The role of switch maintenance therapy in urothelial cancers

Abstract

Maintenance therapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm of metastatic urothelial carcinoma (mUC). The JAVELIN Bladder 100 trial established avelumab, one of several ICIs in use today, as a life-prolonging maintenance therapy for patients with advanced urothelial carcinoma. Platinum-based chemotherapy is most often used in the first-line treatment of mUC, and while response rates approach about 50%, disease control is usually short-lived upon completion of the standard three to six cycles of chemotherapy. Much progress has been made in recent years in the second-line space and beyond with the use of ICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) in eligible patients at the time of disease progression post-platinum-based chemotherapy. However, many patients with progressive mUC after first-line chemotherapy suffer from rapid progression of disease, treatment toxicity with subsequent lines of therapy, and a limited life expectancy. Until the results of the JAVELIN Bladder 100 trial were presented in 2020, there were no maintenance strategies proven to be beneficial over best supportive care after disease control is achieved with first-line platinum-based chemotherapy. To date, standard of care frontline treatment of metastatic urothelial cancer remains to be four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. This review summarizes the current evidence available on maintenance therapies in mUC, as well as several highly anticipated clinical trials that we hope will result in further progress in the management of this aggressive cancer and improve patient outcomes.

Introduction

Urothelial cancer encompasses cancers arising from the renal calyces, renal pelvis, ureters, bladder, and urethra as these surfaces all have the same embryologic origin.¹ The most common site of origin for urothelial carcinomas (UCs) is the urinary bladder. Worldwide, bladder cancer results in over 160,000 deaths and is the fourth most common cancer in the United States accounting for approximately 80,000 new cases and 17,000 deaths each year.² There is a male predominance for urothelial cancer of the bladder. Most bladder cancers are superficial or non-muscle-invasive, at diagnosis with approximately 25% of cases presenting with invasion of the muscularis propria.

The diagnosis of metastatic urothelial carcinoma (mUC) of the bladder portends a poor prognosis. First-line treatment options for mUC include chemotherapy with gemcitabine and cisplatin (GC) or methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) which can also be given in a dose-dense fashion (ddMVAC). When GC and MVAC were compared with each other in a multicenter phase III non-inferiority trial, there was no significant difference in median overall survival (OS) or time to progression but GC had a significantly better toxicity profile.³ However, responses to chemotherapy are rarely durable. Therefore, efforts to maintain good responses to chemotherapy have been a topic of intense investigation in the field of urothelial cancer. Prior to the approval of avelumab as a switch maintenance strategy, mUC patients with disease control following completion of first-line chemotherapy with GC or MVAC were typically observed and moved onto next-line therapy at the time of disease progression. Although disease control is achieved in 75–80% of patients after first-line chemotherapy, progression typically occurs with 1 year of treatment and median OS is limited to 9–15 months.^{4 –6} For those who are cisplatin-ineligible, substitution with carboplatin is acceptable in the metastatic setting when treatment is not curative in intent. For those who are not considered eligible for platinum-based chemotherapy, first-line atezolizumab (a programmed cell death ligand, PD-L1, inhibitor) and pembrolizumab (a programmed cell death protein 1, PD-1, inhibitor) are Food and Drug Administration (FDA)-approved options based on the results of the IMvigor210 and KEYNOTE-052 trials, respectively.^7,8 In the first-line setting for the palliative treatment of mUC, immune checkpoint inhibitor (ICI) therapy is continued indefinitely until the development of disease progression or unacceptable toxicity, in contrast to chemotherapy which is usually stopped after a defined number of cycles. The addition of pembrolizumab to platinum-based chemotherapy was studied in the KEYNOTE-361 trial, but there was no improvement in progression-free survival (PFS) or OS with the addition of pembrolizumab compared with chemotherapy alone.⁹ Similarly, dual checkpoint inhibitor use has not been found to be superior to chemotherapy in those whose tumor cells express PD-L1 ⩾1% as seen in the CheckMate-901 trial, a phase III study comparing nivolumab plus ipilimumab versus platinum-based chemotherapy versus nivolumab in combination with cisplatin-based chemotherapy in patients with untreated mUC.¹⁰

