Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer

Abstract

Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcinoma histology, with manageable toxicity. Here, we present an analytical review of literature regarding nintedanib and we focus on its particular importance in NSCLC treatment.

Keywords:

• adenocarcinoma
• angiogenesis
• nintedanib
• non-small-cell lung cancer
• tyrosine kinase inhibitor

Acknowledgements

We acknowledge the assistance of the scientific secretary Vasso Athanasaki in the preparation of this manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• BIBF 1120 – nintedanib is a tyrosine kinase inhibitor which blocks VEGF, FGF, PDGF receptors and inhibits Fms-like tyrosine kinase 3 and members of the Src-family.

• Preclinical studies showed its antitumor activity and synergy with chemotherapy agents (doxorubicin and paclitaxel), and its eventual importance on restoring multidrug resistance.

• Despite its conjugation to glucuronic acid, the majority of BIBF 1120 metabolism is CYP450 enzyme-independent, allowing a combination with cytotoxic chemotherapy. Its metabolites are excreted via the biliary system into the feces whereas urinary excretion is minor.

• Nintedanib maximum tolerated dose is 400 mg and is administered as capsules 200 mg twice daily orally after food intake.

• Toxicity is easily manageable and mainly involves nausea, vomiting, diarrhea, abdominal pain, fatigue and liver enzymes elevation.

• In the LUME-Lung 1 study, patients with advanced non-small-cell lung cancer (NSCLC) who received second-line chemotherapy with the combination docetaxel-nintedanib showed improved progression-free survival (hazard ratio: 0.79) compared with those who received docetaxel. Patients with adenocarcinoma derived an overall survival benefit with the combination (hazard ratio: 0.83).

• The combination of nintedanib with pemetrexed is feasible in NSCLC patients receiving second-line chemotherapy.

• Many ongoing clinical trials are investigating the role of nintedanib in the treatment of advanced NSCLC. Importantly, some of them molecularly select patients who harbor certain mutations in order to define potential predictive markers.

• In the EU, it has been approved in November 2014 in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumor histology after first-line chemotherapy, marketed under the brand name VARGATEF^®.