Giorgio V Scagliotti1, Rabab Gaafar2, Anna K Nowak3, Takashi Nakano4, Jan van Meerbeeck5, Sanjay Popat6, Nicholas J Vogelzang7, Federica Grosso8, Rasha Aboelhassan9, Marko Jakopovic10, Giovanni L Ceresoli11, Paul Taylor12, Francisco Orlandi13, Dean A Fennell14, Silvia Novello15, Arnaud Scherpereel16, Kozo Kuribayashi17, Susana Cedres18, Jens Benn Sørensen19, Nick Pavlakis20, Martin Reck21, Derek Velema22, Ute von Wangenheim23, Miyoung Kim24, José Barrueco25, Anne S Tsao26. 1. Department of Oncology, University of Turin, San Luigi Hospital, Torino, Italy. Electronic address: giorgio.scagliotti@unito.it. 2. National Cancer Institute, Cairo University, Fom El Khalig, Cairo, Egypt. 3. National Centre for Asbestos Related Diseases, School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, WA, Australia. 4. Center for Respiratory Medicine, Otemae Hospital, Osaka, Japan. 5. Department of Pulmonology and Thoracic Oncology, Antwerp University Hospital, Antwerp, Belgium. 6. Royal Marsden Hospital NHS Foundation Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK. 7. US Oncology Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA. 8. Mesothelioma Unit, SS Antonio e Biagio General Hospital, Alessandria, Italy. 9. Nasser Institute Hospital for Research and Treatment, Cairo, Egypt. 10. Zagreb Medical School, Department for Respiratory Diseases Jordanovac, University Hospital Centre, Zagreb, Croatia. 11. Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy. 12. Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK. 13. Oncología-Health and Care, Santiago de Chile, Chile. 14. University of Leicester and University Hospitals of Leicester, Leicester, UK. 15. Department of Oncology, University of Turin, San Luigi Hospital, Torino, Italy. 16. Pulmonary and Thoracic Oncology Department, University of Lille, Centre Hospitalier Universitaire de Lille, Lille, France. 17. Department of Respiratory Medicine, Hyogo College of Medicine, Hyogo, Japan. 18. Medical Oncology, Vall d'Hebron Institute of Oncology/Vall d'Hebron University Hospital, Barcelona, Spain. 19. Department of Oncology, Finsen Centre, Rigshospitalet, Copenhagen, Denmark. 20. Northern Cancer Institute, University of Sydney, Sydney, NSW, Australia. 21. Department of Thoracic Oncology, Airway Research Center North Member of the German Center for Lung Research, LungenClinic, Grosshansdorf, Germany. 22. Boehringer Ingelheim (Canada) Ltd/Ltée, Burlington, ON, Canada. 23. Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. 24. Boehringer Ingelheim Korea, Seoul, South Korea. 25. Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA. 26. Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Abstract
BACKGROUND:Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, 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/m2) plus cisplatin (75 mg/m2) 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.
RCT Entities:
BACKGROUND:Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, 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/m2) plus cisplatin (75 mg/m2) 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.
Authors: Kaushal Parikh; Sumithra J Mandrekar; Katie Allen-Ziegler; Brandt Esplin; Angelina D Tan; Benjamin Marchello; Alex A Adjei; Julian R Molina Journal: Oncologist Date: 2019-12-24
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Authors: Gregor Vlacic; Mir A Hoda; Thomas Klikovits; Katharina Sinn; Elisabeth Gschwandtner; Katja Mohorcic; Karin Schelch; Christine Pirker; Barbara Peter-Vörösmarty; Jelena Brankovic; Balazs Dome; Viktoria Laszlo; Tanja Cufer; Ales Rozman; Walter Klepetko; Bettina Grasl-Kraupp; Balazs Hegedus; Walter Berger; Izidor Kern; Michael Grusch Journal: Cells Date: 2019-09-16 Impact factor: 6.600