What question did this study set out to answer?

This analysis aims to identify biomarkers that indicate which patients benefit from nivolumab plus ipilimumab in metastatic urothelial carcinoma.

May 29, 2026

CheckMate-901: Association of tumor and peripheral biomarker profiles with durable disease control in metastatic urothelial carcinoma treated with nivolumab plus ipilimumab.

Key Points

This analysis aims to identify biomarkers that indicate which patients benefit from nivolumab plus ipilimumab in metastatic urothelial carcinoma.
Conducted an exploratory analysis of serum samples from CheckMate 901 trial participants.
Compared clinical variables and cytokine/protein biomarker levels between patients with durable benefit and early progression.
Performed RNA-seq analysis for gene signature comparisons.
Patients achieving durable benefit showed significantly lower levels of granulocyte count, TSH, and NLR, and higher hemoglobin.
Cytokine/protein biomarkers were lower in durable benefit patients compared to early progressors.
RNA-seq revealed significant differences in tumor gene expression related to epithelial-mesenchymal transition and TGFβ activation.

Abstract

4525 Background: Patients (pts) with untreated, unresectable, or metastatic urothelial carcinoma (mUC) have limited therapeutic options and poor prognosis. The phase 3, global, open-label, randomized CheckMate 901 trial compared nivolumab plus ipilimumab (NIVO+IPI) vs gemcitabine–carboplatin/gemcitabine–cisplatin (gem–carbo/gem–cis) with previously untreated unresectable or mUC. A subset of pts treated with NIVO+IPI experienced durable disease control. This exploratory analysis seeks to identify biomarkers that might characterize pts deriving particular benefit from NIVO+IPI. Methods: Serum samples from CheckMate 901 (NIVO+IPI, n = 288–300; gem–carbo/gem–cis, n = 222–236) underwent multiplex analysis at Myriad RBM using Luminex and Simoa technology. Pts were stratified by progression-free survival (<8 months early progressor; EP vs ≥8 months durable benefit; DB), and clinical laboratory variables (granulocyte count GRANC, hemoglobin HB, thyroid-stimulating hormone TSH, neutrophil-lymphocyte ratio NLR) and cytokine/protein biomarkers (alpha-1 antitrypsin AAT, beta2-microglobulin B2M, C-reactive protein CRP, ferritin FRTN, interleukin IL-2 receptor alpha IL-2ra, IL-8, vascular cell adhesion molecule-1 VCAM-1, and von Willebrand factor vWF) were compared in EP vs DB pts. In addition, tumor RNA-seq was used for gene signature analysis (NIVO+IPI, n = 134; gem–carbo/gem–cis, n = 117), including 8-gene epithelial–mesenchymal transition (EMT)/stroma core, 9-gene transforming growth factor beta (TGFβ) activation, 13-gene high-risk TGFβ, and cluster of differentiation 4 (CD4). Results: Distinct biomarker patterns emerged between EP and DB pts. Pts achieving DB vs EP with NIVO+IPI exhibited significantly lower levels of GRANC, TSH, and NLR, and higher HB (all P < 0.05). Similarly, levels of proteins AAT, B2M, CRP, FRTN, IL-2ra, IL-8, VCAM-1, and vWF were significantly lower in NIVO+IPI-treated pts achieving DB vs EP (all P < 0.05). RNA-seq analysis showed significant differences between NIVO+IPI-treated pts achieving DB vs EP for 8 EMT/stroma core and 9 TGFβ activation ( P < 0.05). Conclusions: In untreated, unresectable, or mUC, distinct clinical and cytokine/protein biomarker profiles were associated with DB vs EP with NIVO+IPI therapy. Pts with EP exhibit features in the tumor microenvironment and circulation suggestive of tumor-promoting inflammation, several of which have been linked to resistance to immune checkpoint blockade in prior analyses. These findings underscore the heterogeneity of mUC and the potential of routinely measured circulating analytes for risk stratification and treatment decisions. Prospective studies should confirm their clinical applicability. Clinical trial information: NCT03036098 .

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