Marguet, S.

AU - Grun, D.

AU - Barinoff, J.

AU - Cameron, D.

AU - Cobleigh, M.

AU - Di Leo, A.

AU - Johnston, S.

AU - Gasparini, G.

AU - Kaufman, B.

AU - Marty, M.

AU - Nekljudova, V.

AU - Paluch-Shimon, S.

AU - Penault-Llorca, F.

AU - Slamon, D.

AU - Vogel, C.

AU - von Minckwitz, G.

AU - Buyse, M.

AU - Piccart, M.

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N2 - 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 R2 = 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.

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