Predictive Biomarkers for Ramucirumab Response in Patients with Urothelial Cancer - Expert Commentary

The RANGE trial enrolled platinum-refractory urothelial cancer patients who were randomized to receive either the angiogenesis inhibitor ramucirumab and docetaxel or placebo and docetaxel. A recent study by van der Heijden et al. sought to identify predictive biomarkers for determining response to treatment with ramucirumab. Of the intention-to-treat 530 patients in the trial, 394 met assay criteria for gene expression profiling data, and 227 also met criteria for PD-L1 immunohistochemistry data.

The investigators found that a higher PD-L1 combined positive score (CPS) was associated with longer overall survival in the ramucirumab treatment group compared to the placebo group. mRNA expression data showed that tumors with higher PD-L1 expression showed higher scores for angiogenesis and immune signatures than tumors with lower PD-L1 expression (CPS ≥ 10 vs. CPS < 10, respectively). A high immune signature score was also associated with increases in overall survival among ramucirumab-treated patients.

Upon analysis of the mRNA data using molecular subtyping classifiers, there was an apparent association between basal tumors and CPS ≥ 10, while luminal tumors were more likely to have CPS < 10. Analysis by treatment revealed that the highest treatment benefit from ramucirumab was seen in basal tumors, and the least was seen in luminal tumors.

Interestingly, an adjusted multivariable analysis revealed significantly lower angiogenesis and immune signatures scores in East Asia compared to patients from other regions. This was observed across all molecular subtypes, suggesting ancestry-specific differences in the tumor microenvironment. These patients also did not show the same increase in overall survival upon ramucirumab treatment compared to patients in other regions. Analysis of Overall survival outcomes based on Decipher GSCv1 molecular subtype revealed that patients with basal type tumors had longer median OS with ramucirumab treatment compared to placebo (Basal, 10.48 vs. 7.75 months; Claudin Low, 8.48 vs. 5.65 months). This association between the Basal/Squamous subtype and shorter overall survival was consistent when using a TCGA 2017 classification. On the other hand, the luminal subtypes, which had the lowest overall mean angiogenesis and immune signature scores, showed the least treatment benefit.

This study illustrates the complex interactions in the tumor microenvironment that determine treatment response beyond PD-L1 expression, including angiogenesis, immune signature, and tumor molecular subtypes. It must be noted that some changes in molecular subtype and PD-L1 expression could be secondary treatment administered before clinical trial enrollment. Understanding the contributions of molecular subtypes and their cell type components to different classes of treatments is a priority for future research.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. van der Heijden MS, Powles T, Petrylak D, et al. Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial. Nat Commun. 2022;13(1):1878. Published 2022 Apr 6. doi:10.1038/s41467-022-29441-y

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