Neoadjuvant Immunotherapy in Bladder Cancer: Ushering in a New Era of Treatment—A Systematic Review of Current Evidence

Take Home Message

Neoadjuvant immunotherapy shows promising efficacy and manageable toxicity in muscle-invasive bladder cancer. Recent phase 3 data support its potential to redefine the standard of care, offering new hope, particularly for patients ineligible for cisplatin-based chemotherapy.

Abstract

Background and objective

Immune checkpoint inhibitors (ICIs), alone or with platinum-based chemotherapy, have increasingly been studied as neoadjuvant therapy for muscle-invasive bladder cancer (BC). We sought to evaluate the current evidence about neoadjuvant immunotherapy for BC.

Methods

In this systematic review, conducted in October 2024, only prospective studies on neoadjuvant immunotherapy for BC were included. Extracted variables encompassed study design, clinical-pathological characteristics, perioperative outcomes, pathological complete response (pCR) rates, overall survival (OS), event-free survival, and immune-related (irAEs) and treatment-related (TRAEs) adverse events.

Key findings and limitations

From 726 records, 35 studies met the inclusion criteria. The highest pCR rate observed was 54%, utilizing durvalumab. Perioperative chemoimmunotherapy with durvalumab plus cisplatin/gemcitabine showed greater OS than chemotherapy alone in the NIAGARA trial. The NEMIO trial achieved the highest 12-mo OS rate of 97%, using durvalumab in combination with tremelimumab and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin, followed by the AURA trial (95%) and the LCCC1520 trial (91%). At 24 mo, the NEBULA trial reported a 100% OS rate with three doses of atezolizumab, while PrECOG PrE0807 reached and OS rate of 89% with nivolumab and lirilumab. The highest rates of grade 3 and 4 irAEs were reported for nivolumab combined with ipilimumab (54%) and for durvalumab combined with tremelimumab (64%). The most common grade 3/4 irAEs were hepatitis (2–27%), kidney injury (2–100%), and skin rash (1.1–41%). Grade 3/4 TRAEs were comparable between the ICI and chemotherapy groups.

Conclusions and clinical implications

Neoadjuvant immunotherapy for BC has shown promising efficacy and a manageable adverse event profile. However, financial toxicity, the absence of predictive biomarkers, and the risk of significant irAEs remain challenges.

Patient summary

This study reviewed recent clinical trials that tested immunotherapy before surgery in patients with bladder cancer. The results suggest that a combination of immunotherapy and chemotherapy may improve outcomes and reduce the risk of cancer returning. These findings could help shape future treatment options for patients with muscle-invasive bladder cancer.

1. Introduction

Bladder cancer (BC) remains a global public health challenge. In the USA, it ranks as the sixth most common cancer, comprising approximately 4.2% of all newly diagnosed cancer cases. According to the recent surveillance data, the incidence of BC is 18.2 per 100 000 individuals annually, while the mortality rate is 4.1 per 100 000 annually [1,2]. Muscle-invasive BC (MIBC) is defined by tumor invasion into the muscularis propria (stage T2 or higher), and it is detected in approximately 30% of patients at diagnosis [2] with a high risk of progression to metastatic disease, necessitating prompt and aggressive treatment to improve outcomes.

Radical cystectomy with pelvic lymphadenectomy remains the gold standard for the treatment of nonmetastatic MIBC, offering local disease control [3]. The addition of neoadjuvant chemotherapy with cisplatin-based regimens has been shown to significantly improve overall survival (OS) when combined with surgery [4]. However, despite this established benefit, approximately 50% of patients experience disease recurrence within 3 yr [5], and only 25–50% of patients are eligible for cisplatin-based neoadjuvant chemotherapy, underscoring the need for alternative therapeutic approaches [6].

In the last decades, many phase 1/2 and phase 2 clinical trials have studied the safety and efficacy of immune checkpoint inhibitors (ICIs) as neoadjuvant monotherapy or combined with platinum-based chemotherapy for BC [7]. The recent phase 3 NIAGARA trial reported improved OS with ICI-based neoadjuvant therapy compared with gemcitabine and cisplatin, positioning it as a potential new standard of care for MIBC treatment [8]. This systematic review evaluates the existing evidence on neoadjuvant immunotherapy for MIBC.

