Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression

Jun Miyakoshi ¹, Tatsuya Yoshida ², Jumpei Kashima ³

¹Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Respiratory Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-0856, Japan; Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
²Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
³Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁴Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁶Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁷Department of Respiratory Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-0856, Japan.

⁰Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Respiratory Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-0856, Japan; Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Lung Cancer (Amsterdam, Netherlands) +

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April 9, 2024

View abstract on PubMed

Summary

Inter-assay discrepancies in programmed cell death ligand-1 (PD-L1) testing for non-small cell lung cancer (NSCLC) indicate primary resistance to pembrolizumab. This finding highlights the clinical significance of PD-L1 assay variations in advanced NSCLC.

Area Of Science

Oncology
Immunology
Molecular Biology

Background

Programmed cell death ligand-1 (PD-L1) expression is a key biomarker for predicting response to anti-PD-1/PD-L1 therapies in advanced non-small cell lung cancer (NSCLC).
Multiple assays exist for PD-L1 evaluation, but observed inter-assay discordance raises questions about their clinical implications.

Purpose Of The Study

To investigate the clinical significance of inter-assay discrepancies in PD-L1 expression between the 22C3 and SP142 assays in NSCLC patients.
To explore the underlying molecular mechanisms, including distinct immune profiles and CD274 splice variants, associated with these discrepancies.

Main Methods

Retrospective review of treatment-naïve NSCLC patients with PD-L1 evaluated by both 22C3 and SP142 assays.
Efficacy analysis of first-line pembrolizumab monotherapy in patients with PD-L1 tumor proportion score (TPS) ≥50% (22C3 assay).
Transcriptome analysis of tumors with high PD-L1 expression (TPS ≥50%) to identify molecular differences.

Main Results

Among 198 patients with PD-L1 TPS ≥50% (22C3), 91 (46%) showed discordance (SP142 tumor cell score ≤1).
In 52 patients receiving first-line pembrolizumab, those with inter-assay discrepancy had significantly lower objective response rates (18% vs. 83%) and shorter progression-free survival (3.2 vs. 8.3 months).
Transcriptome analysis revealed increased CD274 splice variants with aberrant 3'-terminal sequences in tumors with inter-assay discrepancy.

Conclusions

Inter-assay discrepancy in PD-L1 tumor cell status between 22C3 and SP142 assays, linked to CD274 splice variant imbalance, may serve as a biomarker for primary resistance to pembrolizumab monotherapy.
This finding underscores the importance of considering assay-specific PD-L1 expression and potential molecular alterations in advanced NSCLC treatment decisions.

Keywords:

22C3 PD-L1 Pembrolizumab SP142 Splice variants