ICIs have also been explored in the second-line setting for disease progression during or after platinum-based chemotherapy. In KEYNOTE-045, investigators’ choice of single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine) was compared with pembrolizumab in patients who relapsed or progressed after platinum-based chemotherapy.¹¹ Pembrolizumab significantly improved OS compared with single-agent chemotherapy in this setting. Based on the efficacy of ICI monotherapy in the treatment of mUC, it was logical to study their potential as a maintenance strategy prior to the inevitable development of relapse and disease progression after platinum-based chemotherapy in the first-line setting. Herein, we discuss the evolution of switch maintenance therapy in advanced UC leading up to the results of the JAVELIN Bladder 100 trial which brought forth the routine use of avelumab as a maintenance strategy. Future maintenance trials include those that will study the addition of other oncolytics to avelumab.

Methods

The relevant studies pertaining to maintenance therapy in mUC were identified utilizing a PubMed search, ResearchGate, and the 2022 American Society of Clinical Oncology Annual meeting proceedings. The MeSH terms used were ‘metastatic urothelial carcinoma’ or ‘metastatic urothelial cancer’ or ‘advanced urothelial carcinoma’ and ‘maintenance therapy’ or ‘maintenance treatment’ or ‘switch maintenance therapy’ or ‘switch maintenance treatment’. No limitations were applied for search period. A total of 224 original articles were obtained from database search. Irrelevant studies, non-English articles, and duplicates were excluded during the initial screening process. Two studies were excluded due to other reasons including unavailability of the complete article and use of sequential maintenance therapy alternating with induction chemotherapy.^12,13 Eight relevant phase II or III randomized controlled clinical trials were ultimately selected for discussion in this current review article.

Switch maintenance therapy in the pre-ICI era

Treatment with platinum-based chemotherapy followed by active surveillance until disease progression has remained the standard of care for at least 3 decades in patients with locally advanced or metastatic urothelial cancer.^6,14,15 Although UC is a chemotherapy-sensitive disease with response rates ranging between 40% and 50% with first-line platinum-based regimens, responses are oftentimes not durable. PFS is limited to 6–8 months, and the median OS ranges from 9 to 15 months.^14,16

The role of maintenance therapy has been well established in other solid tumors including lung, breast, ovarian, and gastrointestinal cancers.^{17 –23} Three types of treatment strategies after initial induction therapy have been reported in the literature. Continuation maintenance refers to the continuation of a single or multiple agent(s) given as a part of an initial induction regimen. Consolidation therapy refers to an intensification treatment protocol given to enhance tumor cell kill following a fixed number of cycles of an initial treatment or chemotherapy regimen. Switch maintenance therapy refers to sequential treatment with a new agent with a different mechanism of action and less toxic drug to maintain disease control after a fixed duration of initial systemic therapy.²⁴ The risk of cumulative toxicity from long-term, indefinite chemotherapy, immunogenic effects of chemotherapy, and immunogenic characteristics of UC drove the study of switch maintenance immunotherapy in advanced UC.^{24 –27} Several classes of drugs including chemotherapy, targeted therapy, and immunotherapy have been evaluated as switch maintenance strategies in metastatic urothelial cancer.

In 2009, vinflunine, a vinca alkaloid which works by inhibiting microtubule polymerization was approved by the European Medicines agency (EMA) in the second-line setting for the treatment of advanced UC after demonstrating a PFS benefit in a phase III trial.²⁸ A phase II randomized, placebo-controlled, multicenter trial (MAJA, SOGUG 2011-02) investigated vinflunine as a switch maintenance strategy in mUC.²⁹ In this trial, 88 patients with mUC who achieved disease control after receiving four to six cycles of platinum-based chemotherapy were randomized 1:1 to receive vinflunine 280 or 320 mg/m² every 3 weeks plus best supportive care (BSC) or BSC only until disease progression. Median PFS was the primary endpoint for this trial. OS, objective response (OR), median duration of disease control, and safety were evaluated as secondary endpoints. Median PFS was 6.5 months (range, 2.0–11.1 months) in the vinflunine + BSC arm compared with 4.2 months (range, 2.1–6.3 months) in the BSC only arm [hazard ratio (HR) = 0.59, 95% confidence interval (CI) = 0.37–0.96, p = 0.03]. Grade 3 or 4 adverse events including neutropenia, constipation, and fatigue were higher in the vinflunine arm. However, the final OS analysis failed to show a survival benefit due to insufficient power.³⁰ A small, international phase II trial (JASiMA) evaluated the response rate in 20 patients who received vinflunine maintenance therapy after platinum-based chemotherapy. This study demonstrated intensified response in 28% of patients.³¹

