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

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 .