BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.

Importance Four assays have been registered with the FDA to detect PD-L1 to enrich for patient response to anti-PD-1/PD-L1 therapies. The tests use four separate PD-L1 antibodies on two separate staining platforms and have their own scoring systems which raises questions about their similarity and potential cross-utilization. Objective We compared the performance of four PD-L1 platforms, including two FDA-cleared assays and two laboratory developed tests (LDTs). Design Four serial histology sections from 90 archival NSCLCs were distributed to three sites that performed the following IHCs: 1) 28-8 antibody on Dako Link 48; 2) 22c3 antibody on Dako Link 48; 3) SP142 antibody on Ventana Benchmark; and 4) E1L3N antibody on Leica Bond. Slides were scanned and scored by thirteen pathologists by estimating the percentage of malignant and immune cells expressing PD-L1. Intraclass correlation coefficients (ICC) and paired and mixed effects statistical analyses were performed to compare antibodies and pathologists scoring of tumor and immune cells. Results The SP142 Ventana assay was an outlier with a significantly lower mean score of PD-L1 expression in both tumor and immune cells. Pairwise comparisons showed the 28-8 and E1L3N were not significantly different, but that 22c3 showed a slight but statistically significant reduction in tumor cell labeling. Evaluation of ICC between antibodies to quantify inter-assay variability using the average of thirteen pathologists scores for tumor shows very high concordance between antibodies for tumor cell scoring (0.813) and lower levels of concordance for immune cell scoring (0.277). When examining inter-pathologists variability for any single antibody, the concordance between pathologists’ reads for tumor ranged from ICC of 0.83 to 0.88 for each antibody while the ICC from immune cells for each antibody ranged from 0.17 to 0.23. Conclusions The assay using the SP142 antibody is a clear outlier detecting significantly less tumor cell and immune cell PD-L1 expression. Antibody 22c3 shows slight yet statistically significantly lower staining than either 28-8 or E1L3N, but this significance is only detected when using the average of thirteen pathologist scores. Pathologists show excellent concordance when scoring tumor cells stained with any antibody, but poor concordance for scoring immune cell staining.

Immunotherapies targeted against programmed death ligand 1 (PD-L1) and its receptor (PD-1) have improved survival in a subset of patients with advanced lung cancer. PD-L1 protein expression has emerged as a biomarker that predicts which patients are more likely to respond to immunotherapy. The understanding of PD-L1 as a biomarker is complicated by the history of use of different immunohistochemistry platforms with different PD-L1 antibodies, scoring systems, and positivity cut-offs for immunotherapy clinical trials with different anti-PD-L1 and anti-PD-1 drugs. Herein, we summarize the brief history of PD-L1 as a biomarker and describe the challenges remaining to harmonize PD-L1 detection and interpretation for best patient care.

The lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti–PD-1/PD-L1 monotherapy. Judicious dosing of antiangiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti–PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance the therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages in tumor and decreased TGFβ amounts in both tumor and serum. Combining low-dose apatinib with anti–PD-L1 significantly retarded tumor growth, reduced the number of metastases, and prolonged survival in mouse models. Anticancer activity was evident after coadministration of low-dose apatinib and anti–PD-1 in a small cohort of patients with pretreated advanced non–small cell lung cancer. Overall, our work shows the rationale for the treatment of lung cancer with a combination of PD-1/PD-L1 blockade and low-dose apatinib.