Perioperative immune-checkpoint inhibitors for muscle-invasive bladder cancer

Abstract

Muscle-invasive bladder cancer (MIBC) has a high risk of recurrence following radical cystectomy. Neoadjuvant cisplatin-based chemotherapy has been used for decades to lower recurrence rates but a significant proportion of patients still have disease relapse. Recently, immune-checkpoint inhibitors (ICIs) have been evaluated for patients with MIBC, with some success. This has led to regulatory approval of adjuvant nivolumab, sandwich perioperative durvalumab and sandwich perioperative pembrolizumab with enfortumab vedotin. This review summarizes the history of practice-informing and practice-changing neoadjuvant, adjuvant and sandwich perioperative application of ICIs for MIBC, looks ahead to the promising developments in other ICI-based sandwich perioperative regimens, and highlights controversies surrounding overtreatment versus undertreatment and the need for predictive biomarkers.

PLAIN LANGUAGE SUMMARY

What is this article about?

This review discusses how immune-checkpoint inhibitors (ICIs), which are drugs that empower your own immune system to fight cancer, are being integrated into the treatment of muscle-invasive bladder cancer. The review assesses various clinical trials to see how these drugs work when given at different stages of the surgical process: before the operation, after the operation, or both. It also explores the next generation of treatments such as combining immunotherapy with antibody–drug conjugates (ADCs).

Why is it important?

For decades, the standard treatment was chemotherapy followed by surgery. However, this approach has two major flaws:

• High recurrence: many patients still see their cancer return within a few years.

• Ineligibility: many patients are too frail or have kidney issues that prevent them from receiving standard chemotherapy (cisplatin).

This article is important because it highlights a paradigm shift. New drug combinations are proving to be more effective and less toxic, offering hope to patients who previously had very limited options.

The review breaks down the ‘new era’ of bladder cancer care into three main pillars: timing of treatment, antibody–drug conjugates and precision monitoring with ctDNA

Timing of treatment

The medical community is testing the best time to use these drugs:

• Neoadjuvant (before surgery): shrinking the tumour to make surgery more successful. Trials like PURE-01 showed that some tumours disappeared entirely before surgery.

• Adjuvant (after surgery): cleaning up microscopic cancer cells. Nivolumab is now a standard option here to prevent the cancer from returning.

• Sandwich (perioperative): a ‘before-and-after’ achieving excellent results. The NIAGARA trial recently led to the approval of durvalumab, which is given both before and after surgery to maximize survival.

Antibody–drug conjugates

ADCs (like enfortumab vedotin) deliver chemotherapy directly to cancer cells while sparing healthy tissue. When combined with immunotherapy, these drugs are outperforming traditional chemotherapy.

Precision monitoring with ctDNA

Liquid biopsies (sensitive blood tests that look for circulating tumor DNA) are being used to test patients.

• If the test is positive: The patient likely needs aggressive immunotherapy.

• If the test is negative: In the future, these patients might be able to skip extra treatments, avoiding unnecessary side effects and costs.

While surgery remains a cornerstone of treatment, the addition of immunotherapy and ADCs is significantly increasing survival rates and finally providing effective options for patients who cannot tolerate traditional chemotherapy.

Introduction

Once a bladder tumour penetrates the muscle wall but has not spread to distant sites in the body, it is termed muscle-invasive bladder cancer (MIBC). Epidemiologically, MIBC accounts for ~25% of new bladder cancer cases and has a 5-year survival of <60%, underscoring the urgency for improved perioperative interventions. Since the early 2000s, the standard of care for MIBC has been cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). An early regimen, methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) followed by RC, was shown to be better than RC alone.1 More recently, other cisplatin-containing NAC regimens have been adopted for better patient tolerance, including dose-dense MVAC (ddMVAC) with growth factors and gemcitabine with cisplatin (GC).2–4 These regimens were compared in the GETUG-AFU V05 VESPER trial (NCT01812369). Based on the results of this trial, six cycles of ddMVAC may be more effective compared to four cycles of GC, but this remains controversial. The 3-year progression-free survival benefit was improved but was not significant at HR 0.77 (95% CI 0.57–1.02), and the 5-year overall survival (OS) difference was also not significant at HR 0.79 (95% CI 0.59–1.05).5,6 Regardless, recurrence rates remain high. Additionally, many patients with MIBC are ineligible for cisplatin-based chemotherapy, as defined by the Galsky criteria, which account for ECOG performance status, creatinine clearance, hearing loss, neuropathy and heart failure.7 Unlike in the metastatic setting, cisplatin is not replaced by carboplatin for NAC, given decreased efficacy with lower response rates, offering no substantial benefit over RC alone.8 This limits treatment options for patients with MIBC ineligible for cisplatin.

Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies that block inhibitory receptor–ligand pairs, most commonly CTLA4–CD80–CD86 and PD-1–PD-L1, to increase anti-tumour immune activity. ICIs were initially evaluated in the metastatic setting with some success, after which research was expanded into the MIBC setting. More recently, ICIs have been evaluated in various combinations with chemotherapy or other novel agents, including antibody–drug conjugates (ADCs). Chemotherapy and ICIs can be synergistic, with chemotherapy resulting in upregulation of the antitumour immune response.9 In MIBC specifically, NAC combined with ICI has been shown to increase the development of tertiary lymphoid structures associated with a higher pathological complete response (pCR) rate.10

This review summarizes the neoadjuvant, adjuvant and sandwich perioperative application of ICIs involving the surgical management of MIBC and looks ahead to the promising developments in ICI-based sandwich perioperative regimens (Figure 1). The benefits and controversies of ICIs in these settings are highlighted, and the review emphasizes recent practice-informing and practice-changing trials. Of note, some trials enrolled patients with upper tract urothelial carcinoma (UTUC) and not just primary tumour of the bladder; this is clarified when applicable.

Figure 1.

Summary of neoadjuvant, adjuvant and sandwich perioperative trials involving immune-checkpoint inhibitors that are discussed in this review. Figure was developed courtesy of BioRender^®.