Another phase II, double-blinded, randomized trial by Grivas et al.³² evaluated sunitinib, an oral multitargeted tyrosine kinase inhibitor (TKI), as a switch maintenance therapy in patients with advanced UC. A total of 50 patients who had stable disease (SD), partial response (PR), or complete response (CR) after four to six cycles of standard first-line chemotherapy were randomized to receive sunitinib or placebo. Patients in the sunitinib arm had higher rates of adverse events, including grade 3–4 thrombocytopenia, diarrhea, fatigue, and hypertension. The study did not meet its primary endpoint and was terminated early due to slow accrual.³²

Given the high rate (37–50%) of human epidermal growth factor receptor 2 (HER2) expression in urothelial cancers, lapatinib, a dual HER1/HER2 TKI, was studied as a switch maintenance therapy for advanced or mUC. In a phase III, randomized controlled, double-blinded trial, a total of 232 HER1 or HER2-positive advanced UC patients who attained disease control after receiving four to eight cycles of first-line chemotherapy were randomized 1:1 to receive lapatinib or placebo. Unfortunately, this trial failed to show statistically significant improvement in the median PFS or OS in lapatinib over placebo.³³

More recently, the phase II ATLANTIS trial which evaluated maintenance cabozantinib following chemotherapy demonstrated no significant benefit compared with placebo.³⁴ This trial included only 61 patients, including 30 patients randomized to receive cabozantinib and 31 to receive placebo. The median PFS was 13.7 weeks with maintenance cabozantinib versus 15.8 weeks with placebo (adjusted HR of 0.89 favoring cabozantinib, p = 0.35). In addition, OS was not significantly different with median OS of 75.5 weeks with cabozantinib compared with 82.9 weeks in the placebo group, HR: 0.8 (80% CI = 0.52–1.3), p = 0.25. Table 1 summarizes key maintenance therapy trials in UC to date, which are predominantly negative studies except for those that utilized ICIs.

Table 1.

Resulted maintenance therapy trials in advanced urothelial carcinoma.

Study	Author	Year	Phase	Intervention	N	PFS (months)	OS (months)
CALGB 90102	Phillips et al.63	2009	2	Gefitinib maintenance following CG + gefitinib	58	7.4	15.1
NCT00393796	Grivas et al.32	2014	2	Sunitinib versus placebo	54	2.9 versus 2.7	10.5 versus 10.3
JASiMA	De Wit et al.31	2015	2	Vinflunine	20	8.2	NA
NCT00949455	Powles et al.33	2016	3	Lapatinib versus placebo	232	4.5 versus 5.1	12.6 versus 12
MAJA	García-Donas et al.29	2017	2	Vinflunine versus BSC	88	6.5 versus 4.2	16.7 versus 13.2
ATLANTIS	Jones et al.34	2022	2	Cabozantinib versus placebo	61	3.425 versus 3.95	18.8 versus 20.7
JAVELIN 100	Powles et al.47	2020	3	Avelumab + BSC versus BSC	700	3.7 versus 2	21.4 versus 14.3
HCRN GU14-182	Galsky et al.53	2020	2	Pembrolizumab versus placebo	108	5.4 versus 3	22 versus 18.7

BSC, best supportive care; CG, cisplatin + gemcitabine; NA, not available; PFS, progression-free survival; OS, overall survival.

Switch maintenance with the use of immunotherapy

While there was a dormant period for several years in the mUC treatment landscape, the accelerated approval of five ICIs (pembrolizumab, durvalumab, atezolizumab, avelumab, and nivolumab) by the FDA in the United States based on several positive phase I/II trials in the last 6 years led to the initial use of these agents in the treatment of mUC that progressed during or after platinum-based chemotherapy.^{11,35 –38} All five of these ICI agents demonstrated clinically significant survival benefits with favorable safety outcomes in the second-line setting compared with investigators’ choice of chemotherapy.^{11,35 –38} However, the accelerated approvals for durvalumab and atezolizumab were voluntarily withdrawn by their respective pharmaceutical companies in the United States as they failed to meet primary endpoints in subsequent confirmatory phase III trials.^39,40 It is worthwhile to take into consideration that only a small proportion of patients who develop disease progression during or after first-line chemotherapy remain fit to receive second-line therapy because of rapid disease progression, decline in performance status, or toxicity from cytotoxic chemotherapy.^41,42

