Endpoints in phase II trials for advanced non-small cell lung cancer.
BACKGROUND
We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer.


METHODS
Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index).


RESULTS
The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59-0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes.


CONCLUSIONS
FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.
Mandrekar
Sumithra J
SJ
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA. mandrekar.sumithra@mayo.edu
Qi
Yingwei
Y
Hillman
Shauna L
SL
Allen Ziegler
Katie L
KL
Reuter
Nicholas F
NF
Rowland
Kendrith M
KM
Kuross
Steven A
SA
Marks
Randolph S
RS
Schild
Steven E
SE
Adjei
Alex A
AA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000628:therapy*; D017322:Clinical Trials, Phase II as Topic; D003131:Combined Modality Therapy; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome