Locally advanced or metastatic urothelial carcinoma (mUC) is often treated with cisplatin-based chemotherapy as a standard first-line approach.1 2 However, many patients are cisplatin-ineligible, and carboplatin-based alternatives are associated with shorter overall survival (OS).3 Most patients eventually progress following platinum-based regimens.4 Evidence shows that non-treatment is common1 2 5 and 5-year survival rates in the USA have historically been low.6 Recently, checkpoint inhibitors have been approved in the USA, Europe, and elsewhere for patients with mUC who experience progression during or following platinum-based chemotherapy.7 8 Prior to atezolizumab’s US approval, and based on favorable data from earlier studies,9–11 an expanded access program (EAP) was conducted to grant access to this patient population. This EAP12 enrolled a broader range of patients than those who are typically enrolled in phase 1–3 clinical trials, providing an opportunity to better understand the role of atezolizumab in special populations.

In patients with mUC, baseline clinical characteristics or pre-existing comorbidities can limit treatment options and lead to treatment complications. One condition that is common to many patients with mUC is renal insufficiency (eg, creatinine clearance (CrCl) of <60 mL/min), which may be due to factors such as age, smoking-related vascular disease, urothelial carcinoma (UC)-related urinary tract obstruction,5 recent nephroureterectomy,13 and postcystectomy hydronephrosis.14Renal insufficiency can preclude first-line cisplatin administration5 or stem from treatment with cisplatin.15 Since renal function declines steadily after age 3016 and the median age at UC diagnosis in the USA is 72 years, significant decline in renal function is not uncommon among newly diagnosed patients,5 6 as demonstrated in a study of patients undergoing radical cystectomy, wherein >40% of patients older than 70 years had a CrCl of <60 mL/min.17 One meta-analysis with data from >5000 UC cases demonstrated a correlation between preoperative renal insufficiency and worse prognosis, underscoring the importance of renal function in developing an optimal treatment plan.18

Another consideration is that although the most common histological type of urinary tract cancers is UC, with bladder being the most common location (followed by renal pelvis, ureter, and urethra),19 UC with mixed histological features, including micropapillary, glandular, squamous, sarcomatoid, plasmacytoid, lymphoepithelioma like, and/or nested histology components, as defined by the WHO,19 is quite common. In cystectomy specimens, the incidence of UC with mixed variant histology (MVH; sometimes termed divergent differentiation) may reach 33%.19 Data suggested that some variants of pure non-UC (eg, small-cell and squamous bladder cancer) portend worse prognosis than UC and should be treated differently, but whether these results extend to all patients with MVH remains less well characterized.20 Although MVH appears to be associated with predictors of tumor aggressive behavior and adverse outcome in some studies, outcome data are limited,19 21 with occasional case reports suggesting that immunotherapy is active.22 In this analysis from the EAP study, we evaluated efficacy and safety outcomes with atezolizumab in patients with impaired baseline renal function or UC with MVH.

The availability of checkpoint inhibitors such as atezolizumab has greatly changed the treatment landscape for patients with UC, including those who progress on platinum-based chemotherapy for whom treatment options were previously limited to chemotherapy. However, there still exists an unmet need for patients with comorbidities or uncommon tumor features—who are often excluded, under-represented, or not comprehensively evaluated in clinical trials―resulting in limited outcomes data for these subsets. In particular, patients with renal insufficiency or non-UC histology may have worse prognoses than their counterparts.18 21 Following a protocol amendment, this EAP allowed for enrollment of patients irrespective of CrCl levels or the presence of renal disorders requiring dialysis or indications for renal transplant, permitting characterization of patients not eligible for the pivotal phase 2–3 IMvigor210 and IMvigor211 studies (atezolizumab in platinum-treated mUC). Furthermore, this EAP reported an 11% frequency (n=24) of treated patients with UC with MVH tumors.12 This post hoc analysis aimed to evaluate outcomes with checkpoint inhibitor therapy in these subsets of patients.