A significant proportion of patients with advanced or mUC are ineligible for frontline platinum-based chemotherapy due to poor performance status or comorbid conditions including chronic kidney disease or pre-existing neuropathy.^43,44 As previously mentioned, pembrolizumab and atezolizumab received conditional approval in the frontline setting in the treatment of cisplatin-ineligible patients with advanced UC based on the results of the KEYNOTE-052 and IMvigor-210 phase II trials, respectively.^7,45 However, subsequent phase III trials (KEYNOTE-361 and Imvigor-130) reported decreased OS in patients with low PD-LI expression receiving investigational treatment, thus validating the use of these agents only in mUC patients with high PD-LI expression levels or high combined positive score (CPS).^9,46 These observations warranted further exploration of novel treatment strategies to improve outcomes in both cisplatin-ineligible and eligible patients with advanced UC. Specifically, the use of ICIs as a maintenance strategy to delay disease progression after first-line chemotherapy is appealing based on their demonstrated efficacy in the second-line, post-chemotherapy setting and first-line setting in mUC.

The JAVELIN Bladder 100 trial is a phase III, open-label, international, multicenter study that enrolled 700 patients with unresectable locally advanced or metastatic urothelial carcinoma.⁴⁷ The study compared the outcomes of patients who received maintenance avelumab plus BSC to BSC alone. The study population initially received four to six cycles of platinum-based chemotherapy with gemcitabine plus cisplatin or carboplatin depending on cisplatin eligibility and patients who attained SD, PR, or CR after completion of first-line chemotherapy were allowed to continue on trial to receive avelumab. These patients were randomized 1:1 to start avelumab 10 mg/kg intravenously every 2 weeks plus BSC or BSC alone within 4–10 weeks of completing chemotherapy. In this trial, BSC included antibiotic therapy, pain management, nutritional support, hydration, and palliative radiation therapy to solitary lesions. The primary end point was OS, evaluated both in the overall study population and the biomarker (PD-L1) positive population. In the overall study population, 51% of patients had PD-L1-positive tumors. In the avelumab + BSC and BSC only arms, 57% and 56% of patients had PD-L1 positive tumors, respectively. Secondary end points were PFS, OR (CR or PR), duration of response, time to response, disease control (defined as CR, PR, non-CR or non-progressive disease, or SD), and safety. After a median follow-up of more than 19 months in both arms, avelumab maintenance significantly improved OS in the overall study population. The median OS was 21 months in the avelumab arm versus 14 months in the BSC arm (HR = 0.69, 95% CI = 0.56–0.86, p = 0.001). OS in the PD-L1-positive population was also significantly prolonged in avelumab arm with median OS not reached in the avelumab arm versus 17 months in the BSC arm (HR = 0.56, 95% CI = 0.40–0.79, p < 0.001). Avelumab maintenance prolonged PFS in the overall population (median PFS of 3.7 months) and PD-L1-positive population (median PFS of 5.7 months), compared with those who received BSC only. The confirmed OR rates in the avelumab group were 13.8% in PD-L1-positive patients and 9.7% in the overall patient population. Grade 3 or higher treatment-related toxicity rates were higher in avelumab arm (47%) compared with BSC arm (25%). Grade 3 immune-related adverse events were reported in 24 patients treated with avelumab. In the avelumab arm, 11.9% of patients discontinued treatment due to an adverse event.⁴⁷ Based on the results of the JAVELIN Bladder 100 trial, the FDA-approved avelumab maintenance therapy for patients with locally advanced or metastatic urothelial carcinoma that had not progressed on initial platinum-based chemotherapy.⁴⁸ Since the initial publication of the trial, several subgroup analyses have demonstrated that the time interval from completion of chemotherapy to start of avelumab maintenance does not impact outcomes as long as avelumab is started within 4–10 weeks after completing chemotherapy.⁴⁹ In addition, benefit is seen across patients with varying responses to initial platinum-based chemotherapy with the achievement of long-term response or disease stability and sustained OS benefit even with extended follow-up of over 38 months in both arms of the trial without detrimental effects on patient quality of life.^{50 –52}

