Arnaud Scherpereel1, Julien Mazieres2, Laurent Greillier3, Sylvie Lantuejoul4, Pascal Dô5, Olivier Bylicki6, Isabelle Monnet7, Romain Corre8, Clarisse Audigier-Valette9, Myriam Locatelli-Sanchez10, Olivier Molinier11, Florian Guisier12, Thierry Urban13, Catherine Ligeza-Poisson14, David Planchard15, Elodie Amour16, Franck Morin16, Denis Moro-Sibilot17, Gérard Zalcman18. 1. Department of Pulmonary and Thoracic Oncology, University of Lille, University Hospital (CHU) of Lille, Lille, France; French National Network of Clinical Expert Centers for Malignant Pleural Mesothelioma Management (MESOCLIN), Lille, France. Electronic address: arnaud.scherpereel@chru-lille.fr. 2. Department of Pneumology, University Hospital of Toulouse, Université Paul Sabatier, Toulouse, France. 3. Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, Assistance Publique-Hôpitaux de Marseille, Marseille, France. 4. Department of BioPathology, MESOPATH, Centre de Lutte Contre le Cancer Léon Bérard, Lyon, France; University Grenoble Alpes, Grenoble, France. 5. Department of Pneumology, Centre de Lutte Contre le Cancer Baclesse, Caen, France. 6. Department of Pneumology, Hôpital d'instruction des Armées, Percy, Clamart, France. 7. Department of Pneumology, Centre Hospitalier Intercommunal de Créteil, Créteil, France. 8. Department of Pneumology, University Hospital of Rennes, Rennes, France. 9. Department of Pneumology, Hôpital Sainte-Musse, Toulon, France. 10. Department of Pneumology, Centre Hospitalier Lyon-Sud Pierre-Bénite, Lyon, France. 11. Department of Pneumology, Le Mans Regional Hospital, Le Mans, France. 12. Department of Pneumology, University Hospital of Rouen, Rouen, France. 13. Department of Pneumology, University Hospital of CHU Angers, Angers, France. 14. Department of Medical Oncology, Clinique Mutualiste de l'Estuaire, Saint-Nazaire, France. 15. Department of Thoracic Oncology, Institut Gustave Roussy, Villejuif, France. 16. Intergroupe Francophone de Cancérologie Thoracique IFCT, Paris, France. 17. Department of Pneumology, University Hospital of Grenoble, Grenoble, France. 18. University Hospital Bichat Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University Paris, Paris, France.
Abstract
BACKGROUND: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma. METHODS: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272. FINDINGS:Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure). INTERPRETATION: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials. FUNDING: French Cooperative Thoracic Intergroup.
RCT Entities:
BACKGROUND: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma. METHODS: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272. FINDINGS: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure). INTERPRETATION: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials. FUNDING: French Cooperative Thoracic Intergroup.
Authors: Francoise Galateau Salle; Nolwenn Le Stang; Franck Tirode; Pierre Courtiol; Andrew G Nicholson; Ming-Sound Tsao; Henry D Tazelaar; Andrew Churg; Sanja Dacic; Victor Roggli; Daniel Pissaloux; Charles Maussion; Matahi Moarii; Mary Beth Beasley; Hugues Begueret; David B Chapel; Marie Christine Copin; Allen R Gibbs; Sonja Klebe; Sylvie Lantuejoul; Kazuki Nabeshima; Jean-Michel Vignaud; Richard Attanoos; Luka Brcic; Frederique Capron; Lucian R Chirieac; Francesca Damiola; Ruth Sequeiros; Aurélie Cazes; Diane Damotte; Armelle Foulet; Sophie Giusiano-Courcambeck; Kenzo Hiroshima; Veronique Hofman; Aliya N Husain; Keith Kerr; Alberto Marchevsky; Severine Paindavoine; Jean Michel Picquenot; Isabelle Rouquette; Christine Sagan; Jennifer Sauter; Francoise Thivolet; Marie Brevet; Philippe Rouvier; William D Travis; Gaetane Planchard; Birgit Weynand; Thomas Clozel; Gilles Wainrib; Lynnette Fernandez-Cuesta; Jean-Claude Pairon; Valerie Rusch; Nicolas Girard Journal: J Thorac Oncol Date: 2020-03-09 Impact factor: 15.609
Authors: Timothy A Yap; Eileen E Parkes; Weiyi Peng; Justin T Moyers; Michael A Curran; Hussein A Tawbi Journal: Cancer Discov Date: 2021-04-02 Impact factor: 39.397