Methods

A literature search was conducted using PubMed, along with ASCO and ESMO abstracts, to identify articles and abstracts through June 2025 with the terms “neoadjuvant”, “adjuvant”, “perioperative” and “sandwich” therapies for “muscle-invasive bladder cancer” and “muscle-invasive urothelial carcinoma”. The search was updated to incorporate published literature through February 2026 and key data presented at the 2026 ASCO Genitourinary Cancers Symposium. Only original clinical trials were considered. Retrieved articles and abstracts were screened and selected based on relevance, using the authors’ clinical and scientific expertise. A narrative review article was written, reporting the published evidence to date and the expert opinion of the authors.

Review

Neoadjuvant therapy

Different ICIs have been used as single-agent neoadjuvant therapy for patients with MIBC. These are neoadjuvant options for patients who are either ineligible for cisplatin-based chemotherapy or declined chemotherapy. ICIs have also been combined with various chemotherapy agents to increase the efficacy over traditional chemotherapy alone (Table 1).

Table 1.

Notable phase II/III immune-checkpoint inhibitor-based neoadjuvant trials for patients with muscle-invasive bladder cancer.

Trial	Phase	Experimental arm	Control arm	Number of patients enrolled	Notable results
PURE-01 (NCT02736266)11	II	Pembrolizumab for 3 cycles	NA	155	pCR rate 36.8% 36-month EFS 74.4% (95% CI 67.8–81.7) 36-month OS 83.8% (95% CI 77.8–90.2)
ABACUS (NCT02662309)12	II	Atezolizumab for 2 cycles	NA	95	pCR 31% (95% CI 21–41) 2-year DFS 68% (95% CI 58–76) 2-year OS 77% (95% CI 68–85)
NABUCCO (NCT03387761)13	II	Ipilimumab and nivolumab for 2 cycles (not given concurrently)	NA	24	pCR 46% (95% CI 26–67)
NCT0352049114	II	Ipilimumab and nivolumab followed by nivolumab 3 weeks later for two 6-week cycles	NA	15	<ypT2N0 20%, including pCR of 7%
DUTRENEO (NCT03472274)16	II	Durvalumab and tremelimumab for 2 cycles	GC or ddMVAC	61	pCR 36.4% vs 34.8% (OR 0.923, 0.26–3.24) in the pro-inflammatory ‘hot’ tumour arm
NCT0298958417	II	Atezolizumab for 1 cycle, then atezolizumab with GC for 4 cycles, then atezolizumab for 1 cycle	NA	44	<ypT2N0 69% including pCR 41%
NCT0269055818	II	Pembrolizumab with GC for 4 cycles	NA	39	<ypT2N0 56% (95% CI 40–72) pCR 36% (95% CI 21–53)
HCRN GU14-188 (NCT02365766)19	Ib/II	Cisplatin-eligible: pembrolizumab with GC for 4 cycles followed by additional cycle of pembrolizumab Cisplatin-ineligible: pembrolizumab with gemcitabine for 4 cycles followed by additional cycle of pembrolizumab	NA	82	Cisplatin-eligible: ypT1N0 54% (95% CI 38–69), pCR 41% of patients (95% CI 27–57), 18-month RFS 82% (95% CI 66–91), 36-month OS 79% (95% CI 65–90) Cisplatin-ineligible: ypT1N0 53% (95% CI 37–69), pCR 41% of patients (95% CI 26–58), 18-month RFS 65% (95% CI 48–78), 36-month OS 66% (95% CI 47–79)
BLASST-1 (NCT03294304)20	II	Nivolumab with GC for 4 cycles	NA	41	≤ypT1N0 66%, 12-month RFS rate 85.4%
NCT0486158422	II	Toripalimab with GC for 4 cycles	NA	16	≤ypT1N0 86%
AURA (NCT03674424)23	II	Cisplatin-eligible: avelumab for 6 cycles with either ddMVAC for 4 cycles or GC for 4 cycles in 1:1 randomization Cisplatin-ineligible: avelumab for 4 cycles with or without paclitaxel and gemcitabine for 4 cycles in 1:1 randomization	NA	137	Cisplatin-eligible: for ddMVAC with GC, pCR 58% (95% CI 42–72), 36-month OS 87% (95% CI 76–98); for avelumab with GC, pCR 53% (95% CI 37–68) and 36-month OS 67% (95% CI 53–84) Cisplatin-ineligible: for avelumab with paclitaxel and gemcitabine, pCR 14% (95% CI 6–31), 36-month OS 48% (95% CI 33–71); for avelumab, pCR 32% (95% CI 18–51), 36-month OS 42% (95% CI 27–65)
SunRISe-4 (NCT04919512)25	II	TAR-200 and cetrelimab or cetrelimab monotherapy for 4 cycles	NA	122	pCR 42% (95% CI 28–56) for the combination and 23% (95% CI 10–41) for monotherapy
NCT0438374326	II	Pembrolizumab for 3 cycles and ddMVAC for 4 cycles	NA	17	pCR 53% 2-year EFS 64% (95% CI 32–84) 2-year OS 79% (95% CI 47–93)
RETAIN-2 (NCT04506554)24	II	3 cycles of nivolumab and ddMVAC	NA	71	2-year MFS for all patients 83.5% (95% CI 75.0–92.9%) 2-year MFS for the active surveillance cohort 85.2%

ddMVAC, dose-dense methotrexate, vinblastine, doxorubicin and cisplatin; DFS, disease-free survival; EFS, event-free survival; GC, gemcitabine and cisplatin; MFS, metastasis-free survival; NA, not available OS, overall survival; pCR, pathological complete response; RFS, relapse-free survival.

ICI monotherapy

PURE-01 (NCT02736266) is a phase II trial that enrolled 155 patients with cT2-3bN0M0 disease with at least 50% urothelial histology, regardless of cisplatin eligibility, who received three cycles of pembrolizumab prior to RC; this trial has the longest follow-up of the single-agent ICI neoadjuvant trials.11 Twelve patients received additional MVAC chemotherapy per investigator’s decision if there was a lack of radiographic response after receiving pembrolizumab or developed a treatment-limiting adverse event before RC, and nine patients received adjuvant chemotherapy. The ypT0N0 rate was 36.8%, and 53.5% patients had a pathological downstaging to <ypT2N0. The 36-month event-free survival (EFS) was 74.5% (95% CI 67.8–81.7) and 35-month OS was 83.8% (95% CI 77.8–90.2). High PD-L1 combined positive score (CPS) appeared to be associated with better EFS when stratified by PD-L1 tertiles (p=0.0013).