The Hoosier Cancer Research Network (HCRN) GU14-182 trial was a multicenter, phase II double-blinded study that randomly assigned 108 patients who achieved at least SD with up to eight cycles of first-line chemotherapy to receive either pembrolizumab 200 mg once every 3 weeks (n = 55) or placebo (n = 53) for a period of 24 months in the absence of disease progression or severe drug toxicity. PFS was the primary endpoint and OS was a secondary endpoint in this trial. Crossover was allowed from the placebo group to the pembrolizumab group at the time of disease progression. A significant improvement in OR was observed in the pembrolizumab group (23%) compared with the placebo group (10%). Notably, 27 out of 57 patients who progressed on placebo who crossed over to receive pembrolizumab had an OR rate of 22%, median PFS of 2.7 months, and median OS of 15.8 months after crossover. The study met its primary endpoint with a median PFS of 5.4 months in the pembrolizumab group versus 3 months in the placebo group (HR = 0.65, 95% CI = 3.1–7.3, p = 0.04). Median OS was 22 months in patients treated with pembrolizumab versus 18.7 months for those in the placebo group; however, the difference was not statistically significant (HR = 0.91, 95% CI = 0.52–1.59, p = 0.7). Grade 3–4 treatment emergent adverse events (TEAEs) were higher in pembrolizumab group (59%) compared with placebo (38%).⁵³

Conceivably, pembrolizumab may be substituted for avelumab use in clinical practice given convenience, scheduling differences (pembrolizumab may be given every 6 weeks), and formulary preferences. However, based on the robust data of the JAVELIN Bladder 100 trial, avelumab remains the only category 1 maintenance ICI agent recommended by the National Comprehensive Cancer Network (NCCN) after platinum-based chemotherapy.^54,55

Future maintenance therapy trials

JAVELIN Bladder Medley is a phase Ib/II, open-label, multi-arm trial that aims to evaluate the safety of avelumab in combination with other cancer immunotherapies in advanced malignancies including bladder cancer. JAVELIN Bladder Medley (NCT05327530) consists of four treatment arms for advanced UC patients: avelumab alone, avelumab plus sacituzumab govitecan, avelumab plus M6223 (an anti-T-cell-immune-receptor with Ig and ITM domains), and avelumab plus NKTR-255 (a novel polymer-conjugated recombinant human interleukin-15). Key inclusion criteria for participants are a diagnosis of stage III or IV UC at the start of first-line chemotherapy and no disease progression following four to six cycles of first-line platinum-containing chemotherapy. Primary outcome measures for this study include PFS and number of participants with TEAEs. Key secondary endpoints include OS, OR, and duration of response (DoR)⁵⁶ (see Table 2).

Table 2.

Ongoing maintenance therapy trials in advanced urothelial carcinoma.

Study	Phase	N	Investigational agent(s) = Mechanism of action	Treatment arms	Primary endpoint	Estimated primary completion date
PRESERVE3	2	90	Trilaciclib = CDK4/6 inhibitor	1. CG→Avelumab 2. CG + Trilaciclib→Avelumab + Trilaciclib	PFS	March 2023
TALASUR	2	50	Talazoparib = PARP inhibitor	Maintenance avelumab + talazoparib after platinum-based chemotherapy	PFS	July 2022
AVENU	2	30	MRx0518 = live biotherapeutic product consisting of a lyophilised formulation of a proprietary strain of bacterium	Maintenance avelumab + MRx0518 after platinum-based chemotherapy	Safety, 6-month PFS	October 2023
JAVELIN Bladder Medley	2	252	Sacituzumab govitecan = Trop-2-directed antibody-drug conjugate M6223 = anti-T-cell-immuno-receptor with Ig and ITM domains [anti-TIGIT] NKTR-225 = Interleukin-15 receptor agonist	After platinum-based chemotherapy: 1. Avelumab 2. Avelumab + Sacituzumab Govitecan 3. Avelumab + M6223 Avelumab + NKTR-225	PFS, TEAEs	August 2026
MAIN-CAV	3	654	Cabozantinib = tyrosine kinase inhibitor (c-Met, VEGFR2)	After platinum-based chemotherapy: 1. Avelumab 2. Avelumab + cabozantinib	OS	December 2024

CDK4/6, cyclin-dependent kinase 4 and 6; CG, cisplatin or carboplatin + gemcitabine; OS, overall survival; PARP, poly ADP ribose polymerase; PFS, progression-free survival; TEAEs, treatment emergent adverse events; Trop-2, trophoblast cell surface antigen 2; VEGFR2, vascular endothelial growth factor receptor 2.

