Carmine Pinto1, Paolo Andrea Zucali2, Maria Pagano1, Federica Grosso3, Giulia Pasello4, Marina Chiara Garassino5, Marcello Tiseo6, Hector Soto Parra7, Francesco Grossi8, Federico Cappuzzo9, Filippo de Marinis10, Paolo Pedrazzoli11, Maria Bonomi12, Letizia Gianoncelli13, Matteo Perrino14, Armando Santoro15, Francesca Zanelli1, Candida Bonelli1, Antonio Maconi16, Stefano Frega17, Erika Gervasi1, Luca Boni18, Giovanni Luca Ceresoli19. 1. Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. 2. Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Oncology, IRCCS Humanitas Research Hospital, Milan, Italy. Electronic address: paolo.zucali@hunimed.eu. 3. Mesothelioma Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; Infrastruttura Ricerca Formazione e Innovazione, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. 4. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padua, Italy. 5. Thoracic Oncology Unit, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 6. Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy. 7. Medical Oncology Unit, AOU Policlinico Vittorio Emanuele, Catania, Italy. 8. Medical Oncology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore, Milan, Italy; Medical Oncology Unit, University of Insubria, Varese, Italy. 9. Medical Oncology Unit, IRCCS Istituto Nazionale Tumori Regina Elena, Rome, Italy. 10. Thoracic Oncology Division, Istituto Europeo di Oncologia IRCCS, Milan, Italy. 11. Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy. 12. Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy; Department of Oncology, ASST Cremona, Cremona, Italy. 13. Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy; Department of Oncology, Ospedale San Paolo, Milan, Italy. 14. Department of Oncology, IRCCS Humanitas Research Hospital, Milan, Italy. 15. Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Oncology, IRCCS Humanitas Research Hospital, Milan, Italy. 16. Infrastruttura Ricerca Formazione e Innovazione, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. 17. Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padua, Italy. 18. Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. 19. Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy.
Abstract
BACKGROUND: There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma. METHODS: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36. FINDINGS: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths. INTERPRETATION: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting. FUNDING: Eli Lilly Italy. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.
BACKGROUND: There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma. METHODS: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36. FINDINGS: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths. INTERPRETATION: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting. FUNDING: Eli Lilly Italy. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.
Authors: Dean A Fennell; Catharine Porter; Jason Lester; Sarah Danson; Paul Taylor; Michael Sheaff; Robin M Rudd; Aarti Gaba; Sara Busacca; Lisette Nixon; Georgina Gardner; Liz Darlison; Charlotte Poile; Cathy Richards; Peter-Wells Jordan; Gareth Griffiths; Angela Casbard Journal: EClinicalMedicine Date: 2022-05-19