ABACUS (NCT02662309) is a phase II trial that enrolled 95 patients with MIBC (T2-4aN0M0) who were ineligible for or refused cisplatin-based NAC to receive two cycles of atezolizumab prior to RC.12 The pCR rate was 31% (95% CI 21–41), the 2-year disease-free survival (DFS) was 68% (95% CI 58–76%), and the 2-year OS was 77% (95% CI 68–85%). In this trial, PD-L1 positivity (defined by ≥5% of immune cell staining) was not associated with relapse-free survival (RFS). Patients who were negative for circulating tumour DNA (ctDNA) at baseline, as well as patients who were ctDNA positive at baseline but became negative after atezolizumab, were more likely to achieve a pCR and have higher RFS.

ICI doublet

NABUCCO (NCT03387761) is a phase II trial that enrolled 24 patients with stage 3 urothelial carcinoma to receive one dose of the anti-CTLA4 antibody ipilimumab, then one dose of ipilimumab with nivolumab, and finally one dose of nivolumab prior to RC.13 The pCR rate was 46%. Grade 3/4 immune-related adverse events (irAEs) occurred in 55% of patients. There was a trend towards a higher complete response (CR) rate for patients with PD-L1-positive tumours (CPS >10) compared to PD-L1-negative tumours (73% versus 33%; p=0.15), and patients with pCR trended towards a higher tumour mutational burden (p=0.056). There were no biomarkers predictive of pCR, as both baseline CD8⁺ T cell presence and T cell-effector signatures were independent of pCR.

A phase II trial (NCT03520491) enrolled 15 patients with cisplatin-ineligible MIBC to receive two doses of ipilimumab and four doses of nivolumab.14 Three patients (20%) achieved pathological downstaging to <ypT2N0, including one patient with pCR. The 12-month RFS was 61% (95% CI 39–95%). The combination of immunotherapies led to delays in surgery due to irAEs, and the primary endpoint was not met, preventing further enrolment.

Two different trials have reported outcomes using durvalumab with the anti-CTLA4 antibody tremelimumab. One phase I trial (NCT02812420) enrolled 28 cisplatin-ineligible patients with high-risk MIBC (defined by bulky T3/T4 tumours, subtype histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease) to receive two cycles of durvalumab and tremelimumab prior to cystectomy.15 Six of the 28 patients (21%) developed grade ≥3 irAEs. The pCR rate was 37.5%, and 58% had pathological downstaging to pT1 or less. There was no correlation between responses and PD-L1 expression, tumour mutational burden, predicted neoantigens or DNA-damage response genes. A phase II trial, DUTRENEO (NCT03472274), enrolled 61 cisplatin-eligible patients with MIBC (cT2-4a, N≤1, M0) to receive either three cycles of durvalumab and tremelimumab or standard cisplatin-based chemotherapy (GC or ddMVAC) based on a tumour pro-inflammatory IFNγ signature.16 Patients with hot tumours from this gene signature received either an immunotherapy doublet or chemotherapy, whilst all patients with cold tumours received chemotherapy. For patients in the hot-tumour arms, the pCR rate was 36.4% for the 22 patients receiving immunotherapy doublet and 34.8% for the 23 patients receiving chemotherapy. Grade 3–4 toxicities were higher for patients who received chemotherapy (47.4%) than for those who received immunotherapy doublet (21.7%). A pro-inflammatory IFNγ signature did not select patients more likely to benefit from immunotherapy in the trial.

ICI with chemotherapy

Several trials have explored synergy between ICI and platinum-based chemotherapy to enhance responses, to intensify the pathological downstaging, and to increase pCR rates. A phase II trial of neoadjuvant atezolizumab with GC was evaluated (NCT02989584).17 Of 39 evaluable patients with MIBC (cT2-T4aN0M0) who received one dose of atezolizumab followed by four additional cycles of atezolizumab with GC, then one last cycle of atezolizumab before RC, 69% (27 patients) achieved downstaging to <pT2N0, and 41% (16 patients) had ypT0N0. Grade 3 irAEs occurred in 11% of patients, and two patients needed steroids. There was no significant association for PD-L1 status and <pT2N0.

Neoadjuvant pembrolizumab with GC for four cycles was evaluated in a phase II trial (NCT02690558) for 39 patients with cT2-4aN0/XM0 MIBC.18 The majority of patients received split-dose cisplatin. The pathological downstaging (<pT2N0) rate was 56%, and 36% achieved pT0N0. ICI-mediated toxicities were minimal, as no patients required steroids for irAEs in the trial, although one patient developed type 1 diabetes mellitus with ketoacidosis due to pembrolizumab.

HCRN GU14-188 (NCT02365766) is a phase Ib/II trial of neoadjuvant pembrolizumab of five cycles with either four cycles of GC for cisplatin-eligible patients (cohort A) or four cycles of gemcitabine for cisplatin-ineligible patients (cohort B). All patients had T2-4aN0M0 disease.19 The rate of ≤ypT1N0 was 61% for 43 patients in cohort A and 52% for 38 patients in cohort B, which met the prespecified thresholds. The pCR rate was 44% for cohort A and 45% for cohort B.

BLASST-1 (NCT03294304) is a phase II trial evaluating 41 patients with MIBC (cT2-4a, N≤1, M0) with neoadjuvant nivolumab and GC for four cycles. The ≤ypT1, N0 response rate was 65.8%, and overall, there were few irAEs.20 Genetic analyses to predict the responders for this regimen suggested ERCC2, ARID1A, DSP, HMCN1, ERBB2, ERBB3, STAG2 and BRCA2 to be correlated with response, whilst VHL, ERCC4, PALB2, CDKN2A and CSMD3 correlated with lack of response.21

A phase II trial (NCT04861584) evaluated four cycles of toripalimab in combination with GC for 16 patients with MIBC (cT2-4a, N≤1, M0).22 The ≤ypT1, N0 rate for the 14 patients who underwent RC was 85.7% (12 patients, with 4 pT0 and 8 pT1/a/is). No patients had any grade ≥3 adverse events related to toripalimab.