2. Methods

2.1. Literature search

This systematic review was conducted in strict compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [9] statement on October 1, 2024, and it was registered in the PROSPERO international database of prospectively registered systematic reviews (CRD 42024591923).

A research question was established based on the Patient-Index test-Comparator-Outcome-Study design (PICOS) criteria, which is as follows [8]: what is the current evidence regarding the use of neoadjuvant immunotherapy in BC?

The search strategy was as follows: (Neoadjuvant Therapies) OR (Therapy, Neoadjuvant) OR (Neoadjuvant Treatment) OR (Neoadjuvant Treatments) OR (Neoadjuvant Chemotherapy) OR (Neoadjuvant Chemotherapies) OR (Neoadjuvant Systemic Therapy) OR (Neoadjuvant Systemic Therapies) OR (Systemic Therapy, Neoadjuvant) OR (Therapy, Neoadjuvant Systemic) OR (Neoadjuvant Systemic Treatment) OR (Neoadjuvant Systemic Treatments) OR (Systemic Treatment, Neoadjuvant) OR (Treatment, Neoadjuvant Systemic) AND (Neoplasm, Urinary Bladder) OR (Urinary Bladder Neoplasm) OR (Bladder Neoplasms) OR (Neoplasm, Bladder) OR (Bladder Tumors) OR (Bladder Tumor) OR (Tumor, Bladder) OR (Tumors, Bladder) OR (Neoplasms, Bladder) OR (Urinary Bladder Cancer) OR (Bladder Cancer) OR (Bladder Cancers) OR (Cancer, Bladder) OR (Cancer of Bladder) OR (Cancer of the Bladder) OR (Malignant Tumor of Urinary Bladder) AND (Immunotherapy).

We searched the following databases up to October 2024: PubMed/MEDLINE, Embase, and ClinicalTrials.gov (http://www.clinicaltrials.gov). We also reviewed the bibliographies of the included studies for further references to relevant trials. We included randomized clinical trials and cohort studies without language restrictions. Reviews, case reports, case series, letters to the editor, and editorials were excluded.

2.2. Study screening and selection criteria

Two independent authors screened all the retrieved records. Discrepancies were resolved by discussion. If relevant to the present review, the full text of the screened papers was selected. We included studies that met the following criteria: prospective studies with completed or partial results that enrolled patients with BC who underwent neoadjuvant treatment with immunotherapy.

2.3. Data extraction

The following variables were extracted from studies with partial or completed results: study initiation date, last update date, study type, mean patient age, number of patients per treatment arm, cisplatin eligibility, clinical and pathological staging, pathological response rates, oncological outcomes, immune-related adverse events (irAEs), and the designs of ongoing studies. All the extracted data were systematically organized into an Excel sheet for a comprehensive analysis.

2.4. Quality assessment and risk of bias

The risk of bias was analyzed in the prospective trials using ROBINS-1 [9], and randomized control trials were appraised with ROB-2 [9]; both these tools are developed by the Cochrane Collaboration for assessing the risk of bias in nonrandomized studies of interventions and in randomized trials, respectively (Supplementary Fig. 1 and 2).

3. Results

3.1. Literature screening

The literature search identified 726 records. After removing 170 duplicates, 556 records underwent screening based on title and abstract. Of these records, 479 were excluded as these did not align with the study's objectives. The full texts of the remaining 77 records were assessed for eligibility, resulting in 35 studies being included in the final analysis. Fig. 1 illustrates the PRISMA flowchart summarizing the search and selection processes.

Fig. 1.

PRISMA flowchart summarizing the search and selection processes. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses.

3.2. Quality assessment and risk of bias

In domain 1, most studies lacked a control group, presented incomplete study design information, and failed to adjust for confounders in single-arm prospective designs. Factors such as surgical approach, histological subtypes, and institutional variability in multicenter studies were often not accounted for. In domain 2, most studies were well rated, except for MDAACC [10], which modified its study design midway. In domain 3, the randomized controlled trial DUTRENEO [11] had a serious risk of bias, excluding 17% of patients from the primary analysis. In domain 4, one study [12] had a serious risk of bias due to not reporting the number of patients who discontinued treatment because of adverse events. In domain 5, one study excluded 28% of patients from the primary endpoint analysis [13], and another had 24% of patients with missing outcome data [14]. In domain 6, no serious risk of bias was identified. In domain 7, several studies [13,[15], [16], [17], [18], [19]] were at risk due to partial results, failure to reach planned sample size, or not meeting pre-established statistical power (Supplementary Fig. 1 and 2).

