Time since start of first-line therapy as a predictive clinical marker for nintedanib in patients with previously treated non-small cell lung cancer

Birgit Gaschler-Markefski, Patricia Sikken, John V. Heymach, Maya Gottfried, Anders Mellemgaard, Silvia Novello, Claudia Nanette Gann, José Barrueco, Martin Reck, Nasser Hanna, Rolf Kaiser

Research output: Contribution to journalArticle

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Abstract

Introduction No predictive clinical or genetic markers have been identified or validated for antiangiogenic agents in lung cancer. We aimed to identify a predictive clinical marker of benefit for nintedanib, an angiokinase inhibitor, using data from two large second-line non-small cell lung cancer Phase III trials (LUME-Lung 1 ([LL1] and LUME-Lung 2). Methods Predictive marker identification was conducted in a multi-step process using data from both trials; a hypothesis was generated, confirmed and validated. Statistical analyses included a stepwise selection approach, a recursive partitioning method and the evaluation of HRs, including treatment-by-covariate interactions. The marker was finally validated using a prospectively defined hierarchical testing procedure and treatment-by-covariate interaction for overall survival (OS) based on LL1. Results Time since start of first-line therapy (TSFLT) was identified as the only predictive clinical marker. A cut-off of 9 months was chosen for further analysis, based on HRs and recursive partitioning. The prospectively defined final validation using OS data from LL1 established the strong relationship between TSFLT and treatment with nintedanib. Patients with adenocarcinoma with TSFLT <9 months showed a greater survival benefit (median OS 10.9 vs 7.9 months, HR 0.75 [95% CI 0.60-0.92]; p=0.0073) compared with patients in the TSFLT >9 months group (median OS 17.0 vs 15.1 months, HR 0.89 [95% CI 0.66-1.19]). Conclusions Patients with shorter TSFLT derive a greater progression-free survival and OS benefit from nintedanib. This clinical marker could be used for patient selection and further investigation is warranted regarding pathways promoting aggressive tumour growth and antiangiogenic tyrosine kinase inhibitor benefit.

Original languageEnglish (US)
Article numbere000102
JournalESMO Open
Volume2
Issue number1
DOIs
StatePublished - Apr 1 2017

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Non-Small Cell Lung Carcinoma
Biomarkers
Lung
Survival
Therapeutics
Angiogenesis Inhibitors
nintedanib
Genetic Markers
Protein-Tyrosine Kinases
Patient Selection
Disease-Free Survival
Lung Neoplasms
Adenocarcinoma
Growth
Neoplasms

Keywords

  • Adenocarcinoma
  • Clinical marker
  • Nintedanib
  • Non-small cell lung cancer
  • Time since first-line treatment

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gaschler-Markefski, B., Sikken, P., Heymach, J. V., Gottfried, M., Mellemgaard, A., Novello, S., ... Kaiser, R. (2017). Time since start of first-line therapy as a predictive clinical marker for nintedanib in patients with previously treated non-small cell lung cancer. ESMO Open, 2(1), [e000102]. https://doi.org/10.1136/esmoopen-2016-000102

Time since start of first-line therapy as a predictive clinical marker for nintedanib in patients with previously treated non-small cell lung cancer. / Gaschler-Markefski, Birgit; Sikken, Patricia; Heymach, John V.; Gottfried, Maya; Mellemgaard, Anders; Novello, Silvia; Gann, Claudia Nanette; Barrueco, José; Reck, Martin; Hanna, Nasser; Kaiser, Rolf.

In: ESMO Open, Vol. 2, No. 1, e000102, 01.04.2017.

Research output: Contribution to journalArticle

Gaschler-Markefski, B, Sikken, P, Heymach, JV, Gottfried, M, Mellemgaard, A, Novello, S, Gann, CN, Barrueco, J, Reck, M, Hanna, N & Kaiser, R 2017, 'Time since start of first-line therapy as a predictive clinical marker for nintedanib in patients with previously treated non-small cell lung cancer', ESMO Open, vol. 2, no. 1, e000102. https://doi.org/10.1136/esmoopen-2016-000102
Gaschler-Markefski, Birgit ; Sikken, Patricia ; Heymach, John V. ; Gottfried, Maya ; Mellemgaard, Anders ; Novello, Silvia ; Gann, Claudia Nanette ; Barrueco, José ; Reck, Martin ; Hanna, Nasser ; Kaiser, Rolf. / Time since start of first-line therapy as a predictive clinical marker for nintedanib in patients with previously treated non-small cell lung cancer. In: ESMO Open. 2017 ; Vol. 2, No. 1.
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abstract = "Introduction No predictive clinical or genetic markers have been identified or validated for antiangiogenic agents in lung cancer. We aimed to identify a predictive clinical marker of benefit for nintedanib, an angiokinase inhibitor, using data from two large second-line non-small cell lung cancer Phase III trials (LUME-Lung 1 ([LL1] and LUME-Lung 2). Methods Predictive marker identification was conducted in a multi-step process using data from both trials; a hypothesis was generated, confirmed and validated. Statistical analyses included a stepwise selection approach, a recursive partitioning method and the evaluation of HRs, including treatment-by-covariate interactions. The marker was finally validated using a prospectively defined hierarchical testing procedure and treatment-by-covariate interaction for overall survival (OS) based on LL1. Results Time since start of first-line therapy (TSFLT) was identified as the only predictive clinical marker. A cut-off of 9 months was chosen for further analysis, based on HRs and recursive partitioning. The prospectively defined final validation using OS data from LL1 established the strong relationship between TSFLT and treatment with nintedanib. Patients with adenocarcinoma with TSFLT <9 months showed a greater survival benefit (median OS 10.9 vs 7.9 months, HR 0.75 [95{\%} CI 0.60-0.92]; p=0.0073) compared with patients in the TSFLT >9 months group (median OS 17.0 vs 15.1 months, HR 0.89 [95{\%} CI 0.66-1.19]). Conclusions Patients with shorter TSFLT derive a greater progression-free survival and OS benefit from nintedanib. This clinical marker could be used for patient selection and further investigation is warranted regarding pathways promoting aggressive tumour growth and antiangiogenic tyrosine kinase inhibitor benefit.",
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AU - Gaschler-Markefski, Birgit