AURA (NCT03674424) is a phase II trial for 137 patients with cT2-4aN0-2M0 MIBC evaluating neoadjuvant avelumab with chemotherapy followed by RC.23 Cisplatin-eligible patients were randomized to either ddMVAC or GC with avelumab, whereas cisplatin-ineligible patients were randomized to paclitaxel-gemcitabine versus no treatment in addition to avelumab. For the 79 cisplatin-eligible patients, the pCR was 58% (95% CI 42–72%) for ddMVAC with avelumab and 53% (95% CI 37–68%) in the GC with avelumab arm. The 36-month OS rates were 87% (95% CI 76–98%) for ddMVAC with avelumab and 67% (95% CI 53–84%) for GC with avelumab. Out of the 58 patients in the cisplatin-ineligible arm, the pCR rate was 14% (95% CI 6–31%) for the patients who received avelumab, paclitaxel and gemcitabine, and the pCR rate was 32% (95% CI 18–51%) for the patients who received avelumab monotherapy. The 36-month OS rates were 48% (95% CI 33–71%) and 42% (95% CI 27–65%), respectively. These results suggested that chemotherapy may potentially reduce avelumab efficacy for platinum-ineligible patients.

RETAIN-2 (NCT02710734) is a phase II trial that enrolled patients with cT2-T3N0M0 MIBC to receive three cycles of ddMVAC and nivolumab.24 This trial notably aimed to spare patients from RC if possible. Patients with a mutation in ATM, ERCC2 or RB1 on tumour tissue and a cCR based on restaging via transurethral resection, urine cytology and CT imaging after completion of chemo-immunotherapy entered active surveillance. Otherwise, patients received an intervention including cystectomy or bladder-sparing chemoradiation. For 71 total evaluable patients (of whom 49 received intervention and 22 underwent active surveillance), the 2-year metastasis-free survival (MFS) was 83.5% (95% CI 75.0–92.9%). The 2-year MFS for the active surveillance cohort was 85.2%, and 4 patients later required salvage cystectomy.

SunRISe-4 (NCT04919512) is a phase II trial that enrolled 122 patients with cT2-4N0M0 MIBC ineligible for or refusing platinum-based chemotherapy and randomized them in a 5:3 ratio to the combination of four cycles of TAR-200 (slow-releasing intravesical gemcitabine) and cetrelimab or cetrelimab monotherapy.25 For 53 evaluable patients in the combination arm, the pCR rate was 42% (95% CI 28–56%), and for 31 evaluable patients in the cetrelimab monotherapy arm, the pCR rate was 23% (95% CI 10–41%). Grade ≥3 treatment-related adverse events occurred in 11% of patients in the combination cohort and 5% in the cetrelimab cohort. This trial supports continued investigation of this combination.

One notable phase II trial (NCT04383743) enrolled 17 patients with pure or predominant variant histology to receive three cycles of pembrolizumab with four cycles of ddMVAC.26 Squamous histology was the most common variant. The pCR rate was 53%, and the total downstaging rate was 59%. Another patient achieved a clinical CR (cCR) and underwent consolidation chemoradiation. Grade ≥3 adverse events occurred in 47% of patients. The 2-year EFS was 64% (95% CI 32–84%), and the 2-year OS was 79% (95% CI 47–93%).

Adjuvant therapy

Most recurrences or metastases of MIBC occur within 3 years of RC.27 Therefore, adjuvant treatment has been explored as a strategy to reduce early recurrence and improve OS, especially for patients with a high risk of recurrence. More recently, ICIs have been evaluated in this setting (Table 2).

Table 2.

Notable phase II/III immune-checkpoint inhibitor-based adjuvant trials for patients with muscle-invasive bladder cancer.

Trial	Phase	Experimental arm	Control arm	Number of patients enrolled/planned	Notable results
CheckMate 274 (NCT02632409)28	III	Nivolumab for 12 months	Placebo	709	DFS 21.9 vs 11.0 months (HR 0.74, 95% CI 0.61–0.90) for ITT and 55.5 vs 8.4 months (HR 0.58, 95% CI 0.42–0.79) for tumour PD-L1 ≥1% OS 75.0 vs 50.1 months (HR 0.83, 95% CI 0.67–1.02) for ITT and NR vs 59.4 months (HR 0.63, 95% CI 0.44–0.90) for tumour PD-L1 ≥1%
AMBASSADOR (NCT03244384)29	III	Pembrolizumab for 12 months	Observation	702	DFS 29.6 vs 14.2 months (HR 0.73, 95% CI 0.59–0.90; p=0.003) 3-year OS 60.8% vs 61.9% (HR 0.98, 95% CI 0.76–1.26)
IMvigor010 (NCT02450331)30,31,56	III	Atezolizumab for 12 months	Observation	809	DFS 19.4 vs 16.6 months (HR 0.89, 95% CI 0.74–1.08; p=0.24) ctDNA+ after RC: DFS 5.9 vs 4.4 months (HR 0.58, 95% CI 0.43–0.79) and OS 29.8 vs 14.1 months (HR 0.59, 95% CI 0.42–0.83) ctDNA− after RC: DFS NR vs NR (HR 1.14, 95% CI 0.81–1.62) and OS NR vs NR (HR 1.38, 95% CI 0.93–2.05)
IMvigor011 (NCT04660344)32	III	ctDNA+ cohort after RC: atezolizumab for 12 months ctDNA− cohort after RC: surveillance	Placebo	761	ctDNA+ after RC: DFS 9.9 vs 4.8 months (HR 0.64, 95% CI 0.47–0.87; p=0.005) and OS 32.8 vs 21.1 months (HR 0.59, 95% CI 0.3–0.90; p=0.01) ctDNA− after RC: 24-month DFS 88%
TOMBOLA (NCT04138628)33	III	ctDNA+ cohort after RC: atezolizumab for 12 months ctDNA− cohort after RC: surveillance	NA	192	58% were ctDNA+ after RC within 2 years ctDNA− after RC had 12-month DFS 97% 60% of the 84 patients with ctDNA+ had a molecular and radiographic complete response with atezolizumab
MODERN (NCT05987241)	II/III	ctDNA+ cohort after RC: nivolumab and relatlimab for 12 months ctDNA− cohort after RC: surveillance	ctDNA+ cohort after RC: nivolumab for 12 months ctDNA− cohort after RC: nivolumab for 12 months	1190	Pending

ctDNA. Circulating tumour DNA; DFS, disease-free survival; ITT, intention-to-treat population; OS, overall survival; NA, not available; RC, radical cystectomy.