The MAIN-CAV study (NCT05092958) is a phase III, open-label randomized trial of maintenance cabozantinib plus avelumab versus avelumab alone in patients with metastatic UC who did not experience disease progression on first-line platinum-based chemotherapy. The study aims to enroll 654 participants. The primary outcome for this trial is OS assessed up to 5 years. Key secondary endpoints for the study include PFS, tumor response, and incidence of adverse events. Patients may have received four to six cycles of previous gemcitabine-cisplatin, gemcitabine-carboplatin, MVAC, or ddMVAC in the first-line setting.⁵⁷

TALASUR (NCT04678362) is an ongoing single-arm phase II trial investigating the efficacy of maintenance therapy with talazoparib, an orally bioavailable poly [adenosine diphosphate (ADP) ribose] polymerase (PARP) inhibitor in combination with avelumab in platinum-sensitive metastatic or locally advanced UC. The primary outcome measure is PFS and secondary outcome measures are OS and DoR.⁵⁸ DISCUS (CPMS 50666, IRAS 1003775) is a randomized phase II study in the United Kingdom comparing the three cycles versus six cycles of platinum-based chemotherapy prior to maintenance avelumab in advanced UC. Eligible patients will be randomized 1:1 to receive either three cycles of gemcitabine plus carboplatin or cisplatin every 3 weeks followed by avelumab every 2 weeks up to maximum of 2 years duration or six cycles of gemcitabine plus carboplatin or cisplatin every 3 weeks followed by avelumab every 2 weeks up to a maximum of 2 years duration. The trial aims to evaluate quality of life as a primary outcome measure from baseline to the completion of chemotherapy.⁵⁹ Table 2 summarizes key ongoing and future maintenance therapy trials in UC.

Conclusion

Maintenance avelumab following first-line, platinum-based chemotherapy represents a new standard of care since the results of the JAVELIN Bladder 100 trial were reported in 2020. Recent trials have established that immediate sequential switch maintenance to avelumab is more beneficial compared with combination ICI and chemotherapy or waiting until progression or failure before initiating an ICI as a second-line therapy. There are trials currently ongoing investigating the use of avelumab in combination with targeted therapies and other novel agents in the maintenance space following the achievement of disease control with first-line chemotherapy. Disease progression is inevitable following first-line systemic therapy so the efforts toward achieving sustained disease control with drugs that can be tolerated long-term are well justified. The optimal management of mUC patients after progression of disease on ICI therapy, whether in the maintenance or first-line (platinum-ineligible patients) setting is not yet well established but is an important issue to address because for many patients, response to ICI therapy remains limited. Apart from traditional cytotoxic chemotherapy agents (paclitaxel, docetaxel, gemcitabine), current standard treatment options for mUC progressing after platinum-based chemotherapy and immunotherapy are limited. Enfortumab vedotin-ejfv is FDA-approved for those who previously received a PD-(L)1 inhibitor and were considered cisplatin-ineligible and did not receive platinum in the locally advanced or metastatic setting based on the results of the EV-201 trial (Cohort 2).⁶⁰ Erdafitinib is approved for use in patients with locally advanced or metastatic UC with susceptible fibroblast growth factor (FGFR)3 or FGFR2 alterations who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within a year of neoadjuvant or adjuvant chemotherapy based on the results of the BCL2001 study.⁶¹ Sacituzumab govitecan-hziy is approved for the treatment of patients with locally advanced or metastatic UC who have previously received both platinum-based chemotherapy and either a PD-1 or PD-L1 inhibitor.⁶² Efforts to further improve treatment in the frontline cisplatin-ineligible setting, use of ICI in the neoadjuvant and adjuvant muscle-invasive bladder cancer, and use of maintenance immunotherapy approaches in these various settings are all underway. Much progress has been made in the UC treatment landscape in the last several years, but we hope for further improvement in long-term outcomes in these patients by way of effectively and safely intensifying treatment earlier on in the disease course with the incorporation of novel agents to current standard treatment protocols.