3.3. Fundamental concepts about immune checkpoint pathways

The roots of immunotherapy trace back to the 1890s when William Coley first used bacterial toxins to stimulate an immune response against tumors. Coley’s early work demonstrated the potential for harnessing the immune system to target cancer cells, but its widespread adoption faced challenges due to toxic side effects. The development of bone marrow transplantation by Fritz Bach in the 1960s marked an important milestone, leading to the integration of cellular therapies into cancer treatment [20]. By the 1990s, high-dose interleukin-2 (IL-2) therapy was approved for treating metastatic melanoma and metastatic renal cell carcinoma, ushering in a new era of immunotherapy [21,22]. Today, it includes a range of approaches, such as ICIs, T-cell transfer therapies, monoclonal antibodies, therapeutic vaccines, and immune system modulators.

The main ICIs used in cancer therapy reactivate the immune system to better recognize and destroy tumor cells, and target two key cellular interactions. The first involves the programmed cell death protein 1 (PD-1) and its ligands, programmed death ligand 1 (PD-L1) and PD-L2; these pathways are important for maintaining immune homeostasis by preventing excessive immune cell activation. PD-1 is expressed on the surface of activated T and B lymphocytes and macrophages, while PD-L1 is predominantly found on antigen-presenting cells. The interaction between PD-1 and PD-L1 inhibits T-cell activation, resulting in reduced production of IL-2 and interferon-gamma, ultimately promoting immune tolerance. While this mechanism prevents autoimmunity, it also enables tumor cells expressing PD-L1 to evade immune surveillance. ICIs targeting the PD-1/PD-L1 axis block this interaction, effectively restoring T-cell activation and enhancing antitumor immunity (Fig. 2) [23].

Fig. 2.

Mechanism of action of checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 pathways. APC = antigen-presenting cell; CTLA-4 = T-lymphocyte–associated protein 4; PD-1 = programmed cell death protein 1; PD-L1 = programmed death ligand 1.

The second main mechanism involves cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), an immune checkpoint receptor expressed on activated T cells. CTLA-4 acts as a negative regulator of immune responses by competing with CD28 for binding to the B7.1 and B7.2 ligands on antigen-presenting cells. This competition reduces T-cell activation, preventing excessive immune responses and maintaining immune balance. Although the precise molecular pathways through which CTLA-4 exerts its inhibitory effects are still being studied, blocking of this receptor has been shown to enhance immune responses, particularly in cancer [[23], [24], [25]]. Ipilimumab, the first ICI approved by the US Food and Drug Administration (FDA) in 2011, exploits this mechanism. While CTLA-4 inhibitors remain among the most studied and widely used ICIs, newer agents targeting other checkpoint receptors are currently under investigation [[26], [27], [28]].

3.4. Clinical trial design and clinical characteristics of patients

Our systematic review of the literature identified 35 published studies on neoadjuvant immunotherapy for BC, with two being phase 3 trials. The first study to evaluate neoadjuvant immunotherapy in patients with BC was a phase 1 trial initiated in 2007 involving 12 cisplatin-ineligible patients treated with ipilimumab. This study demonstrated the safety of using the immunotherapeutic agent in this clinical setting [12]. The second study on neoadjuvant immunotherapy was at phase 1–2, which included, for the first time, a cohort of cisplatin-eligible patients (HCRN GU14-188) [15]; it had two cohorts both of which received five doses of neoadjuvant pembrolizumab (200 mg every 3 wk). The cisplatin-eligible cohort also received gemcitabine with cisplatin, and the cisplatin-ineligible cohort received gemcitabine.

There are only two phase 3 studies with neoadjuvant ICIs in BC, the PIVOT IO 009 study [29], initiated in 2020, included 114 cisplatin-ineligible patients distributed across three cohorts: neoadjuvant nivolumab + bempegaldesleukin followed by adjuvant nivolumab + bempegaldesleukin (C1), neoadjuvant nivolumab followed by adjuvant nivolumab (C2), and radical cystectomy alone (C3) [29]. The second phase 3 study was the NIAGARA [8] trial, which randomized 1063 patients into two arms: the first arm received neoadjuvant durvalumab + cisplatin + gemcitabine followed by adjuvant durvalumab, while the second arm received neoadjuvant cisplatin + gemcitabine alone [8].

