Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced...

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.