Analyses of PD-L1 and Inflammatory Gene Expression Association with Efficacy of Nivolumab ± Ipilimumab in Gastric Cancer/Gastroesophageal Junction Cancer

Abstract

In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors. Experimental Design:In post-hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO±IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1-staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression.Results: There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1-positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent %TC cutoffs. Longer survival was demonstrated in patients with PD-L1-positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1-negative status.Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg (NIVO1+IPI3) subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of 4 genes (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO±IPI.Research.

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743

“…As previously reported, the 4gene inflammatory signature score measured expression of CD8A, STAT1, LAG3, and CD274 (PD-L1). [17][18][19] Analysis of the 4-gene inflammatory signature was performed via RNA sequencing of baseline formalin-fixed, paraffin-embedded tumor samples, and z-scores were calculated using log-transformed counts per million. High or low scores were ranked relative to the median z-score value across the dataset.…”

Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score

“…In studies of gastroesophageal adenocarcinoma, raising the CPS cut-off from 1 to 5 or 10 maximized the therapeutic index of immunotherapy. 20,21 This concept of biomarker-based enrichment was prospectively validated by the CheckMate 649 trial, which met its primary endpoint of OS prolongation in the primary population of adenocarcinoma patients with CPS !5. 22 We suggest that future trials of immunotherapy for ESCC patients are enriched in the same way to refine the molecular selection of the optimal candidates for immunotherapy.…”

Stemness-related LncRNA pair signature for predicting therapy response in gastric cancer

“…The efficacy and accuracy of the CPS has actually not been well elucidated [ 33 ]. Recently, an inflammatory gene signature was tested for its efficacy to predict the treatment response of ICB treatments for gastric cancer [ 34 ]. Considering that the criteria were established based on objective indexes, the detection stability may be better compared with the CPS.…”