المؤلفون: Dolled-Filhart, Marisa¹ marisa.dolled-filhart@merck.com, Roach, Charlotte², Toland, Grant², Stanforth, Dave², Jansson, Malinka², Lubiniecki, Gregory M.³, Ponto, Gary², Emancipator, Kenneth¹

المصدر: Archives of Pathology & Laboratory Medicine. Nov2016, Vol. 140 Issue 11, p1243-1249. 7p. 3 Color Photographs, 3 Charts, 3 Graphs.

مصطلحات موضوعية: *THERAPEUTIC use of monoclonal antibodies, *DIAGNOSTIC errors, *IMMUNOHISTOCHEMISTRY, *LONGITUDINAL method, *LUNG cancer, *DECISION making in clinical medicine, *EVALUATION research, *PREDICTIVE tests, *PATIENT selection, *RECEIVER operating characteristic curves, *KAPLAN-Meier estimator, *IN vivo studies, *IMMUNOLOGIC receptors

مستخلص: * Context.--Programmed death ligand-1 (PD-L1) expression by tumors may enable them to avoid immunosurveillance. Objective.--To develop a PD-L1 immunohistochemical assay using the 22C3 anti-PD-L1 murine monoclonal antibody on the Dako platform as a possible companion diagnostic for pembrolizumab in patients with non-small cell lung cancer. Design.--Tumor samples from 146 patients with non-small cell lung cancer treated with pembrolizumab in KEYNOTE-001 and for whom response data were available were scored according to their staining intensity by a single pathologist using 4 methods: percentage of tumor cells staining at any intensity (PS1), moderate/strong intensity (PS2), strong intensity (PS3), and H-score (PS1 + PS2 + PS3). The cutoff score for predicting response to pembrolizumab was determined using receiver operating characteristic analysis. Progression-free and overall survival were assessed in patients with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (n = 146). Results.--The 4 scoring methods assessed performed similarly; PS1 with a 50% cutoff score is the simplest and easiest method to implement in practice. Response to pembrolizumab was observed in 19 of 44 patients (43%) with a PS1 score of 50% or higher and 8 of 102 patients (8%) with PS1 lower than 50% (odds ratio, 8.93). Median progression-free and overall survival was 4.0 months and not yet reached, respectively, for patients with a PS1 of 50% or higher, and 2.1 and 6.1 months, respectively, for those with PS1 lower than 50%. Conclusion.--The PD-L1 immunohistochemical assay shows the potential for enrichment of trial populations and as a companion diagnostic tool in non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

المؤلفون: Herbst, Roy S.¹ roy.herbst@yale.edu, Baas, Paul², Dong-Wan Kim³, Felip, Enriqueta⁴, Pérez-Gracia, José L.⁵, Ji-Youn Han⁶, Molina, Julian⁷, Joo-Hang Kim⁸, Dubos Arvis, Catherine⁹, Myung-Ju Ahn¹⁰, Majem, Margarita¹¹, Fidler, Mary J.¹², de Castro Jr., Gilberto¹³, Garrido, Marcelo¹⁴, Lubiniecki, Gregory M.¹⁵, Yue Shentu¹⁵, Im, Ellie¹⁵, Dolled-Filhart, Marisa¹⁵, Garon, Edward B.¹⁶, Kim, Dong-Wan¹⁷ (AUTHOR)

المصدر: Lancet. 4/9/2016, Vol. 387 Issue 10027, p1540-1550. 11p. 1 Diagram, 2 Charts, 4 Graphs.

مصطلحات موضوعية: *PEMBROLIZUMAB, *DOCETAXEL, *CANCER treatment, *NON-small-cell lung carcinoma, *DRUG efficacy, *RANDOMIZED controlled trials, *ANTIGEN analysis, *THERAPEUTIC use of monoclonal antibodies, *ANTINEOPLASTIC agents, *DRUG therapy, *COMPARATIVE studies, *DRUG administration, *GENES, *LUNG cancer, *HYDROCARBONS, *LUNG tumors, *RESEARCH methodology, *MEDICAL cooperation, *MONOCLONAL antibodies, *PROGNOSIS, *RESEARCH, *EVALUATION research, *TREATMENT effectiveness, *PATIENT selection, *KAPLAN-Meier estimator, *THERAPEUTICS

مستخلص: Background: Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.Methods: We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.Findings: Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).Interpretation: Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.Funding: Merck & Co. [ABSTRACT FROM AUTHOR]