Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Approved indications: idiopathic pulmonary fibrosis, non-small cell lung cancer
Ofev (Boehringer Ingelheim)
100 mg and 150 mg capsules
Australian Medicines Handbook section 14.2.3
Growth factors contribute to the proliferation of cells in cancers and conditions such as pulmonary fibrosis. This proliferation involves tyrosine kinases such as fibroblast growth factor, vascular endothelial growth factor and platelet-derived growth factor. Nintedanib inhibits these growth factors by binding to their receptors intracellularly. This disrupts the signalling needed for cell proliferation.
Nintedanib capsules are taken twice daily with food. There is extensive first-pass metabolism so the bioavailability is under 5%. The drug is also mainly cleared by metabolism with most of the metabolites being excreted in the faeces. The terminal half-life is 10–15 hours. As nintedanib is a substrate of P-glycoprotein, inducers of this transporter, such as phenytoin and St John’s wort, will reduce the concentration of nintedanib. Its plasma concentration will be increased by inhibitors of P-glycoprotein such as ketoconazole.
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis is one of the interstitial lung diseases. A proliferation of fibroblasts leads to progressive breathlessness. The median survival is 3–5 years.
The main clinical trials of nintedanib in pulmonary fibrosis were INPULSIS-1 and -2.1 In these trials a total of 638 patients were randomised to take 150 mg nintedanib twice daily for 52 weeks and 423 were given a placebo. These patients all had a forced vital capacity (FVC) that was at least 50% of the predicted value. In INPULSIS-1 the FVC fell by 239.9 mL/year with placebo and by 114.7 mL/year with nintedanib. The respective figures in INPULSIS-2 were reductions of 207.3 mL/year and 113.6 mL/year. The smaller decline in lung function with nintedanib was statistically significant.
In INPULSIS-1, 21% of the patients had to discontinue nintedanib because of adverse events. In both trials more than 60% of the patients taking nintedanib developed diarrhoea compared with about 18% of the placebo group. Other adverse events that were more common with nintedanib than with placebo included nausea, vomiting, weight loss and elevated liver enzymes.1
The inhibition of growth factors by nintedanib has been studied in patients with non-small cell lung cancer of different histological types. The LUME-Lung 1 trial involved 1314 patients with locally advanced, metastatic or recurrent disease that had not responded to first-line chemotherapy. All the patients were given an infusion of docetaxel every 21 days and 652 also took 200 mg nintedanib twice daily on days 2–21 of the cycle. The median duration of treatment was 2.8 months with docetaxel alone and 3.4 months with the combination. After a median follow-up of 7.1 months, progression-free survival was 2.7 months in the control group and 3.4 months in the combination group. This difference is statistically significant.2
Adverse events led to 21.7% of the patients taking docetaxel and 22.7% of those taking docetaxel and nintedanib withdrawing from the trial. Deaths from adverse events were more frequent with the combination treatment. Nausea, vomiting, diarrhoea, altered liver function and febrile neutropenia were also more frequent.2
The adverse effects of nintedanib may require treatment to be interrupted or reduced. Blood counts and liver function should be regularly monitored. Nintedanib is not recommended for patients with moderate or severe liver disease. In addition to the common adverse effects, there may also be an increased risk of gastrointestinal perforation, impaired wound healing, bleeding and thromboembolism. Although patients with a history of myocardial infarction or stroke were excluded from the INPULSIS trials, myocardial infarctions were more frequent with nintedanib than placebo (1.6 vs 0.5%).
Idiopathic pulmonary fibrosis has a poor prognosis, so reducing the decline in lung function is a benefit. However, in a pooled analysis of the INPULSIS trials, nintedanib had no significant advantage over placebo in preventing acute exacerbations in pulmonary fibrosis or in health-related quality of life.1
In non-small cell lung cancer adding nintedanib to docetaxel increases progression-free survival, but the median overall survival is not significantly increased unless the cancer is an adenocarcinoma. The median overall survival for patients with an adenocarcinoma given the combination was 12.6 months compared with 10.3 months for patients treated with docetaxel alone. Pemetrexed is another drug that can be used to treat non-small cell lung cancer. In March 2015 the Pharmaceutical Benefits Advisory Committee concluded that an indirect comparison did not show that the effectiveness of nintedanib and docetaxel was non-inferior to pemetrexed.3
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
At the time the comment was prepared, information about this drug was available on the following websites:
- Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
- Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143-55.
- Pharmaceutical Benefits Advisory Committee. Public Summary Document – March 2015 PBAC meeting. Nintedanib, 100 mg capsule, 60; 150 mg capsule, 60; Ofev®. Canberra: Australian Government Department of Health; 2015. [cited 2016 Feb 12]