The addition of nintedanib to standard, second-line docetaxel therapy did not increase the frequency of adverse events (AEs) associated with antiangiogenic treatment in patients with non-small-cell lung cancer (NSCLC), according to research presented by Anders Mellemgaard, MD, at the 2015 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Annual Meeting on Supportive Care in Cancer.
Antiangiogenic treatments, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated antitumor activity, but their use is partly limited because of their characteristic AEs (eg, bleeding, thrombosis, perforation, serious skin reactions, and hypertension).
"There is a characteristic group of adverse events more frequently seen in populations taking these drugs," stated Dr Mellemgaard, Medical Oncologist, Department of Oncology, Herlev University Hospital, Herlev, Denmark.
To evaluate the frequency of AEs associated with antiangiogenic agents, Dr Mellemgaard and colleagues extended their LUME-Lung 1 study-a large, randomized, placebo-controlled, phase 3 trial assessing the impact of docetaxel plus nintedanib (n = 655) versus docetaxel plus placebo (n = 659) on survival in patients with advanced NSCLC after failure of first-line chemotherapy. As part of this study, the authors assessed whether these AEs impeded the use of nintedanib.
Improved Survival Seen in LUME Lung-1
Nintedanib is an oral, twice-daily, triple angiokinase inhibitor that, in combination with docetaxel, is approved in the European Union for use after first-line chemotherapy in patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma histology.
"Nintedanib works by effectively suppressing vascular growth, the theory being that by doing so, there will be an additional antitumor effect with the drug in addition to chemotherapy, which will increase the effect of the treatment," Dr Mellemgaard explained.
The LUME-Lung 1 study demonstrated significant improvement of progression-free survival-regardless of histology-and survival improvement for patients with adenocarcinoma. The frequency and intensity of antiangiogenic-associated AEs were evaluated in all patients who received ≥1 doses of nintedanib, docetaxel, or placebo.
Adverse Events Observed, Histology
AEs linked to vascular endothelial growth factor inhibition, which were defined as ≥2% growth versus placebo, were more common in the nintedanib versus placebo arm. These AEs included bleeding (all grades, 14.1% vs 11.6%; grade ≥3, 2.3% vs 1.8%) and hypertension (all grades, 3.5% vs 0.9%; grade ≥3, 0.6% vs 0.2%).
"However, treating hypertension in these patients is not complicated," said Dr Mellemgaard. " The same drugs used for central hypertension can be used, and it's usually not too difficult to achieve control of the hypertension."
Gastrointestinal and nongastrointestinal perforations were very infrequent, and the risks were identical in both arms.
When evaluating the histologic differences in antiangiogenic-associated AEs, the investigators observed nominal differences. More bleeding events were reported in nintedanib-treated patients with squamous-cell carcinoma (SCC) than in patients with adenocarcinoma (all grades, 17.1% vs 10.9%; grade ≥3, 2.9% vs 1.5%)
Researchers observed no overall increased risk for arterial or venous thromboembolic complications. "In the arterial group, there was actually a lower risk with nintedanib," Dr Mellemgaard added.
The frequency of fatal bleeding events, serious skin reactions, thrombosis, and perforations was low and comparable in both arms, regardless of histology.
Data Provide a Better Understanding of Toxicity
Investigators concluded that adding nintedanib to standard, second-line docetaxel for NSCLC therapy did not increase the frequency of AEs associated with antiangiogenic treatment; grade 1-2 bleeding events were observed in patients with SCC.
"AEs were moderate with the exception of hypertension and skin-related AEs in all populations, and bleeding only in [SCC] patients," noted Dr Mellemgaard. AE nature, frequency, and severity were consistent with under-lying NSCLC, concomitant docetaxel chemotherapy, and expected AEs of nintedanib, investigators reported.
"Survival was definitely improved for patients with adenocarcinoma," explained Dr Mellemgaard. Based on these results, nintedanib was found to meet the medical need for treatment after first-line chemotherapy for patients with adenocarcinoma, and has a manageable safety profile.
Weighing in on the study, Dorothy Keefe, PSM, MBBS, MD, FRACP, FRCP, session moderator, Professor of Cancer Medicine at the University of Adelaide, and a Senior Medical Oncologist at Royal Adelaide Hospital Cancer Centre in Adelaide, Australia, stated that despite the impressive number of participants in this trial (N = 1314), it still probably requires further study. "But these types of studies help to build on our knowledge by increasing the clarity of the epidemiology of toxicity of targeted agents."