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.
- Gaschler-Markefski, B.
- Sikken, P.
- Heymach, J. V.
- Gottfried, M.
- Mellemgaard, A.
- Novello, S.
- Gann, C. N.
- Barrueco, J.
- Reck, M.
- Hanna, N. H.
- Kaiser, R.
Keywords
- Adenocarcinoma
- Clinical marker
- Nintedanib
- Non-small cell lung cancer
- Time since first-line treatment
- 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.
