Immunoa??Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PDa??L1 Testing May Not Be Enough

摘要

Purpose. The treatment of patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas has been transformed by the U.S. Food and Drug Administration approval of pembrolizumab. Tumor and adjacent tissue must stain positively for the programmed cell death ligand 1 (PDa??L1) protein by companion diagnostic testing. However, some patients with PDa??L1a??negative tumors also benefit from pembrolizumab. High microsatellite instability (MSI) and tumor mutational load (TML) are positive predictive biomarkers for immune checkpoint inhibition (ICI) in other tumors. We sought to identify more patients who could benefit from ICI using alternative PDa??L1 thresholds, MSI, and TML. Methods. Tumor specimens underwent nexta??generation sequencing (NGS) and PDa??L1 testing using immunohistochemistry. NGS was used to determine TML and MSI. Results. We profiled 581 G/GEJ adenocarcinoma specimens. PDa??L1 staining was scored for intensity (0, none; 1+, weak; 2+, moderate; 3+, strong). Using 2+ staining at a 5% threshold, 9.3% of tumors were PDa??L1 positive, and using 1+ staining at 1%, 16.2% were PDa??L1 positive. 6.9% of tumors had high MSI. High TML (a?￥17 mutations per megabase) was seen in 6.9%, and medium TML (a?￥7) was seen in 56.5% of tumors. Thirty (5.2%) PDa??L1a??negative tumors at the 1+, 1% threshold had high TML or high MSI. Primary tumors had higher rates of high TML (8.8% vs. 3.9%; pa??=a??.0377) and high MSI (8.5% vs. 3.9%; pa??=a??.0471) than metastases. Conclusion. PDa??L1 testing alone fails to detect patients who may benefit from ICI. Lower PDa??L1 thresholds and TML testing should be considered in future clinical trials. Implications for Practice. Pembrolizumab is approved by the U.S. Food and Drug Administration for patients with refractory gastric and gastroesophageal cancers if the tumor and adjacent tissue stain positively for the programmed cell death ligand 1 (PDa??L1) protein by companion diagnostic testing. Tumor mutational load, microsatellite instability (MSI), and alternative PDa??L1 testing thresholds may serve as predictive biomarkers for response to immune checkpoint inhibition, and standard PDa??L1 testing will not identify all patients who may benefit from this therapy.