Association of RNA-based immune gene expression with immunotherapy duration in advanced non–small cell lung cancer.

Abstract

e20538 Background: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is commonly used to guide immunotherapy selection in advanced non–small cell lung cancer (NSCLC); however, its ability to consistently reflect tumor immune biology and treatment benefit remains limited. RNA-based immune gene expression profiling provides a complementary approach to characterize the tumor immune microenvironment using formalin-fixed paraffin-embedded specimens. We evaluated associations between RNA-based immune gene expression and duration of immunotherapy (IO) in advanced NSCLC. Methods: This retrospective biomarker study included patients with stage IV, non– EGFR , non– ALK NSCLC treated with immune checkpoint inhibitors. Tumor RNA expression profiling was performed using a multiplex, amplification-free gene expression assay quantifying 204 genes. Gene expression was analyzed as categorical variables (high expression defined as log 2 ≥1) and as continuous measures. The primary endpoint was duration of IO, defined as time from initiation of IO until progression of disease as documented by treating physician, initiation of alternative therapy, or death. Overall survival (OS) was evaluated as an exploratory secondary endpoint. Associations were assessed using univariate duration analyses, Kaplan–Meier methods, and Cox proportional hazards models. All tests were two-sided, and p<0.05 was considered significant. Analyses were exploratory and hypothesis-generating. Results: Sixty-one patients were included. Median duration of IO was 108 days (range, 7–2006). PD-L1 IHC categories (<1%, 1–49%, ≥50%) were not associated with IO duration (log-rank p=0.538). In contrast, multiple RNA-based tumor immune gene expression markers were significantly associated with duration of IO in Cox models (Table). Higher dichotomized (categorical) expressions of CDK6 , ERBB3 , MDM2 , PCSK9 , and STK11 were associated with shorter IO duration, whereas STK11 mutation status was not associated with IO duration. Of these genes, high CDK6 and PCSK9 expressions were also associated with worse OS. Conclusions: RNA expression profiling identified multiple biomarkers associated with IO duration and, for select genes, OS that were not captured by PD-L1 IHC or DNA-based mutation status. These findings suggest RNA-based assays may provide complementary biologic correlates of IO benefit in advanced NSCLC and warrant prospective validation. RNA Biomarker IO duration Hazard Ratio HR (95% CI) p Value OS HR p Value CDK6 3.25 (1.24-8.50) 0.017 28.86 (7.31-114.02) <0.001 ERBB3 2.19 (1.12-4.27) 0.022 0.70 (0.27-1.83) 0.767 MDM2 2.10 (1.08-4.08) 0.030 1.78 (0.79-4.01) 0.166 PCSK9 2.67 (1.16-6.13 0.021 3.64 (1.44-9.16) 0.006 STK11 2.57 (1.08 -6.12) 0.033 1.16 (0.40-3.33) 0.787