title: Development of a Companion Diagnostic PD-L1 Immunohistochemistry Assay for Pembrolizumab Therapy in Non-Small-cell Lung Cancer.
abstract: A companion diagnostic assay was codeveloped by Dako for pembrolizumab non-small-cell lung cancer clinical trials to detect PD-L1 expression by immunohistochemistry (IHC). This automated IHC assay has been analytically verified and validated using Dako's autostainer Link 48 and 22C3 mouse anti-PD-L1 monoclonal antibody to detect the PD-L1 expression in formalin-fixed paraffin-embedded human tumor tissue specimens. The PD-L1 22C3 IHC assay was optimized for high sensitivity and specificity. Repeatability and reproducibility studies were conducted at Dako and at 3 Clinical Laboratory Improvement Amendments certified laboratories during assay development. The studies included: intersite and intrasite, interobserver and intraobserver, interinstrument, interoperator, interday, and interlot, and intraday and intrarun. All precision studies performed at Dako and external laboratories achieved >85% point-estimate agreements for all 3 agreement types (negative, positive, and overall). A clinical cutoff (tumor proportion score ≥50%) of PD-L1 expression was determined and evaluated through a phase 1 clinical trial (KEYNOTE-001) for advanced non-small-cell lung cancer patients treated with pembrolizumab. The treatment effect of pembrolizumab in the 61 subjects who had a tumor PD-L1 of tumor proportion score ≥50% was substantial, with an overall response rate of 41% (95% confidence interval, 28.6-54.3) as compared with 20.6% (95% confidence interval, 15.5-26.5) observed in the 223 subjects irrespective of PD-L1 status. PD-L1 IHC 22C3 pharmDx is a sensitive, precise, and robust companion diagnostic assay, which will facilitate safe and effective use for pembrolizumab in cancer patients.
authors.affiliation: *Dako North America Inc., an Agilent Technologies Company, Carpinteria, CA †Merck & Co. Inc., Kenilworth, NJ.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Roach
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Ellie
authors.initials: E
authors.lastname: Corigliano
authors.forename: Malinka
authors.initials: M
authors.lastname: Jansson
authors.forename: Grant
authors.initials: G
authors.lastname: Toland
authors.forename: Gary
authors.initials: G
authors.lastname: Ponto
authors.forename: Marisa
authors.initials: M
authors.lastname: Dolled-Filhart
authors.forename: Kenneth
authors.initials: K
authors.lastname: Emancipator
authors.forename: Dave
authors.initials: D
authors.lastname: Stanforth
authors.forename: Karina
authors.initials: K
authors.lastname: Kulangara
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D057230:Limit of Detection; D008175:Lung Neoplasms / Q000188:drug therapy*; D015203:Reproducibility of Results
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C582435:pembrolizumab