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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3-9
Number of pages7
JournalJournal of Thoracic Oncology
Volume5
Issue number1
DOIs
StatePublished - Jan 2010

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Non-Small Cell Lung Carcinoma
Survival
Disease-Free Survival
Proportional Hazards Models

Keywords

  • Advanced NSCLC
  • Endpoints
  • Failure-free survival
  • Progression-free survival
  • Tumor response

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Endpoints in Phase II trials for advanced non-small cell lung cancer. / Mandrekar, Sumithra J; Qi, Yingwei; Hillman, Shauna L.; Allen Ziegler, Katie L.; Reuter, Nicholas F.; Rowland, Kendrith M.; Kuross, Steven A.; Marks, Randolph Stuart; Schild, Steven E.; Adjei, Alex.

In: Journal of Thoracic Oncology, Vol. 5, No. 1, 01.2010, p. 3-9.

Research output: Contribution to journalArticle

Mandrekar, SJ, Qi, Y, Hillman, SL, Allen Ziegler, KL, Reuter, NF, Rowland, KM, Kuross, SA, Marks, RS, Schild, SE & Adjei, A 2010, 'Endpoints in Phase II trials for advanced non-small cell lung cancer', Journal of Thoracic Oncology, vol. 5, no. 1, pp. 3-9. https://doi.org/10.1097/JTO.0b013e3181c0a313
Mandrekar, Sumithra J ; Qi, Yingwei ; Hillman, Shauna L. ; Allen Ziegler, Katie L. ; Reuter, Nicholas F. ; Rowland, Kendrith M. ; Kuross, Steven A. ; Marks, Randolph Stuart ; Schild, Steven E. ; Adjei, Alex. / Endpoints in Phase II trials for advanced non-small cell lung cancer. In: Journal of Thoracic Oncology. 2010 ; Vol. 5, No. 1. pp. 3-9.
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AU - Qi, Yingwei

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AU - Allen Ziegler, Katie L.

AU - Reuter, Nicholas F.

AU - Rowland, Kendrith M.

AU - Kuross, Steven A.

AU - Marks, Randolph Stuart

AU - Schild, Steven E.

AU - Adjei, Alex

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N2 - 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.

AB - 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.

KW - Advanced NSCLC

KW - Endpoints

KW - Failure-free survival

KW - Progression-free survival

KW - Tumor response

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