CheckMate 274 (NCT02632409) enrolled 709 patients with muscle-invasive urothelial carcinoma (MIUC), with the majority of primary tumour sites in the bladder, although primary renal pelvis and ureteral tumours were included. Patients were randomized to receive 1 year of adjuvant nivolumab or placebo within 120 days after radical surgical resection following confirmation of high-risk disease, defined as at least pT2 or N+ for patients who received neoadjuvant cisplatin and at least pT3 or N+ if no neoadjuvant cisplatin was given. CheckMate 274 was a positive trial with a DFS benefit of HR 0.71 (95% CI 0.58–0.86) in favour of adjuvant nivolumab in the intention-to-treat population, with a more pronounced benefit in the tumour PD-L1 ≥1% population with DFS HR 0.52 (95% CI 0.37–0.72). This study led to the FDA approval of adjuvant nivolumab for patients with MIBC following RC in August 2021, regardless of PD-L1 status. A 5-year extended follow-up continued to favour an OS benefit for adjuvant nivolumab (HR 0.83, 95% CI 0.67–1.02) in the intention-to-treat population and in the PD-L1 ≥1% population (HR 0.63, 95% CI 0.44–0.90).28

AMBASSADOR (NCT03244384) is a phase III trial comparing 1 year of adjuvant pembrolizumab to observation in 702 patients with MIUC or lymph node-positive disease with high risk of recurrence following radical surgical resection.29 Primary tumour sites were predominantly the bladder but included renal pelvis, ureter and urethra. This trial was positive for DFS (HR 0.73, 95% CI 0.59–0.90). PD-L1 CPS ≥10 was not predictive of DFS benefit, with a HR of 0.81 (95% CI 0.61–1.08). These findings suggest that PD-L1 status should not be used for decision-making for adjuvant ICI in MIUC. In addition, at the last data reporting, no OS benefit for patients receiving adjuvant pembrolizumab (HR 0.98, 95% CI 0.76–1.26) has been achieved, possibly due to the control arm later receiving an ICI after early closure of AMBASSADOR following the CheckMate 274 results.

In contrast to the positive results of CheckMate 274 and AMBASSADOR, IMvigor010 (NCT02450331) failed to meet its primary endpoint. The study enrolled 809 patients with MIUC with high risk of recurrence following RC to receive either 1 year of adjuvant atezolizumab or observation. Primary tumour sites included the bladder and upper urothelial tract. The trial failed to demonstrate a significant DFS benefit (HR 0.89, 95% CI 0.74–1.08), including no treatment benefit observed in PD-L1 enriched tumours.30 However, an interim exploratory analysis of the ctDNA-positive subgroup (defined by two or more mutations detected in plasma) demonstrated an OS benefit (HR 0.59, 95% CI 0.42–0.83).31

Building on the ctDNA-positive subgroup findings of IMvigor010, IMvigor011 (NCT03660344) is a phase III trial that prospectively assessed serial ctDNA monitoring for patients with MIBC.32 Patients with (y)pT2-4aN0M0 or (y)pT0-4aN+M0 staging following cystectomy were enrolled within 24 weeks of cystectomy. Patients received serial ctDNA testing, and the patients who had ctDNA positivity at any timepoint without radiographic recurrence were randomized to receive atezolizumab for up to 1 year versus placebo in a 2:1 ratio. Of 761 total patients enrolled, there were 250 patients with ctDNA positivity, and 167 received atezolizumab, whilst 83 patients received placebo. The median DFS for the atezolizumab arm was 9.9 months versus 4.8 months for placebo (HR 0.64, 95% CI 0.47–0.87; p=0.005), and an OS benefit favouring atezolizumab of 32.8 months versus 21.1 months (HR 0.59, 95% CI 0.39–0.90; p=0.01) was observed.

TOMBOLA (NCT04138628) is a single-arm phase II trial that similarly evaluated the utility of serial ctDNA for patients with MIBC (cT2-4aN0-1M0) following prior NAC and RC.33 Patients with ctDNA positivity initiated atezolizumab for up to 1 year, whilst ctDNA-negative patients received immunotherapy only upon radiographic detection of metastases. Of 178 patients assessed, 104 (58%) patients were ctDNA-positive within 2 years of RC. There were 84 patients with ctDNA positivity who completed atezolizumab, and 60% of these patients had a CR. TOMBOLA also supports immunotherapy for patients with ctDNA positivity despite negative imaging.

The clinical utility of ICIs for all patients with MIBC following RC remains unclear. It appears that not all patients require adjuvant ICI after RC. Biomarker-stratified trials using plasma ctDNA to better understand the risk of recurrence and the impact of later lines of therapy, as shown in IMvigor011 and TOMBOLA, could further enhance the value of ICIs in this setting. MODERN (NCT05987241) is another actively recruiting phase II/III trial utilizing ctDNA to stratify usage of adjuvant ICIs. MODERN will also notably enrol patients with UTUC.

Sandwich perioperative therapy

Several trials have added ICIs to the previous standard of care for cisplatin-eligible patients with MIBC. Encouraging results from the positive trials for ICIs in the neoadjuvant and adjuvant settings have provided a rationale for the escalation of immunotherapy regimens to a sandwich perioperative approach encompassing neoadjuvant and adjuvant treatment (Table 3).

Table 3.

Notable phase II/III immune-checkpoint inhibitor-based perioperative sandwich trials for patients with muscle-invasive bladder cancer.

