Dual Immune Checkpoint Blockade in Metastatic Non-Urothelial Cancer of the Urinary Tract - Expert Commentary

Non-urothelial histologic variants of bladder cancer (non-UC), including adenocarcinoma, squamous cell carcinoma (SCC), and neuroendocrine (NE) tumors, are rare, aggressive cancers. The genomic landscape of these tumors is heterogeneous, making a tailored therapy approach challenging. It is unclear if combined ICB of PD-L1 and CTLA-4 pathways will be effective in non-UC variants.

A recently published phase 2 clinical trial by Sarfaty et al. in Cancer Medicine investigated the efficacy of dual ICB by durvalumab, an anti-programmed death ligand (PDL1) antibody, and tremelimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody. Eligible patients had metastatic urinary tract non-UC variants regardless of prior therapy. The study included seven bladder NE (54%), three bladder SCC (23%), and three ADC (23%, two urachal ADC and one primary bladder ADC).  

The trial showed no objective response, with 11 of 14 (85%) enrolled patients having disease progression, 2 (15%) had stable disease. One patient with an NE tumor showed mixed response who developed brain metastasis but achieved stable extracranial disease on therapy for 13 months. There were no concerning safety signals observed with combination therapy.

The trial shed light on the genomic complexity of these heterogeneous variants. Using MSK-IMPACT gene panel to sequence eight tumors, all showed microsatellite stability, and the most frequent somatic alterations identified were TP53 (100%), RB1, and TERT (both 62%). TP53 and RB1 were co-altered in all four neuroendocrine variant tumors. The median TMB was 7.9 mutations/Mb (range 3.5–13.2 mutations/Mb). The patient with NE tumor who achieved extracranial stable disease had the highest TMB (13.2 mutations/Mb) but was microsatellite stable and PD-L1 negative.  

Other ICB agents have been explored in rare genitourinary cancers, including non-UC variants. For example, the combination of nivolumab and ipilimumab showed a promising objective response rate of 37% in a recently published phase II trial. Several clinical trials are currently recruiting to investigate the role of ICB further.  Combining data reported by Sarfaty et al., together with genomic profiles from similar ICB trials, will improve our understanding of the biology of these rare non-UC tumors.

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. Sarfaty M, Whiting K, Teo MY, Lee CH, Peters V, Durocher J, et al. A phase II trial of durvalumab and tremelimumab in metastatic, non-urothelial carcinoma of the urinary tract. Cancer Med. 2020;(September):1–10. doi:10.1002/cam4.3699. PMID: 33382520.
  2. McGregor BA, Campbell MT, Xie W, Farah S, Bilen MA, Schmidt AL, et al. Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies. Cancer. 2020 Nov 20;doi.10.1002/cncr.33328. PMID: 33216356

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