Solenn Brosseau1, Claire Danel2, Arnaud Scherpereel3, Julien Mazières4, Sylvie Lantuejoul5, Jacques Margery6, Laurent Greillier7, Clarisse Audigier-Valette8, Valérie Gounant9, Martine Antoine10, Denis Moro-Sibilot11, Isabelle Rouquette12, Olivier Molinier13, Romain Corre14, Isabelle Monnet15, Alexandra Langlais16, Franck Morin16, Emmanuel Bergot17, Gérard Zalcman18, Guénaëlle Levallet19. 1. Department of Thoracic Oncology and CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France. 2. Department of Pathology, Hôpital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France. 3. Department of Pulmonary and Thoracic Oncology, Centre Hospitalier Universitaire Lille, University of Lille, U1019 INSERM, Center of Infection and Immunity of Lille, Lille, France. 4. Department of Pulmonology, Hôpital Larrey, University Hospital of Toulouse, Toulouse, France. 5. Department of Biopathology, Reference National Center MESOPATH, Centre Léon Bérard, Grenoble Alpes University, Lyon, France. 6. Medical Oncology Department, Gustave Roussy, Villejuif, France. 7. Department of Multidisciplinary Oncology and Therapeutic Innovations, Assistance Publique Hôpitaux de Marseille, Aix-Marseille Université, Marseille, France; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR1068, CNRS UMR7258, Aix-Marseille Université UM105, Marseille, France. 8. Department of Pulmonology, Centre Hospitalier Toulon Sainte-Musse, Toulon, France. 9. Department of Pulmonology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, France. 10. Department of Pathology, Hôpital Tenon, AP-HP, Université Paris-Diderot, Paris, France. 11. Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire Grenoble, Grenoble, France. 12. Department of Pathology, Universitary Hospital, Toulouse, France. 13. Department of Pulmonology, Centre Hospitalier Le Mans, Le Mans, France. 14. Department of Pulmonology, Ponchaillou University Hospital, Rennes, France. 15. Department of Pulmonology, CHI Créteil, Créteil, France. 16. Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France. 17. Department of Pulmonology and Thoracic Oncology, CHU de Caen, Caen, France; Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Caen, France. 18. Department of Thoracic Oncology and CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France; U830 INSERM "Genetics and Biology of Cancers, ART Group," Curie Institute, Paris, France. Electronic address: gerard.zalcman@aphp.fr. 19. Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Caen, France; Department of Pathology, CHU de Caen, Caen, France.
Abstract
BACKGROUND: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456). PATIENTS AND METHODS: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables. RESULTS:PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047). CONCLUSION: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.
RCT Entities:
BACKGROUND: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456). PATIENTS AND METHODS: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables. RESULTS:PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumorPD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047). CONCLUSION: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.