Trial	Phase	Experimental arm	Control arm	Number of patients enrolled/planned	Notable results
SAKK 06/17 (NCT03406650)34	II	Neoadjuvant GC for 4 cycles, neoadjuvant durvalumab for 4 cycles starting with cycle 2 of GC, and adjuvant durvalumab for 10 cycles	NA	61	2-year EFS 76% (95% CI 62–85) 2-year OS 85% (95% CI 72–92) pCR 33%
NIAGARA (NCT03732677)35,36	III	Neoadjuvant durvalumab and GC for 4 cycles, and adjuvant durvalumab for 8 cycles	Neoadjuvant GC for 4 cycles, then surveillance	1063	pCR 37.3% vs 27.5% (HR 1.34, 95% CI 1.13–1.60) 2-year EFS 67.8% vs 59.8% (HR 0.68, 95% CI 0.56–0.82; p<0.001) 2-year OS 82.2% vs 75.25% (HR 0.75, 95% CI 0.59–0.93; p=0.01)
KEYNOTE-866 (NCT03924856)	III	Neoadjuvant pembrolizumab and GC for 4 cycles, and adjuvant pembrolizumab for 13 cycles	Neoadjuvant placebo and GC for 4 cycles, then adjuvant placebo	907	Pending
NURE-Combo (NCT04876313)39	II	Neoadjuvant nivolumab and paclitaxel for 4 cycles, and adjuvant nivolumab for 13 cycles	NA	31	pCR 32.3% (95% CI 16.7–51.4) ypT≤1N0-x 70.9% (95% CI 55–87) 12-month EFS 89.8% (95% CI 79.5–100)
KEYNOTE-905/EV-303 (NCT03924895)40	III	Neoadjuvant pembrolizumab for 3 cycles, and adjuvant pembrolizumab for 14 cycles; or neoadjuvant pembrolizumab and EV for 3 cycles, and adjuvant pembrolizumab for 14 cycles and EV for 6 cycles	Observation	595	Results for EV and pembrolizumab vs observation: 2-year EFS 74.7% vs 39.4% (HR 0.40, 95% CI 0.28-0.57; p<0.001) 2-year OS 79.7% vs 63.1% (HR 0.50, 95% CI 0.33–0.74; p<0.001) pCR 57.1% vs 8.6% (p<0.001)
KEYNOTE-B15/EV-304 (NCT04700124)41	III	Neoadjuvant pembrolizumab and EV for 4 cycles, and adjuvant pembrolizumab for 13 cycles and EV for 5 cycles	Neoadjuvant GC for 4 cycles	808	2-year EFS 79.4% vs 66.2% (HR 0.53, 95% CI 0.41–0.70; p<0.0001) 2-year OS 86.9% vs 81.3% (HR 0.65, 95% CI 0.48–0.89; p=0.0029) pCR 55.8% vs 32.5% (p<0.0001)
ENERGIZE (NCT03661320)	III	Neoadjuvant linrodostat or placebo, nivolumab, and GC for 4 cycles, and adjuvant linrodostat, or placebo with nivolumab for 9 cycles	Neoadjuvant GC for 4 cycles	861	Pending
VOLGA (NCT04960709)	III	Neoadjuvant durvalumab with or without tremelimumab, and EV for 3 cycles, then adjuvant durvalumab with or without tremelimumab for 9 cycles	No neoadjuvant therapy, and observation or standard-of-care after RC	712	Pending
SURE-02 (NCT05535218)46	II	Neoadjuvant SG with pembrolizumab for 4 cycles, and adjuvant pembrolizumab for 13 cycles	NA	49	cCR 39% (95% CI 25–54) 12-month EFS 71% (95% CI 57–89)

cCR, clinical complete response rate; EFS, event-free survival; EV, enfortumab vedotin; GC, gemcitabine and cisplatin; NA, not available; OS, overall survival; pCR, pathological complete response rate; RC, radical cystectomy; SG, sacituzumab govitecan.

SAKK 06/17 (NCT03406650) is a phase II, single-arm trial that evaluated four cycles of neoadjuvant GC and perioperative durvalumab in 61 cisplatin-eligible patients with operable MIUC (cT2-T4a cN0-1).34 In this trial, durvalumab was given for 4 neoadjuvant cycles, starting with cycle 2 of GC and 10 adjuvant cycles following radical surgery; 52 patients underwent resection, and primary tumour sites were predominantly the bladder, with only three patients with UTUC included. The primary analysis showed 76% EFS (95% CI 62–85) at 2 years and 73% EFS (95% CI 59–83%) at 3 years. A pCR was achieved in 33% of patients, with 60% demonstrating pathological downstaging to <ypT2N0. OS was 85% at 2 years (95% CI 72–92%) and 81% at 3 years (95% CI 67–89%). SAAK 06/17 showed that the addition of sandwich perioperative durvalumab to standard-of-care neoadjuvant cisplatin-based chemotherapy and radical surgery was a promising option.

NIAGARA (NCT03732677) is an open-label phase III trial evaluating perioperative durvalumab and GC for 1,063 patients with cisplatin-eligible MIBC (cT2-T4aN0/1M0).35 Patients underwent randomization to either the experimental arm of neoadjuvant durvalumab and GC for four cycles followed by RC and adjuvant durvalumab for eight cycles, or to the control arm of neoadjuvant GC and RC without adjuvant therapy. A pCR, assessed by central pathology review, occurred in 37.3% (95% CI 33.2–41.6%) of patients in the experimental cohort and 27.5% (95% CI 23.8–31.6%) of those in the control cohort (HR 1.34, 95% CI 1.13–1.60). The experimental arm demonstrated a significant EFS benefit at 24 months (HR 0.68, 95% CI 0.56–0.82) and OS benefit at 24 months (HR 0.75, 95% CI 0.59–0.93), meeting the prespecified primary endpoint. Follow-up analyses demonstrated consistent superiority in MFS and disease-specific survival for patients who received durvalumab, regardless of pCR status.36 The estimated OS at 24 months was 82.2% (95% CI 78.7–85.2%) in the durvalumab group compared to 75.2% (95% CI 71.3–78.8%) in the control group (HR 0.75, 95% CI 0.59–0.93; p=0.01). These findings establish sandwich perioperative durvalumab as a well-tolerated and effective treatment strategy for MIBC, and the results led to FDA approval of durvalumab in this setting in March 2025.