In this study, objective response occurred in patient subgroups with CrCl ranging from 30 to 60 mL/min. These observations are in agreement with data from both the cisplatin-ineligible and platinum-treated cohorts of the IMvigor210 trial, which reported objective responses to atezolizumab in patient subsets with baseline CrCl of 30–60 mL/min.3 10 SD also occurred in three of the six patients with CrCl of <30 mL/min, a subgroup not included in IMvigor210. These observations also agreed with data from the large, international phase 3b SAUL study (atezolizumab in mUC populations broader than/not eligible for IMvigor211), which found that patients with renal impairment (calculated CrCl <30 but ≥15 mL/min) generally demonstrated ORRs consistent with those of the overall population, and SAUL also demonstrated OS in line with that of previous pivotal UC trials.23 In this EAP, responses and SD also occurred in patients with UC with MVH. One patient with other MVH (UC with squamous/glandular differentiation) achieved a CR, and two of the four evaluable patients with UC with a squamous MVH component achieved SD. Furthermore, one of the two evaluable patients with UC mixed with an adenocarcinoma histology component had a PR, and additional instances of PR (n=2) and SD (n=1) in the remaining population were distributed among patients with other mixed histology components (figure 2). Similarly, in the SAUL study that enrolled patients with mixed or non-UC histology, objective responses, including a CR, were also observed.23

The safety of atezolizumab was comparable among the subgroups evaluated in this study. Across all evaluated CrCl subgroups, the frequency of TRAEs was generally comparable, overall ranging from 35% to 54%. Serious TRAEs occurred in two patients with CrCl of <30 mL/min (15%) and at rates of ≤8% in other subgroups. Renal TRAEs were infrequent, did not lead to discontinuation, and did not occur in patients with CrCl of <30 mL/min. These observations add to data from other studies, including the cisplatin-ineligible cohort of IMvigor210 (wherein atezolizumab was tolerable and did not result in decrease of median glomerular filtration rate in a patient cohort that mostly had renal impairment (30–60 mL/min))3 and renally impaired patients from SAUL (in whom safety was similar to that in the overall population).23 Also mirroring these safety results from SAUL,23 TRAEs in the histology subgroups of this EAP were similar, irrespective of histological features.

This study provides new information on outcomes with checkpoint inhibitor therapy in special populations of patients with mUC from an EAP, particularly those with CrCl of <30 mL/min, who have often been excluded from clinical trials. These results complement retrospective data from a recent multicenter analysis of patients with advanced solid tumors and baseline organ dysfunction (including renal) treated with anti-programmed death 1 checkpoint inhibitor therapy,24 which reported similar rates of immune-related AE frequencies as those in more general populations and encouraging efficacy, noting that such agents may be a feasible treatment for this challenging patient population. These data also echo recent results from a study on previously platinum-treated patients given the checkpoint inhibitor pembrolizumab, which reported OS benefit in favor of pembrolizumab over chemotherapy, notably for patients with MVH (although safety data were not reported by histological type).25 A limitation of this EAP study was its short duration, based on the timing of atezolizumab approval,12 which could affect characterization of both efficacy and safety results. Also, sample sizes in certain subsets were small; thus, current results need to be interpreted with caution, and further analyses in larger populations are warranted. Furthermore, minor differences in baseline characteristics between the subgroups (eg, ECOG PS, PD-L1 status) in this study were not controlled for. Still, these efficacy and safety results suggest that atezolizumab provides clinical benefit to a spectrum of patients with platinum-treated mUC, and these results were recently corroborated by findings in similar patient subgroups (eg, with MVH or renal insufficiency) in a more real-world-like population from the SAUL study.23

In this subgroup analysis from a US EAP of atezolizumab in patients with previously platinum-treated mUC, outcomes were evaluated by patient baseline renal function and histology. Efficacy and safety were demonstrated in patients with compromised renal function or UC with MVH. The results suggest that atezolizumab provides clinical benefit in a spectrum of patients with platinum-treated mUC.