Neoadjuvant Immune Checkpoint Blockade in Upper Tract Urothelial Carcinoma - Expert Commentary

The definitive treatment for high-grade localized upper tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU). Neoadjuvant pembrolizumab was tested in patients with muscle-invasive bladder cancer before radical cystectomy and demonstrated promising efficacy in the PURE-01 trial. However, it is unclear if patients with UTUC will draw a similar benefit.

Necchi et al. recently published the findings of an exploratory cohort of patients with high-grade UTUC (PURE-02) treated with a similar protocol as PURE-01 in Urologic Oncology. A total of 10 patients were planned to receive pembrolizumab for three cycles before RNU. Nine patients completed the pembrolizumab courses, and one patient had grade 4 multiorgan immune-related adverse effects after a single dose of pembrolizumab.

One patient achieved a complete clinical response defined by multiparametric MRI and endoscopic evaluation. However, the patient refused to undergo RNU and followed up only for four months. Interestingly, this responder patient harbored a PBRM1 mutation, which was linked to a better response to immunotherapy in clear-cell renal-cell carcinoma.  Two patients had disease progression and needed subsequent chemotherapy before RNU.

This exploratory analysis highlights the unmet need to systematically test neoadjuvant immunotherapy in patients with UTUC, the risks and potential benefits of this approach, and the need for identifying predictive biomarkers for immune checkpoint blockade in patients with UTUC. 

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. Necchi A, Martini A, Raggi D, Cucchiara V, Colecchia M, Lucianò R, et al. A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02. Urol Oncol. 2021 Jun;doi.10.1016/j.urolonc.2021.05.014. PMID: 34147313
  2. Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Dec 1;36(34):3353–60. PMID: 30343614
  3. Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018 Feb 16;359(6377):801–6. PMID: 29301960

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