Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials

Dario Pasalic, Gwendolyn J. McGinnis, C. David Fuller, Aaron J. Grossberg, Vivek Verma, Walker Mainwaring, Austin B. Miller, Timothy A. Lin, Amit Jethanandani, Andres F. Espinoza, Markus Diefenhardt, Prajnan Das, Vivek Subbiah, Ishwaria M. Subbiah, Reshma Jagsi, Adam S. Garden, Emmanouil Fokas, Claus Rödel, Charles R. Thomas, Bruce D. MinskyEthan B. Ludmir

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS. Methods: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes. Results: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045). Conclusions: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval.

Original languageEnglish (US)
Pages (from-to)176-185
Number of pages10
JournalEuropean Journal of Cancer
Volume136
DOIs
StatePublished - Sep 2020

Keywords

  • Accelerated approval
  • Clinical efficacy
  • Clinically meaningful end-point
  • Correlate
  • Indirect measure
  • Metastatic cancer
  • Metastatic disease
  • Randomised clinical trials
  • Replacement end-point
  • Surrogate end-point

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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