The mean age of patients enrolled in the studies ranged from 58 to 76 yr. A total of 21 studies included cisplatin-eligible patients, while 14 studies focused exclusively on cisplatin-ineligible patients. Only a minority of studies included patients with clinically positive lymph nodes in their cohorts. Interestingly, the three studies with the highest proportion of patients presenting a clinical suspicion of lymph node involvement (100%, 42%, and 26%) reported complete response rates exceeding 36% (50%, 46%, and 36%, respectively) [[30], [31], [32]]. Table 1 presents the design of studies and clinical characteristics of patients, and Fig. 3 presents all the studies.

Table 1.

Baseline characteristics of studies and patients included

Trial	NCT	Study start	Last update	Treatment protocol	Phase	Patients (n)	Male/female (%)	Mean age (yr)	Cisplatin eligibility	≥cT2 stage (%)	cN+ stage (%)	Histology
NCT00362713 [12]	NCT00362713	Mar 1, 2007	2009	C1: ipilimumab	1	12	–	–	No	–	–	100% pure urothelial carcinoma
HCRN GU14-188 [15]	NCT02365766	May 27, 2015	2023	C1: pembrolizumab + GC C2: pembrolizumab + gemcitabine	1–2	82 total C1: 42 C2: 40	–	64 73	Yes	C1: 42.9 C2: 60	0	100% pure urothelial carcinoma
ABACUS [53]	NCT02662309	Feb 1, 2016	2019	C1: atezolizumab	2	87	85/15	73	No	100	0	Histopathologically confirmed urothelial carcinoma (T2-T4a) of the bladder. Patients with mixed histologies are required to have a dominant urothelial carcinoma pattern
NEBULA [37]	NCT02451423	Mar 29, 2016	2024	C1: atezolizumab (single dose) C2: atezolizumab (2 doses) C3: atezolizumab (3 doses)	2	20 total C1: 6 C2: 5 C3: 9	74/26	70	No	100	10	Patients with mixed histology are required to have a dominant urothelial carcinoma pattern
LCCC1520 [32]	NCT02690558	May 1, 2016	2022	C1: pembrolizumab + GC	2	39	82/18	66	Yes	100	26	100% pure urothelial carcinoma
NCT02989584 [54]	NCT02989584	Dec 20, 2016	2022	C1: atezolizumab + GC	1–2	39	85/15	65	Yes	100	–	Pure urothelial cell carcinoma: 61.5% UC w/ squamous cell carcinoma: 23.1% UC w/ nested features: 5.1% UC w/ glandular differentiation: 5.1% UC w/ micropapillary features: 2.6% UC w/ focal plasmocytic features: 2.6%
PURE-01 [36]	NCT02736266	Feb 27, 2017	2022	C1: pembrolizumab	2	155	87.1/12.9	68	Yes	100	6	100% pure urothelial carcinoma
MDACC [10]	NCT02812420	Mar 7, 2017	2020	C1: durvalumab + tremelimumab	1	28	71/29	71	No	97	0	Pure urothelial cell carcinoma: 75% UC w/ squamous cell carcinoma component: 7% UC w/ micropapillary features: 7% UC w/ plasmacytoid features: 7% UC w/ small cell component: 3.5% UC w/sarcomatoid features: 3.5%
PANDORE [55]	NCT03212651	Oct 17, 2017	2019	C1: pembrolizumab	2	39	–	–	No	100	0	100% pure urothelial carcinoma
NABUCCO [31]	NCT03387761	Jan 15, 2018	2024	C1: ipilimumab + nivolumab	1	24	75/25	65	Yes	100	42	100% pure urothelial carcinoma
BLASST-1 [16]	NCT03294304	Jan 29, 2018	2022	C1: nivolumab + GC	2	41	35/65	–	Yes	100	3	100% pure urothelial carcinoma
NCT03520491 [35]	NCT03520491	Apr 25, 2018	2022	C1: nivolumab C2: nivolumab + ipilimumab	2	30 total C1: 15 C2: 15	80/20	76	No	100	0	Histologically confirmed diagnosis of urothelial carcinoma of the bladder. Variant histology is acceptable, if there is a predominant urothelial component
SAKK 06/17 [40]	NCT03406650	May 15, 2018	2023	C1: durvalumab + GC →durvalumab	2	58	79/21	68	Yes	100	17	Pure urothelial carcinoma: 75% UC w/ squamous cell carcinoma: 11% UC with adenocarcinoma: 7% UC w/ other subtypes (sarcomatoid, pleomorphic, large cell neuroendocrine, micropapillary): 7%
AURA [42]	NCT03674424	Jun 1, 2018	2024	C1: avelumab + ddMVAC C2: avelumab + GC C3: avelumab + paclitaxel + gemcitabine C4: avelumab	2	137 total C1: 39 C2: 40 C3: 29 C4: 29	–	–	Yes	100	–	Histologically confirmed urothelial carcinoma or mixed histology with predominant urothelial component (>50%)
HCRN GU16-257 [14]	NCT03558087	Jul 13, 2018	2023	C1: nivolumab + GC	2	76	79/21	69	Yes	100	0	Urothelial carcinoma: 75% UC w/ squamous: 9.2% UC w/ glandular: 2.6% UC w/ micropapillary: 7.9% UC w/ other variant: 5.3%
DUTRENEO [11]	NCT03472274	Oct 25, 2018	2023	C1: cold group —standard cisplatin-based CT (GC or ddMVAC) C2: hot group—standard cisplatin-based CT (GC or ddMVAC) C3: hot group—durvalumab + tremelimumab	2	61 total C1: 16 C2: 22 C3: 23	87/13	66	Yes	C1: 100 C2: 100 C3: 100	C1: 6.3 C2: 4.5 C3: 8.7	Histological documentation of urothelial carcinoma