AU - Sikken, Patricia

AU - Heymach, John V.

AU - Gottfried, Maya

AU - Mellemgaard, Anders

AU - Novello, Silvia

AU - Gann, Claudia Nanette

AU - Barrueco, José

AU - Reck, Martin

AU - Hanna, Nasser

AU - Kaiser, Rolf

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N2 - Introduction No predictive clinical or genetic markers have been identified or validated for antiangiogenic agents in lung cancer. We aimed to identify a predictive clinical marker of benefit for nintedanib, an angiokinase inhibitor, using data from two large second-line non-small cell lung cancer Phase III trials (LUME-Lung 1 ([LL1] and LUME-Lung 2). Methods Predictive marker identification was conducted in a multi-step process using data from both trials; a hypothesis was generated, confirmed and validated. Statistical analyses included a stepwise selection approach, a recursive partitioning method and the evaluation of HRs, including treatment-by-covariate interactions. The marker was finally validated using a prospectively defined hierarchical testing procedure and treatment-by-covariate interaction for overall survival (OS) based on LL1. Results Time since start of first-line therapy (TSFLT) was identified as the only predictive clinical marker. A cut-off of 9 months was chosen for further analysis, based on HRs and recursive partitioning. The prospectively defined final validation using OS data from LL1 established the strong relationship between TSFLT and treatment with nintedanib. Patients with adenocarcinoma with TSFLT <9 months showed a greater survival benefit (median OS 10.9 vs 7.9 months, HR 0.75 [95% CI 0.60-0.92]; p=0.0073) compared with patients in the TSFLT >9 months group (median OS 17.0 vs 15.1 months, HR 0.89 [95% CI 0.66-1.19]). Conclusions Patients with shorter TSFLT derive a greater progression-free survival and OS benefit from nintedanib. This clinical marker could be used for patient selection and further investigation is warranted regarding pathways promoting aggressive tumour growth and antiangiogenic tyrosine kinase inhibitor benefit.

AB - Introduction No predictive clinical or genetic markers have been identified or validated for antiangiogenic agents in lung cancer. We aimed to identify a predictive clinical marker of benefit for nintedanib, an angiokinase inhibitor, using data from two large second-line non-small cell lung cancer Phase III trials (LUME-Lung 1 ([LL1] and LUME-Lung 2). Methods Predictive marker identification was conducted in a multi-step process using data from both trials; a hypothesis was generated, confirmed and validated. Statistical analyses included a stepwise selection approach, a recursive partitioning method and the evaluation of HRs, including treatment-by-covariate interactions. The marker was finally validated using a prospectively defined hierarchical testing procedure and treatment-by-covariate interaction for overall survival (OS) based on LL1. Results Time since start of first-line therapy (TSFLT) was identified as the only predictive clinical marker. A cut-off of 9 months was chosen for further analysis, based on HRs and recursive partitioning. The prospectively defined final validation using OS data from LL1 established the strong relationship between TSFLT and treatment with nintedanib. Patients with adenocarcinoma with TSFLT <9 months showed a greater survival benefit (median OS 10.9 vs 7.9 months, HR 0.75 [95% CI 0.60-0.92]; p=0.0073) compared with patients in the TSFLT >9 months group (median OS 17.0 vs 15.1 months, HR 0.89 [95% CI 0.66-1.19]). Conclusions Patients with shorter TSFLT derive a greater progression-free survival and OS benefit from nintedanib. This clinical marker could be used for patient selection and further investigation is warranted regarding pathways promoting aggressive tumour growth and antiangiogenic tyrosine kinase inhibitor benefit.

KW - Adenocarcinoma

KW - Clinical marker

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KW - Time since first-line treatment

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