The phase III trial KEYNOTE-866 (NCT03924856) is evaluating the addition of 1-year sandwich perioperative (4 cycles neoadjuvant and 13 cycles adjuvant) pembrolizumab compared to placebo in addition to neoadjuvant GC followed by RC for 870 previously untreated, cisplatin-eligible patients with MIBC.37 Results have not been reported yet.

Other unique sandwich perioperative immunotherapy combinations are also under investigation. The endogenous enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the conversion of tryptophan into its immunosuppressive derivative, kynurenine. Linrodostat mesylate, a novel inhibitor of IDO1, is hypothesized to improve clinical outcomes in combination with PD-1–PD-L1 inhibitors by promoting tumour infiltration by immune cells, thereby synergizing with ICIs. ENERGIZE (NCT03661320) is an active phase III trial investigating this in the sandwich perioperative setting for cisplatin-eligible patients with MIBC (T2-T4aN0M0). A total of 861 patients will be randomized to one of three trial arms: neoadjuvant GC alone, neoadjuvant GC combined with sandwich perioperative nivolumab and linrodostat, or neoadjuvant GC combined with sandwich perioperative nivolumab and a placebo substituting for linrodostat.38

NURE-Combo is a phase II trial (NCT04876313) of 31 patients with T2-4N0-1M0 and >50% urothelial histology who were cisplatin-ineligible or refused cisplatin chemotherapy who received 4 cycles of nivolumab and nab-paclitaxel followed by RC and then adjuvant nivolumab for 13 cycles.39 The trial met its primary endpoint with 10 patients (32.3%) achieving a pCR. Three patients refused RC after achieving a cCR. The 12-month EFS was 89.8% (95% CI 79.5–100%); 8 (25.8%) patients had grade 3–4 treatment-related adverse events. This trial was the first to demonstrate that perioperative ICI combined with neoadjuvant non-platinum chemotherapy could be effective for patients with MIBC.

The combination of ICIs with ADCs is also being investigated in the setting of sandwich perioperative therapy. KEYNOTE-905/EV-303 (NCT03924895) is a three-arm phase III trial for patients with MIBC (T2-T4aN0M0 or T1-T4aN1M0 with ≥50% urothelial histology) and ineligible for or who have declined cisplatin-based chemotherapy, with all patients receiving RC and primary lymph node dissection and either observation alone, perioperative single-agent pembrolizumab (three neoadjuvant and 14 adjuvant cycles), or perioperative pembrolizumab and the ADC enfortumab vedotin (EV) (3 neoadjuvant cycles of both, and 6 adjuvant cycles of EV and 14 cycles of pembrolizumab after RC). The comparison between 170 patients who received perioperative EV and pembrolizumab (combination term EVP) versus 174 patients on observation has been reported first.40 The 2-year EFS was 74.7% in the EVP group compared to 39.4% in the control group (HR 0.40, 95% CI 0.28–0.57; p<0.001), and the 2-year OS was 79.7% versus 63.1% (HR 0.50, 95% CI 0.33–0.74; p<0.001). The pCR rate was 57.1% versus 8.6%. The rate of grade ≥3 drug-related adverse events was 71.3%. The success of this regimen led to FDA approval of this sandwich perioperative combination for patients with MIBC ineligible for cisplatin in November 2025.

KEYNOTE-B15/EV-304 (NCT04700124) is a phase III trial comparing sandwich perioperative EVP (4 neoadjuvant combination cycles and 5 adjuvant cycles of EV and 13 adjuvant cycles of pembrolizumab) to 4 cycles of neoadjuvant GC followed by RC with pelvic lymph node dissection.41 This trial enrolled 808 cisplatin-eligible patients with histologically confirmed MIUC (T2-T4aN0M0 or T1-T4aN1M0). The median EFS was not reached in the EVP cohort compared to 48.5 months in the GC cohort (HR 0.53, 95% CI 0.41–0.70; p<0.0001). The 2-year EFS was 79.4% versus 66.2%, respectively. The OS also favoured the EVP cohort, with 86.9% still alive at 2 years compared to 81.3% for the GC cohort (HR 0.65, 95% CI 0.48–0.89; p=0.0029). The pCR rate was 55.8% versus 32.5%, respectively. The rate of grade ≥3 drug-related adverse events was 75.7%. This regimen is expected to become a new standard of care for cisplatin-eligible patients with MIBC.

VOLGA (NCT04960709) is an active phase III trial evaluating the combination of durvalumab and tremelimumab with enfortumab vedotin in the sandwich perioperative setting.42 A total of 712 cisplatin-ineligible patients with histologically or cytologically documented MIBC (T2-4aN0-1M0) are randomized to one of three arms: standard of care, neoadjuvant EV with perioperative durvalumab or neoadjuvant EV and tremelimumab with perioperative durvalumab. A preliminary exploratory analysis from the trial’s safety run-in study indicated that ctDNA clearance following neoadjuvant triplet therapy was associated with improved pathological response and EFS.43

Disitamab vedotin (DV) is a HER2-targeting ADC under investigation in MIBC. RC48-C017 (NCT05297552) is an active phase II trial enrolling patients with MIBC (cT2-4aN0-1M0) and HER2 low or positive expression (immunohistochemistry (IHC) ≥1+) to receive 6 cycles of toripalimab, an anti-PD-1 ICI, in combination with DV followed by RC, and subsequent adjuvant toripalimab for 20 cycles.44 Amongst the 47 patients enrolled, 33 underwent RC, with a pCR rate of 63.6% (95% CI 45.1–79.6) and pathological downstaging to ≤ypT1N0M0 of 75.8% (95% CI 57.7–88.9%). A higher pCR rate of 84.6% was noted for patients with HER2 IHC3+.