NEODURVARIB [56]	NCT03534492	Nov 16, 2018	2020	C1: durvalumab + olaparib	2	28	89.7/10.3	70	Yes	100	10.6	Histological confirmation of T2-T4a urothelial carcinoma in the transurethral bladder resection
NIAGARA [8]	NCT03732677	Nov 16, 201	2024	C1: durvalumab + GC →durvalumab C2: cisplatin + gemcitabine	3	1063 total C1: 533 C2: 530	82/18	65	Yes	100	5.3	C1: Urothelial carcinoma: 85.7% UC w/ squamous cell differentiation: 7.1% UC w/ glandular differentiation: 1.9% UC w/ other histological subtype: 5.3% C2: Invasive UC: 83.2% UC w/ squamous cell differentiation: 9.2% UC w/ glandular differentiation: 2.8% UC w/ other histological subtype: 4.7%
NEMIO [41]	NCT03549715	Dec 6, 2018	2023	C1: durvalumab + ddMVAC	1–2	120 total C1: 60 C2: 59	78/22	64	Yes	100	5	Urothelial carcinoma must be >50%
BL-AIR [17]	NCT03498196	Dec 14, 2018	2020	C1: avelumab	1–2	1	100/0	58	No	–	–	–
BLASST-2 [18]	NCT03773666	Feb 20, 2019	2020	C1: durvalumab C2: durvalumab + oleclumab	1	20 total C1: 10 C2: 10	80/20	67	No	100	0	Histologically confirmed bladder urothelial cell carcinoma No component of small cell histology
PrECOG PrE0807 [38]	NCT03532451	Mar 22, 2019	2024	C1: nivolumab C2: nivolumab + lirilumab	1	43	67/33	75	Yes	100	5	Predominant urothelial histology, as well as 20% tumor content at the time of transurethral resection of bladder tumor. The study states that it did not collect data about the possible variant histology components (and the percentages)
NCT03912818 [57]	NCT03912818	Apr 10, 2019	2023	C1: durvalumab + ddMVAC C3: durvalumab + carboplatin + gemcitabine	2	6 total C1: 3 C3: 3	83/17	72	Yes	100	–	Urothelial carcinomas w/ predominant sarcomatoid:16.6% Predominant squamous: 16.6% Predominant plasmacytoid: 16.6% Minority squamous: 33.2% Glandular and sarcomatoid: 16.6%
PIVOT IO 009 [29]	NCT04209114	Feb 5, 2020	2022	C1: nivolumab + B →nivolumab + B C2: nivolumab →nivolumab C3: RC alone	3	114 total C1: 37 C2: 37 C3: 40	80.7/19.3	74	No	100	–	Urothelial carcinoma of the bladder
TRUCE-01 [33]	NCT04730219	Jul 11, 2020	2024	C1: tislelizumab + nab-paclitaxel	2	47	79/21	68	Yes	100	10	Histopathologically confirmed urothelial carcinoma. Patients with mixed histologies are required to have a dominant (ie, 50% at least) urothelial cell pattern
NCT04570410 [30]	NCT04570410	Oct 1, 2020	2024	C1: tislelizumab + GC	2	14	–	67	Yes	100	–	Urothelial carcinoma
NCT04430036 [58]	NCT04430036	Oct 14, 2020	2020	C1: AGEN1884 (anti–CTLA-4 antibody) + AGEN2034 (anti–PD-1) + GC	2	4	50/50	58.5	Yes	100	–	–
NCT04610671 [59]	NCT04610671	Oct 26, 2020	2022	C1: CG0070 + nivolumab	1	21	81/19	75	No	100	–	Histopathologically confirmed urothelial carcinoma, pure or mixed histology urothelial carcinoma
NCT04861584 [34]	NCT04861584	Jun 3, 2021	2023	C1: toripalimab + GC	2	16	75/25	63.5	Yes	100	–	Histopathologically confirmed, locally advanced bladder urothelial carcinoma
ABACUS-2 [19]	NCT04624399	Jul 13, 2021	2023	C1: atezolizumab	2	23	–	70	No	89	0	Histopathologically confirmed carcinoma of the urothelium in the bladder with mixed or rare histological subtypes such as squamous cell or adenocarcinoma. Patients with mixed histologies are required to have a dominant nontransitional cell pattern
ChiCTR2100050763 [13]	ChiCTR2100050763	Sep 20, 2021	2024	C1: tislelizumab	2	21	–	–	Yes	100	–	–
ANTICIPATE [60]	NCT04813107	Dec 28, 2021	2023	C1: APL-1202 (nitroxoline) + tislelizumab	1	9	–	–	No	100	–	Histopathologically confirmed transitional cell carcinoma of the bladder. Patients with mixed histologies are required to have a dominant (ie, >50%) transitional cell pattern
ANTICIPATE II [61]	NCT04813107	Dec 28, 2021	2024	C1: APL-1202 (nitroxoline) + tislelizumab C2: tislelizumab	2	32 total C1:18 C2:14	–	–	No	C1: 61 C2: 72	–	Histopathologically confirmed transitional cell carcinoma of the bladder. Patients with mixed histologies are required to have a dominant (ie, >50%) transitional cell pattern
NURE-COMBO [39]	NCT04876313	Jan 27, 2022	2024	C1: nivolumab + nab-paclitaxel	2	31	–	–	Yes	100	6.4	Urothelial carcinoma: 48.4% Variant histology: 51.6%
SunRISe-4 [62]	NCT04919512	Jul 7, 2022	2024	C1: TAR-200 (intravesical gradual release of gemcitabine) + cetrelimab C2: cetrelimab	2	122 total C1: 80 C2: 42	85/15	73	No	100	0	Histologically proven urothelial carcinoma of the bladder. Participants with variant histological subtypes are allowed if tumor(s) demonstrate urothelial predominance. However, the presence of small cell or neuroendocrine variants will make a participant ineligible

