BACKGROUND: Nintedanib targets VEGF receptors 1-3, PDGF receptors alpha and beta, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma. METHODS: This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged >/=18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100. FINDINGS: Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5.3 months (IQR 2.8-7.3) in the nintedanib group and 5.1 months (2.7-7.8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6.8 months [95% CI 6.1-7.0]) and the placebo group (7.0 months [6.7-7.2]; HR 1.01 [95% CI 0.79-1.30], p=0.91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%]). INTERPRETATION: The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported. FUNDING: Boehringer Ingelheim.
- Scagliotti, G. V.
- Gaafar, R.
- Nowak, A. K.
- Nakano, T.
- van Meerbeeck, J.
- Popat, S.
- Vogelzang, N. J.
- Grosso, F.
- Aboelhassan, R.
- Jakopovic, M.
- Ceresoli, G. L.
- Taylor, P.
- Orlandi, F.
- Fennell, D. A.
- Novello, S.
- Scherpereel, A.
- Kuribayashi, K.
- Cedres, S.
- Sorensen, J. B.
- Pavlakis, N.
- Reck, M.
- Velema, D.
- von Wangenheim, U.
- Kim, M.
- Barrueco, J.
- Tsao, A. S.
