Nivolumab (OPDIVO) in combination with ipilimumab (YERVOY), developed by Bristol Myers Squibb, is being evaluated in the Phase III CheckMate-901 study for patients with previously untreated, unresectable, or metastatic urothelial carcinoma (mUC). The combination leverages dual immune checkpoint inhibition targeting the PD-1 and CTLA-4 pathways, with the goal of improving long-term disease control and survival outcomes in a patient population with historically limited treatment options and poor prognosis.

At the 2026 ASCO Annual Meeting, an exploratory biomarker analysis from CheckMate-901 identified distinct tumor and peripheral biomarker profiles associated with durable disease control in patients treated with nivolumab plus ipilimumab. Patients who achieved durable benefit (progression-free survival ≥8 months) exhibited significantly lower baseline levels of granulocyte count (GRANC), thyroid-stimulating hormone (TSH), neutrophil-to-lymphocyte ratio (NLR), and inflammatory biomarkers including alpha-1 antitrypsin (AAT), beta2-microglobulin (B2M), C-reactive protein (CRP), ferritin (FRTN), interleukin-2 receptor alpha (IL-2ra), interleukin-8 (IL-8), vascular cell adhesion molecule-1 (VCAM-1), and von Willebrand factor (vWF), along with higher hemoglobin (HB) levels compared with patients experiencing early progression (all p < 0.05).

The analysis included serum samples from approximately 300 patients treated with nivolumab plus ipilimumab and over 220 patients receiving gemcitabine-based chemotherapy. Tumor RNA sequencing further demonstrated significant differences in 8-gene epithelial-mesenchymal transition (EMT)/stroma core and 9-gene TGF-β activation signatures between patients achieving durable benefit and those with early progression (p < 0.05). Collectively, these findings suggest that lower systemic inflammation, favorable hematologic parameters, and distinct tumor microenvironment characteristics are associated with sustained responses to dual checkpoint inhibition. The results support the growing potential of biomarker-guided patient selection and personalized immunotherapy approaches in metastatic urothelial carcinoma.

KOL insights

“Despite some progress in recent years, metastatic urothelial carcinoma remains a difficult disease to address, with a limited number of treatment options that can extend patients’ lives.” –Expert Opinion

“OPDIVO plus YERVOY has demonstrated durable, long-term survival improvements in several challenging-to-treat advanced cancers, and we are disappointed that the final analysis of CheckMate -901 did not show this same benefit in urothelial carcinoma patients whose tumor cells express PD-L1 ≥1%. We remain committed to advancing research in urothelial carcinoma, we look forward to seeing data from other parts of the CheckMate -901 trial, and we thank all of the patients, investigators and site personnel involved.”–Expert Opinion

Conclusion

According to global epidemiological estimates, urothelial carcinoma remains one of the most common cancers of the urinary tract, with a significant proportion of patients progressing to locally advanced or metastatic disease. Despite recent therapeutic advances, metastatic urothelial carcinoma continues to be associated with high morbidity and mortality, creating a substantial need for more effective and durable treatment options. The treatment landscape has evolved rapidly with the introduction of immune checkpoint inhibitors, antibody-drug conjugates (ADCs), and targeted therapies, intensifying competition among leading agents such as nivolumab plus ipilimumab (OPDIVO + YERVOY), pembrolizumab (KEYTRUDA), enfortumab vedotin plus pembrolizumab (PADCEV + KEYTRUDA), sacituzumab govitecan (TRODELVY), disitamab vedotin (AIDIXI/RC48), and erdafitinib (BALVERSA).

The biomarker analysis from the CheckMate-901 study highlights the potential of nivolumab plus ipilimumab to deliver durable disease control in a subset of patients with metastatic urothelial carcinoma. Distinct clinical, inflammatory, and tumor microenvironment biomarker profiles were associated with long-term benefit, suggesting that biomarker-driven patient selection may become increasingly important as competition grows among immunotherapy- and ADC-based regimens. As frontline treatment paradigms continue to shift toward more personalized approaches, the ability to identify patients most likely to derive sustained benefit from dual checkpoint blockade could provide a meaningful competitive advantage. If prospectively validated, these findings may help refine treatment algorithms, improve patient outcomes, and further strengthen the position of nivolumab plus ipilimumab within the evolving urothelial carcinoma market.