A three-gene expression score for predicting clinical benefit to anti-PD-1 blockade in advanced renal cell carcinoma

AbstractBackgroundIn the advanced renal cell carcinoma (RCC) scenario there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade. We conducted a retrospective study in order to develop and to validate a gene expression score for predicting clinical benefit to nivolumab in the advanced clear cell RCC setting and to characterize its underlying clinical, molecular, and immune features.MethodsThis is apost hocpooled analysis of 311 patients with available clinical, molecular, and immune tumor data from the CheckMate-009, -010 and -025 trials. Efficacy endpoints were overall survival (OS), disease control rate, and overall response rate. Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control and response were tested with logistic regression. Biomarker-treatment interaction was evaluated with the likelihood ratio test (LRT).ResultsFirst, a three-gene expression score (3GES) with prognostic value for OS integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Favorable 3GES risk category was significantly associated with a better OS in univariable (HR = 0.32, 95% CI 0.21 - 0.48,P<0.001) and multivariable (HR = 0.36, 95% CI 0.24 - 0.56,P<0.001) analyses. Consistent and significant correlation was found with disease control (P=0.066) and response (P=0.002). The 3GES prognostic value was validated in the TCGA-KIRC cohort (HR=0.35,P<0.001). Next, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 trial (LRTP<0.001).ConclusionsIn accRCC, 3GES is not only an independent prognostic factor for OS but also a positive predictive biomarker for nivolumab. The predictive value deserves further validation in other retrospective and large-scale, randomized prospective studies.