Sacituzumab govitecan (SG) is a novel ADC that targets trophoblast cell-surface antigen 2 (Trop2) linked to a topoisomerase I inhibitor SN-38 payload. Despite negative data in the metastatic setting in TROPiCS-04 (NCT04527991),45 there may be promise for management of MIBC. SURE-02 (NCT05535218) is a phase II study investigating either neoadjuvant SG alone or the combination of neoadjuvant SG for 4 cycles with perioperative pembrolizumab (4 neoadjuvant and 13 adjuvant cycles) for MIBC.46 Results for 48 patients showed a cCR rate, encompassing resolution of disease on imaging and ypT0NX staging via transurethral resection of bladder, of 39% (95% CI 25–54%). This treatment approach enabled bladder preservation in 39% of patients without further therapy. Grade 3 adverse events occurred in 16% of patients, and no patients had grade ≥4 adverse events. These findings underscore the potential for sandwich perioperative combinations of ICIs and ADCs to enhance patient outcomes.

Discussion

ICIs have now emerged as effective components in treatment regimens for MIBC, challenging cisplatin-based chemotherapy as the standard perioperative regimen. Regulatory approval has been achieved for adjuvant nivolumab for patients with high-risk MIBC and residual disease after radical surgery. The combination of ICIs with cisplatin-based chemotherapy as sandwich therapy for patients with MIBC has become a standard of care, given the recent regulatory approval of durvalumab.

Even given the success and future promise of cisplatin-based combinations with ICIs, many patients with MIBC are not eligible to receive cisplatin. Upcoming clinical trials, may generate a paradigm shift away from cisplatin eligibility, similar to what was observed in advanced urothelial carcinoma following approval of EVP in that setting.47 Perioperative sandwich pembrolizumab with enfortumab vedotin has already received regulatory approval for patients ineligible for cisplatin based on the KEYNOTE-905/EV-303. This would allow for many more patients with MIBC to get appropriate downstaging with chemo-immunotherapy in conjunction with radical surgery.

Yet, despite the promise of perioperative ICIs, several unanswered questions remain. The optimal time to administer an ICI is unknown, given there is no head-to-head comparison of neoadjuvant versus adjuvant versus sandwich perioperative therapy. The patients who will benefit the most from the addition of ICI need to be characterized, perhaps with ctDNA guidance, given that a subset of patients with MIBC are cured from NAC followed by RC alone despite residual disease on the pathology report. Some patients are at risk for permanent ICI-associated toxicities due to overtreatment, especially during the adjuvant component of sandwich regimens in patients with excellent pathological response at the time of radical surgery. Moreover, the utility of further ICI treatment in patients with poor pathological outcomes at radical surgery is questionable, given potential resistance. Despite significant advances, there is a need for the development of more novel therapies and better combinations. Cost-effectiveness and patient-reported outcomes for perioperative ICIs remain underexplored, representing an important gap that should be explored in future studies.48

Relatively little is known about the use of perioperative ICIs with or without chemotherapy in muscle-invasive UTUC, given the low enrollment of patients with UTUC in landmark perioperative trials. In subset analyses of patients with UTUC in CheckMate 274 and AMBASSADOR trials, adjuvant ICI treatment did not appear to provide benefit.29,49 The first chemo-immunotherapy neoadjuvant phase II trial for patients with localized UTUC, iNDUCT (NCT04617756), which combined durvalumab with platinum chemotherapy, did not meet its primary endpoint of a pCR rate of ≥25%.50 Other trials, including NCT04099589, NCT04628767 and NCT04624399 (ABACUS-2), are also actively evaluating neoadjuvant chemo-immunotherapy, suggesting potential efficacy.

Similarly, MIBC of predominant or pure variant histologies, although rare, merit further study. They remain excluded in most clinical trials, with a notable exception of NCT04383743, as described earlier in this manuscript. Variant histologies tend to be aggressive, and there is currently no standard-of-care involving systemic therapy.

Importantly, bladder-sparing approaches may include chemo-immunotherapy. One notable phase II trial, HCRN GU16-287 (NCT03451331), evaluated four cycles of GC with nivolumab as organ-sparing treatment for patients with MIBC (cT2-T4aN0M0).51 Clinical restaging was used to define cCR and to stratify patients for immediate RC versus organ-sparing treatment with eight additional nivolumab doses and surveillance. Similar trials that aimed to ensure bladder preservation with cCR included RETAIN-2 and SURE-02. Other options include combining ICIs with radiation-based approaches.52 For patients who are poor candidates for RC, and for patients who prefer a bladder-sparing approach, these possibilities appear promising.

Biomarkers may help identify the correct patients for treatment intensification with ICIs and, ultimately, which patients may benefit the most from bladder-sparing approaches. PD-L1 has been investigated but does not adequately differentiate the patients who would benefit.53 Molecular residual disease assessment with ctDNA has yielded promising results in exploratory analyses,54 and prospective studies are being designed to validate this biomarker for the selection of patients for adjuvant ICIs. Urinary tumour DNA (utDNA) is also becoming important, as the combination of both ctDNA and utDNA appears to be more effective in being predictive and prognostic biomarkers than either alone, as demonstrated on exploratory analyses of the NIAGARA trial.55

With systemic chemo-immunotherapy becoming established in the neoadjuvant, sandwich perioperative and adjuvant settings, the question of the next line of therapy upon progression remains unanswered. ICI rechallenge or in a novel combination may be feasible; however, prospective clinical trials will be necessary to answer this question. Moreover, novel biomarkers and regimens to prevent progression and optimize treatment would be welcome to improve upon existing regimens.

Conclusion

In summary, ICIs have been evaluated for patients with MIBC in the neoadjuvant, adjuvant and sandwich perioperative setting, with promising prospective data in all three settings. Nivolumab has been approved in the adjuvant setting, whilst durvalumab and pembrolizumab have been approved in the sandwich perioperative setting. In light of the KEYNOTE-905/EV-303 and KEYNOTE-B15/EV-304 trials, the sandwich perioperative combination of ADCs and ICIs has likely become a new standard-of-care for patients with MIBC. Despite positive outcomes, controversies remain, including the determination of optimal patients for escalation of therapy and concerns of overtreatment. Predictive biomarkers, such as ctDNA and utDNA, may identify the subset of patients who could derive maximum benefit from ICIs but need prospective validation. Even with these advances, the development of more effective novel regimens is essential to improve outcomes for patients with aggressive disease that progresses despite chemoimmunotherapy.