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. 2010 Jan;5(1):3-9.
doi: 10.1097/JTO.0b013e3181c0a313.

Endpoints in phase II trials for advanced non-small cell lung cancer

Sumithra J Mandrekar  1 , Yingwei Qi, Shauna L Hillman, Katie L Allen Ziegler, Nicholas F Reuter, Kendrith M Rowland Jr, Steven A Kuross, Randolph S Marks, Steven E Schild, Alex A Adjei
Affiliations

Endpoints in phase II trials for advanced non-small cell lung cancer

Sumithra J Mandrekar et al. J Thorac Oncol. 2010 Jan.

Abstract

Introduction: 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.

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Figures

Figure 1
Figure 1
Kaplan-Meier curves for overall survival (a), progression-free survival (b), and failure-free survival (c)
Figure 2
Figure 2
Kaplan-Meier curves for overall survival in the landmark analysis subset a) PFS status at 12 weeks, and b) FFS status at 12 weeks.
See this image and copyright information in PMC

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