"Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with gastric and gastroesophageal cancer." #WhyPathologistsMatter

Karina Kulangara, Nancy Zhang, Ellie Corigliano, Lindsay Guerrero, Stephanie Waldroup, Dipeshkumar Jaiswal, Malinka Jansson, MS, Supriya Shah, Debra Hanks, Jiangdian Wang, Jared Lunceford, Mary J. Savage, Jonathan Juco, and Kenneth Emancipator (2018) Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer. Archives of Pathology & Laboratory Medicine In-Press.

Early Online Release

Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer

Karina Kulangara, PhD; Nancy Zhang, MD; Ellie Corigliano, PhD; Lindsay Guerrero, MS; Stephanie Waldroup, BSc; Dipeshkumar Jaiswal, MS; Malinka Jansson, MS; Supriya Shah, PhD; Debra Hanks, MD; Jiangdian Wang, PhD; Jared Lunceford, PhD; Mary J. Savage, PhD; Jonathan Juco, MD; Kenneth Emancipator, MD

Corresponding author: Kenneth Emancipator, MD, Merck Research Laboratory, Merck & Co, Inc, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 (email: kenneth.emancipator@merck.com).

Drs Zhang, Corigliano, and Shah and Mss Guerrero and Jansson are employees of Agilent Technologies. Drs Kulangara and Hanks, Ms Waldroup, and Mr Jaiswal are employees of Agilent Technologies and own stock and hold stock options in the company. Ms Waldroup has pending patents broadly relevant to the work described. Dr Wang is an employee of Merck & Co, Inc. Drs Lunceford, Savage, Juco, and Emancipator are employees of Merck & Co, Inc, and own stock with this company. The authors have no other relevant financial interest in the products or companies described in this article.

Context.— Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD-L1) protein expression as a companion diagnostic to identify likely responders to therapy.

Objective.— To develop an immunohistochemical scoring algorithm that includes PD-L1 expression for tumor and immune cells, that is, the combined positive score.

Design.— Four previously treated tumor types in the KEYNOTE-012 and KEYNOTE-028 studies were analyzed descriptively with a version of the PD-L1 immunohistochemical 22C3 pharmDx assay labeled for investigational use only to determine the relative importance of PD-L1 expression in tumor versus immune cells as a biomarker for pembrolizumab response. A combined positive score was developed as a novel scoring method and was compared with the tumor proportion score in cohort 1 from the KEYNOTE-059 study (G/GEJ cancer). External reproducibility was assessed.

Results.— Per combined positive score cutoff of 1 or more, the prevalence of PD-L1 expression in patients with G/GEJ cancer was 57.6% (148 of 257 patients), with reasonable enrichment of responses (odds ratio, 2.8). Per tumor proportion score cutoff of 1% or more, prevalence was 12.5% (32 of 257 patients), with minimal enrichment (odds ratio, 1.4). External reproducibility assessments demonstrated interpathologist overall agreement of 96.6% (591 of 612; 95% CI, 94.0%–98.7%) and intrapathologist overall agreement of 97.2% (595 of 612; 95% CI, 95.3%–98.9%).

Conclusions.— Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with G/GEJ cancer. This novel scoring method supported US Food and Drug Administration approval of pembrolizumab as third-line therapy for G/GEJ cancer and has facilitated investigation in other indications.