title: Differential Activity of Nivolumab, Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and Genitourinary Cancers.
abstract: BACKGROUND
  The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research.
  
  
  METHODS
  Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed.
  
  
  RESULTS
  Twenty trials (1,475 patients) were identified. A significant interaction (p<0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% (95% CI 27.6-41.3%) in the PD-L1 positive and 19.9% (95% CI 15.4-25.3%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4% and 19.5%, respectively. A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer.
  
  
  CONCLUSIONS
  Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Carbognin
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.affiliation: Medical Oncology, Regina Elena National Cancer Institute, Roma, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Medical Oncology, Regina Elena National Cancer Institute, Roma, Italy.
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caliò
authors.affiliation: Agenzia Italiana del Farmaco (AIFA), Roma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cuppone
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Roma, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Roma, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Pathology and Diagnostic, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; ARC-NET Center for Applied Research on Cancer, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D000077594:Nivolumab; D011379:Prognosis; D016896:Treatment Outcome; D014565:Urogenital Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D014566:Urogenital System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab