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

https://doi.org/10.1136/esmoopen-2016-000102Get rights and content
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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.

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

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Contributors: BG-M, PS, MG, AM, SN, JB, C-NG, MR, NHH and RK contributed to the conception and design of the analysis. MG, AM, SN, MR and NHH were involved in the provision of patients in the trials on which this analysis was based. BG-M, PS, MG, AM, SN, JB, C-NG, MR, NHH, RK and JVH were involved in data analysis and interpretation. BG-M, NHH, JVH and RK jointly prepared the initial draft of the report and contributed equally. All authors actively contributed to subsequent drafts and provided final approval to submit the report for publication. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit for publication.

Disclaimer: This work was presented at the European Cancer Congress 2013(ECCO-ESMO-ESTRO), held in Amsterdam, The Netherlands, 27 September to 1October 2013 (Kaiser R, Barrueco J, Reck M, et al. Identification of a clinicalmarker for second-line combination treatment with nintedanib in adenocarcinomanon-small cell lung cancer (NSCLC) patients in two Phase III trials. AbstractP388).

Funding: The studies on which this analysis was based were sponsored by Boehringer Ingelheim. Analyses were conducted by Boehringer Ingelheim.

Presentation statement: The academic investigators and representatives of the sponsor, Boehringer Ingelheim, co-designed the trials involved in this analysis. The sponsor’s statistical team (of which BG-M and PS are members) performed the statistical analyses. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Competing interests: BG-M, JB, PS and RK are employees of Boehringer Ingelheim. C-NG was an employee of Boehringer Ingelheim at the time this manuscript was developed. RK and BG-M have patents pending for Boehringer Ingelheim. MR has received honoraria for lectures and advisory board meetings from Boehringer Ingelheim Pharma GmbH & Co. KG, Hoffmann-La Roche, Lilly, Pfizer, AstraZeneca, Bristol Myers Squibb and Novartis. AM has received honoraria from Boehringer Ingelheim Pharma GmbH & Co. KG for advisory boards. SN has received non-financial support from Eli Lilly, Roche, AstraZeneca and MSD, during the conduct of this study. NHH and MG have no disclosures to declare. JVH has acted as a consultant for Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca and Genentech, and has received research funding from GlaxoSmithKline and AstraZeneca.

Provenance and peer review: Not commissioned; externally peer reviewed.