TY - JOUR
T1 - Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer
AU - Foster, Nathan R.
AU - Qi, Yingwei
AU - Shi, Qian
AU - Krook, James E.
AU - Kugler, John W.
AU - Jett, James R.
AU - Molina, Julian R.
AU - Schild, Steven E.
AU - Adjei, Alex A.
AU - Mandrekar, Sumithra J.
PY - 2011/3/15
Y1 - 2011/3/15
N2 - 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.
AB - 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.
KW - extensive stage small-cell lung cancer
KW - pooled analysis
KW - progression-free survival
KW - surrogate endpoints
KW - tumor response
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U2 - 10.1002/cncr.25526
DO - 10.1002/cncr.25526
M3 - Article
C2 - 20960500
AN - SCOPUS:79952408951
SN - 0008-543X
VL - 117
SP - 1262
EP - 1271
JO - Cancer
JF - Cancer
IS - 6
ER -