A Comprehensive Analysis of Programmed Cell Death Ligand-1 Expression With the Clone SP142 Antibody in Non–Small-Cell Lung Cancer Patients

Abstract

Background

Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with anti–PD-1 therapy currently the standard treatment for non–small-cell lung cancer (NSCLC) patients after the failure of first-line chemotherapy treatment. The recent phase II POPLAR and phase III OAK studies showed that atezolizumab, a representative PD-L1 inhibitor, exhibited a survival benefit compared with standard therapy in patients with NSCLC.

Patients and Methods

We examined PD-L1 expression in NSCLC using the clone SP142 of POPLAR and OAK studies. PD-L1 expression in 499 surgically resected NSCLC patients was evaluated using immunohistochemistry using SP142. We set cutoff values as 1%, 5%, 10%, and 50%.

Results

The samples from 189 (37.9%), 119 (23.8%), 71 (14.2%), and 39 (7.8%) patients were positive for PD-L1 expression at cutoff values of 1%, 5%, 10%, and 50%, respectively. Fisher exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, advanced stage, the presence of vascular invasion, squamous cell carcinoma, and wild type epidermal growth factor receptor gene mutation status at all cutoff values. Univariate and multivariate survival analyses revealed that PD–L1-positive patients had a worse prognosis than PD–L1-negative patients only at the 1% cutoff value. Forest plot analyses showed that the 1% cutoff provided a more sensitive value for the prediction of postoperative prognosis.

Conclusion

PD-L1 expression varied greatly according to different cutoff values. This study might be a useful reference to understand the results of POPLAR and OAK studies and to select patients likely to benefit from atezolizumab.

Introduction

Lung cancer is the leading cause of cancer-related death worldwide.¹ Multidisciplinary therapy in the form of surgery, chemotherapy, and radiotherapy has been the standard treatment for lung cancer, but targeted molecular therapy has recently greatly improved the clinical course for patients with non–small-cell lung cancer (NSCLC) having common driver mutations, such as those in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase genes.² However, despite advances in such therapies, the prognosis of NSCLC patients lacking driver mutations remains poor.³

Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death ligand (PD-L)-1 has recently been shown to improve prognoses in multiple types of cancers.4, 5 PD-1 is expressed on the surface of T cells and regulates their activity through interaction with its ligands PD-L1 and PD-L2 expressed on the surface of many cancers, including NSCLC. This interaction attenuates the T-cell activity, resulting in the downregulation of the immune response against cancer cells.4, 6, 7 Recently, PD-1 and PD-L1 inhibitors have been developed as anticancer therapy in several cancer types.8, 9 PD-1 inhibitors, such as nivolumab in the CheckMate study and pembrolizumab in the KEYNOTE study, exhibited a survival benefit compared with conventional standard therapy,10, 11, 12 and the treatment has become standard for NSCLC patients after the failure of first-line chemotherapy. The recent clinical trials, the POPLAR and OAK studies, showed that the representative PD-L1 inhibitor atezolizumab yielded significant survival benefits compared with standard therapy in NSCLC,13, 14 and could be used as standard treatment for NSCLC patients as an alternative to nivolumab and pembrolizumab. Moreover, the subset analyses of the studies revealed a close correlation between PD-L1 expression and atezolizumab efficacy.13, 14 It would therefore be useful to examine PD-L1 expression in patients undergoing immunotherapy with atezolizumab using the clone SP142 antibody from the POPLAR and OAK studies supplied by Ventana, Tucson, AZ.

In this translational study, we examined PD-L1 expression in surgically resected primary NSCLC including adenocarcinoma and squamous cell carcinoma using the clone SP142 antibody, and investigated the associations of PD-L1 expression with clinicopathological features and patient outcomes. We set the cutoff values as 1%, 5%, 10%, and 50% for PD-L1, and conducted further analyses using these cutoff values.