Association of a novel 27-gene immuno-oncology assay with efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer

Abstract

Background Immune checkpoint inhibitor (ICI) therapies represent a major advance in treating a variety of advanced-stage malignancies. Nevertheless, only a subset of patients benefit, even when selected based on approved biomarkers such as PD-L1 and tumor mutational burden. New biomarkers are needed to maximize the therapeutic ratio of these therapies. Methods In this retrospective cohort, we assessed a 27-gene RT-qPCR immuno-oncology (IO) gene expression assay of the tumor immune microenvironment and determined its association with the efficacy of ICI therapy in 67 advanced-stage NSCLC patients. The 27-gene IO test score (IO score), programmed cell death ligand 1 immunohistochemistry tumor proportion score (PD-L1 TPS), and tumor mutational burden (TMB) were analyzed as continuous variables for response and as binary variables for one-year progression free survival. The threshold for the IO score was prospectively set based upon a previously described training cohort. Prognostic implications of the IO score were evaluated in a separate cohort of 104 advanced-stage NSCLC patients from The Cancer Genome Atlas (TCGA) who received non-ICI therapy. Results The IO score was significantly different between responders or non-responders (p = 0.007) and associated with progression-free survival (p = 0.001). Bivariate analysis established that the IO score was independent of PD-L1 TPS and TMB in identifying patients benefiting from ICI therapy. In a separate cohort of late-stage NSCLC patients from TCGA, the IO score was not prognostic of outcome from non-ICI-treated patients. Conclusions This study is the first application of this 27-gene IO RT-qPCR assay in a clinical cohort with outcome data. IO scores were significantly associated with response to ICI therapy and prolonged progression-free survival. Together, these data suggest the IO score should be further studied to define its role in informing clinical decision-making for ICI treatment in NSCLC.

The 27-gene IO score is associated with efficacy of PD-1/L1 inhibitors independent of FGFR expression in a real-world metastatic urothelial carcinoma cohort

“…Using data from a real-world UNC-108 cohort, the results confirmed the findings of the IMvigor210 study that the IO score is associated with the efficacy of ICI therapy in mUC [18]. Furthermore, this was accomplished using the same binary classification threshold used in all previous studies, and this study will discuss the potential of an evidence-based likelihood of response assessment to inform therapeutic sequencing in the treatment of advanced mUC [15][16][17][18][19][20][21].…”

“…The IO score classifies cases as positive or negative based on their correlation to established gene expression centroids for immunomodulatory, mesenchymal, and mesenchymal stem-like subtypes [23]. The classification threshold was previously established in breast and lung cancers and validated as a classifier for mUC using TCGA and IMvigor210 datasets [15][16][17][18][19]. To assess data for the UNC-108 cohort, RNA expression analysis was used to determine the IO score of patients with available data downloaded from GSE176307 using the requisite 27-genes as previously described (ITM2A gene missing, Cohen's κ = 0.99 from TCGA-BLCA (RRID:SCR_003193; Project: Bladder Urothelial Carcinoma, Table S1).…”

“…The 27-gene immuno-oncology classifier (IO score) quantifies gene expression to classify the TIME and uses an algorithm that combines results into a continuous score with a pre-specified binary IO positive (IO +) or IO negative (IO− ) classification to predict response to immune therapy [15]. The IO score classification has demonstrated an association with ICI efficacy in multiple tumor types including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), and urothelial carcinoma (UC) [15][16][17][18][19][20][21]. Using data from a real-world UNC-108 cohort, the results confirmed the findings of the IMvigor210 study that the IO score is associated with the efficacy of ICI therapy in mUC [18].…”

Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients

“…An ideal biomarker for predicting ICI benefit would perform well across many tumor types and treatment indications, would be independent of clinicopathologic features, and would improve on currently established biomarkers. The IO Score has been previously shown to be associated with improved response to ICI therapy in NSCLC and TNBC [ 11 – 15 ]. Consistent with the hypothesis that the IO Score classifies three components of the TIME that are common to tumors of epithelial origin, IM, MSL (linked with the expression of cancer associated fibroblasts) and M, we tested whether the IO Score would be applicable to classification of bladder cancer.…”

“…The IO Score has been validated as a biomarker that identifies patients likely to benefit from ICIs in TNBC and NSCLC [11][12][13][14][15]. These studies were conducted across tumor types using the same threshold of positivity for IO Score.…”