Endpoints in Phase II Trials for Advanced Non-small Cell Lung Cancer

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 (P2) trials for advanced NSCLC. Methods Individual data of 284 patients from 4 P2 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 (PH) model for OS, stratified by trial. Subsequently, Cox PH 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 (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 (HR) combination in landmark analyses (HR, 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 Failure-free survival or progression-free survival at 12 weeks is a stronger predictor of subsequent patient survival compared to tumor response, and should be routinely used as endpoints in phase II trials for advanced NSCLC.

The Clinical Viewpoint: Definitions, Limitations of RECIST, Practical Considerations of Measurement

“…16). This is particularly important in the relapsed and refractory setting, where therapies are often associated with a minimal to nil response but may still confer a survival advantage, as is illustrated in the relapsed metastatic NSCLC setting.…”

“…Finally and perhaps the most important point, PFS, in contrast with OS, has the advantage of not being affected by crossover or subsequent therapies (16, 18–20). It is critical to note that OS has the potential to be attenuated by any second-line therapy, but the degree to which it is attenuated is directly related to the population under study and the effectiveness of subsequent lines of therapy in modulating survival postprogression (SPP).…”

Targeted Therapy for Non–Small Cell Lung Cancer

“…Progression-free survival is the primary endpoint of most randomized phase II or III trials. Response rates and survival are usually secondary endpoints (48).…”

Circulating tumour cells: their utility in cancer management and predicting outcomes

“…with novel targeted therapies which are often cytostatic in their effect. There is also a body of evidence to support response by standard CT imaging as an unreliable surrogate for survival [Mandrekar et al 2010;Desar et al 2009]. On the basis of data reported so far, a particularly pertinent clinical setting to which CTCs could be applied is that of phase 1 trials.…”