Nintedanib has been designated a Promising Innovative Medicine for the treatment of malignant pleural mesothelioma (MPM) by the UK Medicine and Healthcare Products Regulatory Agency (MHRA). This is an early indication that the MHRA considers nintedanib a promising candidate for the Early Access to Medicines Scheme, which aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorisation when there is a clear unmet medical need.
Professor Dean Fennell, Chair of Thoracic Medical Oncology at the University of Leicester and University Hospitals of Leicester NHS Trust, UK, said, “This is fantastic news and the right decision taking into account the risk/benefit profile of nintedanib from a very credible phase II trial.”
MPM is a relatively rare but aggressive thoracic cancer that is often rapidly progressive once clinically apparent4. Most cases are related to long-term exposure to asbestos and latest figures show that 2,502 cases of MPM occurred in the UK in 2014. MPM patients have a poor prognosis, with median survival ranges from 8-14 months from diagnosis. Women have a more favourable outlook than men, but due to the occupational nature of the disease, there is a male predominance of 4:1. For patients with unresectable disease, first-line combination doublet chemotherapy treatment with cisplatin or carboplatin and pemetrexed has been the standard of care for more than 10 years.
“The biggest problem has been no change in the standard of care for these patients leading to new therapies since 2003. There has been a therapeutic plateau where there have been no significant improvements in any combination of treatments in the first-line setting to build on to the pemetrexed backbone,” said Professor Fennell. He explained, “The current standard of care is carboplatin or cisplatin with pemetrexed, which has been limited to a progression-free survival (PFS) not getting beyond 6 months. With regards to overall survival (OS), more trials are needed in relapsed patients, where there is no standard of care in the second-line setting.”
The MHRA issued the Promising Innovative Medicine designation after reviewing available non-clinical and clinical data on nintedanib in malignant pleural mesothelioma. This included the phase II LUME-Meso Trial, published recently in the Journal of Clinical Oncology, which showed statistically significant improvements in progression-free survival in patients with MPM treated with nintedanib plus chemotherapy compared to those receiving chemotherapy alone. Results also showed a trend towards an overall survival benefit (a secondary endpoint) with nintedanib which was not statistically significant.
The LUME-Meso trial randomised a total of 87 patients with MPM, including patients from the UK, to first-line treatment with up to six cycles of chemotherapy (pemetrexed plus cisplatin) plus either oral nintedanib (200mg twice daily) or placebo. When chemotherapy cycles concluded, patients could continue on monotherapy, with either nintedanib or placebo, until progression. Results showed significant improvement in median progression-free survival (PFS) in patients treated with nintedanib plus chemotherapy (9.4 months) compared to those treated with chemotherapy alone (4.7 months, hazard ratio [HR] 0.54, 95% confidence interval 0.33-0.87, p=0.010).
When analysed by MPM histology, median PFS was prolonged by 4.0 months in patients with confirmed epithelioid histology treated with nintedanib plus chemotherapy (9.7 vs 5.7 months with placebo, HR 0.49 p=0.006).3 This provided the rationale to proceed to the LUME-Meso phase III trial8, which is recruiting MPM patients at trial sites worldwide, including five in the UK.
Primary analysis of OS showed a 4.1 month improvement in median OS for patients treated with nintedanib plus chemotherapy (18.3 months vs 14.2 months with chemotherapy alone, HR 0.77, p=0.319). This demonstrated an improved trend in the overall survival, without reaching statistical significance. Similarly to PFS, the median increase in OS compared to chemotherapy alone was greater in patients with epithelioid histology, at 5.4 months (20.6 vs 15.2 months with chemotherapy alone, HR 0.70, p=0.197) although statistical significance wasn’t achieved.
Safety data showed the experimental combination with nintedanib was generally well tolerated compared to chemotherapy alone. Neutropenia (an abnormally low level of neutrophils, a type of white blood cell) was the most frequent grade ≥3 adverse event (nintedanib 43.2% vs placebo 12.2%); rates of febrile neutropenia were low (2.3% vs 0%). Serious AEs (SAEs) occurred in 18 patients (40.9%) in the nintedanib arm and in 17 (41.5%) in the placebo arm. The most frequent SAEs (all grades; nintedanib vs placebo) were neutropenia 9.1% vs 2.4%, diarrhoea 6.8% vs 0%, pyrexia 6.8% vs 4.9% and pulmonary embolism 2.3% vs 9.8% respectively. Discontinuations due to adverse events were low, with fewer patients discontinuing treatment in the nintedanib arm than in the placebo arm (3 patients vs 7 patients; 6.8% vs 17.1%). Adverse events typically observed with anti-angiogenesis compounds, such as hypertension, bleeding and thromboembolic event, were seen infrequently.
These findings warrant confirmation and the activity of nintedanib in this setting is already under investigation in the Phase III study.
The MHRA awards a Promising Innovative Medicine designation as an early indication that a drug is a promising candidate for the Early Access to Medicines Scheme, intended for the treatment of a life-threatening or seriously debilitating condition with the potential to address an unmet medical need2. The scheme is voluntary3 and Boehringer Ingelheim worked with the MHRA to ensure it had the information needed to assess nintedanib in MPM against the three criteria that must be fulfilled:
· The condition must be life-threatening or seriously debilitating, with high unmet need (no method of treatment, diagnosis or prevention available or existing methods have serious limitations).
· The medicinal product is likely to offer major advantage over methods currently used in the UK, with preliminary evidence based on non-clinical and clinical data indicating that the advantage and magnitude of the effect is predicted to be of significant relevance to the patient and will address their unmet need.
· The potential adverse effects of the medicinal product are likely to be outweighed by the benefits.
Nintedanib is an oral triple angiokinase inhibitor that targets receptors for three growth factors (VEGF, FGF and PGF), as well as Src and Abl signalling9, which are implicated in the development of malignant pleural mesothelioma.
Nintedanib (Vargatef) is currently indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) or of adenocarcinoma tumour histology after first-line chemotherapy