Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer

Nathan R. Foster, Yingwei Qi, Qian D Shi, James E. Krook, John W. Kugler, James R. Jett, Julian R Molina, Steven E. Schild, Alex Adjei, Sumithra J Mandrekar

Research output: Contribution to journalArticle

65 Scopus citations


BACKGROUND: The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS. METHODS: Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R2 from weighted least squares regression model, Spearman correlation coefficient, and R2 from bivariate survival model (Copula R2). RESULTS: Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P <.01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P <.01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R2 = 0.79; Copula R2 = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R2≤0.48). CONCLUSIONS: PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials.

Original languageEnglish (US)
Pages (from-to)1262-1271
Number of pages10
Issue number6
StatePublished - Mar 15 2011



  • extensive stage small-cell lung cancer
  • pooled analysis
  • progression-free survival
  • surrogate endpoints
  • tumor response

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this