Urothelial carcinoma (UC) represents the fourth most common malignancy worldwide, with an urgent need for tailored approaches in the management of the metastatic disease [1]. Depending on the level of muscle invasion seen on the pathological exam, UC is divided into muscle-invasive (MI) and non-muscle invasive (NMI) disease. MIUC of the bladder represents 25% of tumors [2] as compared to 60% in upper tract urothelial carcinoma (UTUC), explaining their increased aggressiveness [3,4,5,6]. The 5-year extravesical recurrence and overall survival rates are 28% and 23% for UTUC and bladder UC, respectively [7]. While bladder origin represents 90–95% of UCs, UTUC is less common. It represents 5–10% of UCs and can arise within the renal pelvis or ureter, which are derived from a different embryologic origin as compared to the bladder [1,8].

There is a strong relationship between UC of the bladder and UTUC since approximately 50% of patients with UTUC will have urinary bladder urothelial carcinomas either at presentation or subsequently, justifying the need to perform annual cystoscopy in the follow-up of these patients [1].

For high-risk localized disease, nephroureterectomy along with peri-operative chemotherapy is the standard of care management approach [1]. In the metastatic setting, platinum-based chemotherapy regimen remains the first-line recommended treatment [1]. However, there is a growing body of evidence concerning the use of immune checkpoint inhibitors (ICI) in the treatment of urothelial carcinoma [1,9] with the approval of several compounds in the first and second-line settings of advanced UCs. However, given their rarity, patients with UTUC represent a minority of patients included in clinical trials, and there is a paucity of data concerning ICI use in this setting.

UTUC has a different behavior as compared to bladder UC [10], and while molecular alterations of urothelial bladder carcinoma have been widely studied by The Cancer Genome Atlas, data about such alterations in UTUC remain scarce [4,11,12]. However, the novel molecular insights provided by these studies led to a better understanding of this aggressive disease and provided a rationale for new therapeutic approaches.

This review summarizes the available literature regarding the use of ICIs and the biological rationale underlying their use in high-grade urothelial upper tract carcinoma management.

In the adjuvant setting, ICI-based therapy has been widely tested since the role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery was not clear.

Since the first promising results of adjuvant pembrolizumab in the management of UC [59,60], several studies have now included UTUC patients in ICI-based adjuvant treatment (Table 1).

The IMvigor 010 study enrolled 809 high-risk UC patients to be randomized between adjuvant atezolizumab versus placebo. There were only 7% of UTUC patients in the atezolizumab arm as compared to 6% in the placebo arm (Table 1). There was no statistical difference in terms of median disease-free survival, 19.4 months (95% CI 15.9–24.8) with atezolizumab and 16.6 months (11.2–24.8) with observation (stratified hazard ratio 0.89 [95% CI 0.74–1.08]; p = 0.24) [61]. More recently, the data of the Checkmate 274 trial were reported. It was a phase 3 trial, including 709 patients randomized between adjuvant nivolumab versus placebo. A total of 21% of enrolled patients were patients with UTUC (Table 1). However, based on the results of the POUT trial, the inclusion of UTUC patients was prematurely interrupted. In the intention-to-treat population, median disease-free survival was 20.8 months (95% CI, 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo; (HR, 0.70; 98.22% CI, 0.55 to 0.90; p < 0.001). For the UTUC subgroup, the HR for disease recurrence or death were 1.23 (CI 95% 0.67–2.23) and 1.56 (CI 95% 0.7–3.48) for UTUC arising in renal pelvis and ureter, respectively. The percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; p < 0.001), for those expressing PD-L1 more than 1% [62]. Moreover, several neoadjuvant trials combining chemotherapy with ICI are actively recruiting, but available data are currently limited [63,64,65].

In the second or later line, atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab have been demonstrated safe and efficient in platinum pretreated UC population. However, UTUC patients’ data remained scarce (Table 2).