B = bempegaldesleukin; C = cohort; CT = chemotherapy; CTLA-4 = T-lymphocyte–associated protein 4; ddMVAC = dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin; GC = gemcitabine + cisplatin; PD-1 = programmed cell death protein 1; RC = radical cystectomy; UC = urothelial carcinoma; w/ = with.

Fig. 3.

Timeline of all included studies, showing the year of initiation and most recent publication for each. Studies are stratified by the immune checkpoint inhibitor used. CTLA-4 = T-lymphocyte–associated protein 4.

3.5. Pathological response

The concept of a pathological complete response (pCR) is most often defined as pathological pT0N0 and adopted as the primary endpoint in most studies (85.7%). However, one study [14] considered <pT1N0 as the primary endpoint and classified it as a pathological response, while three other studies [16,33,34] used ≤pT1N0 as their pathological response endpoint.

The pCR rates in the immunotherapy arms of studies varied widely, ranging from 0% in the NCT03520491 trial [35], which evaluated durvalumab in combination with carboplatin and gemcitabine, to 54% in the HCRN GU14-188 trial [15], where pembrolizumab was combined with cisplatin and gemcitabine. This significant variability can be attributed to differences in the number of patients in each cohort, the diverse clinical characteristics of patients across studies, and the heterogeneity of treatment regimens employed. These findings highlight the necessity for standardized protocols and larger cohorts to assess the impact of immunotherapy in neoadjuvant settings more accurately.

The NIAGARA study [8], the largest trial involving neoadjuvant immunotherapy, defined pT0N0 as a pCR. In the arm treated with neoadjuvant durvalumab, cisplatin, and gemcitabine followed by adjuvant durvalumab, the pCR rate was 37.3%, compared with 27.5% in the arm receiving neoadjuvant cisplatin and gemcitabine alone. These results underscore the added value of immunotherapy in the neoadjuvant setting compared with chemotherapy alone. When considering patients with a final pathological staging of ≤pT1N0, the immunotherapy group achieved 49.7%, compared with 40.6% in the chemotherapy-only group. Table 2 presents the clinical characteristics and pathological responses.

Table 2.

Pathological responses and oncological outcomes

Trial	Treatment protocol	pCR meaning	pCR rate (%)	pT≤1N0 rate (%)	Survival Outcomes
NCT00362713 [12]	Ipilimumab	–	–	–	–
HCRN GU14-188 [15]	A: Pembrolizumab + GC B: Pembrolizumab + gemcitabine	pT0N0	A: 54 B: 53	A: 41 B: 41	C1: RFS 18 mo, 82%; OS 36 mo, 78.9% C2: RFS 18 mo, 65.1%; OS 36 mo, 65.7%
ABACUS [53]	Atezolizumab	pT0N0	31	–	–
NEBULA [37]	A: Atezolizumab (single dose) B: Atezolizumab (2 doses) C: Atezolizumab (3 doses)	pT0N0	Global: 14 A: 14 B: 14 C: 14	Global: 23 A: 23 B: 23 C: 23	24 mo: RFS—C1: 67%; C2: 83%; C3: 82%; all groups: 77% OS—C1: 80%; C2: 83%; C3: 100%; all groups: 90%
LCCC1520 [32]	Pembrolizumab + GC	pT0N0	36	56	12 mo: EFS: 89% RFS: 75% OS: 91%
NCT02989584 [54]	Atezolizumab + GC	pT0N0	41	69	–
PURE-01 [36]	Pembrolizumab	pT0N0	36.8	16.8	36 mo: RFS: 96.3% for ypT0N0 RFS: 96.1% for ypT1/a/isN0 RFS: 74.9% for ypT2-4N0 RFS: 58.3% for ypTanyN1-3 EFS PD-L1 tertiles (lower tertile: 59.7% vs medium tertile: 76.7% vs higher tertile: 89.8%)
MDACC [10]	Durvalumab + tremelimumab	pT0N0	37.5	58	12 mo: RFS: 82.8%, OS: 88.8%
PANDORE [55]	Pembrolizumab	pT0N0	29.4	–	–
NABUCCO [31]	Ipilimumab + nivolumab	pT0N0	46	58	–
BLASST-1 [16]	Nivolumab + GC	≤T1N0	49	65.9	12 mo: RFS: 85.4% PFS: 83%
NCT03520491 [35]	A: Nivolumab B: Nivolumab + ipilimumab	pT0N0	A: 13 B: 7	A: 26 B: 20	12 mo: C1—EFS: 81%; RFS: 77% C2—EFS: 79%; RFS: 68%
SAKK 06/17 [40]	Durvalumab + GC →durvalumab	pT0N0	32.7	59.6	36 mo: EFS: 73%; OS: 81%
AURA [42]	A: Avelumab + ddMVAC B: Avelumab + GC C: Avelumab + paclitaxel + gemcitabine D: Avelumab	pT0N0	–	–	C1—DFS 12 mo: 97%; DFS 36 mo: 77%; OS 12 mo: 95%; OS 36 mo: 87% C2—DFS 12 mo: 92%; DFS 36 mo: 72%; OS 12 mo: 89%; OS 36 mo: 73% C3—EFS 12 mo: 52%; OS: 67% C4—EFS 12 mo: 68%; OS: 75%
HCRN GU16-257 [14]	Nivolumab + GC	<pT1N0	43	–	–
DUTRENEO [11]	A: Cold group—standard cisplatin-based CT (GC or ddMVAC) B: Hot group—standard cisplatin-based CT (GC or ddMVAC) C: Hot group—durvalumab + tremelimumab	pT0N0	A: 68.8 B: 36.4 C: 34.8	–	–
NEODURVARIB [56]	Durvalumab + olaparib	pT0N0	44.5	–	–
NIAGARA [8]	A: Durvalumab + GC →durvalumab B: Cisplatin + gemcitabine	pT0N0	A: 37.3 B: 27.5	A: 49.7 B: 40.6	24 mo: C1—EFS: 67.8%; OS: 82.2% C2—EFS: 59.8%; OS: 75.2%
NEMIO [41]	A: Durvalumab + ddMVAC B: Durvalumab + tremelimumab+ ddMVAC	pT0N0	Global: 47.8 A: 49 B: 47	Global: 66 A: 71 B: 61	12 mo: C1: DFS: 80%; OS: 89% C2: DFS: 90%; OS: 97%
BL-AIR [17]	Avelumab	–	–	–	–
BLASST-2 [18]	A: Durvalumab B: Durvalumab + oleclumab	pT0N0	12.5	25	–
PrECOG PrE0807 [38]	A: Nivolumab B: Nivolumab + lirilumab	pT0N0	A: 17 B: 21	A: 25 B: 32	24 mo: C1—RFS: 73%; OS: 82% C2—RFS: 71%; OS: 89%
NCT03912818 [57]	A: Durvalumab + ddMVAC B: Durvalumab + GC C: Durvalumab + carboplatin + gemcitabine	pT0N0	A: 33.3 B: 0	A: 0 B: 50	–
PIVOT IO 009 [29]	A: Nivolumab + B →nivolumab + B B: Nivolumab →nivolumab C: RC alone	pT0N0	A: 10.8 B: 10.8 C: 2.5	–	30 mo: C1: EFS: 22% C2: NA C3: EFS: 15%
TRUCE-01 [33]	Tislelizumab + nab-paclitaxel	≤pT1N0	47	34	12 mo: RFS: 82%
NCT04570410 [30]	Tislelizumab + GC	pT0N0	50	57.1	–
NCT04430036 [58]	AGEN1884 (anti–CTLA-4 antibody) + AGEN2034 (anti–PD-1) + GC	pT0N0	50	75	–
NCT04610671 [59]	CG0070 + nivolumab	pT0N0	53	–	–
NCT04861584 [34]	Toripalimab + GC	≤pT1N0	25	85.71	–
ABACUS-2 [19]	Atezolizumab	pT0N0	35	–	–
ChiCTR2100050763 [13]	Tislelizumab	pT0N0	58.8	–	–
ANTICIPATE [60]	APL-1202(nitroxoline) + tislelizumab	pT0N0	12.5	62.5	–
ANTICIPATE II [61]	A: APL-1202(nitroxoline) + tislelizumab B: Tislelizumab	pT0N0	A: 39 B: 21	A: 44 B: 21	–
NURE-COMBO [39]	Nivolumab + nab-paclitaxel	pT0N0	38	72	12 mo: EFS: 96.4%
SunRISe-4 [62]	A: TAR-200 (intravesical gradual release of gemcitabine) + cetrelimab B: Cetrelimab	pT0N0	A: 42 B: 23	A: 60 B: 36	–

B = bempegaldesleukin; C = cohort; CT = chemotherapy; CTLA-4 = T-lymphocyte–associated protein 4; ddMVAC = dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin; DFS = disease-free survival; EFS = event-free survival; GC = cisplatin + gemcitabine; NA = not applicable; OS = overall survival; pCR = pathological complete response; PD-1 = programmed cell death protein 1; PD-L1 = programmed death ligand 1; PFS = progression-free survival; RC = radical cystectomy; RFS = recurrence-free survival.

3.6. Perioperative outcomes

Regarding perioperative outcomes, the lowest completion rate for neoadjuvant therapy was 35% with nivolumab, with the primary adverse event leading to therapy discontinuation being kidney injury, reported in up to 5.7% of cases. The no-surgery rate ranged from 0% to 40%, with the main reasons for not proceeding to surgery being refusal of the procedure (up to 7%) and disease progression (up to 12.5%). Among the studies, only PURE-01 [36] reported the average surgery duration (361 min). The length of hospital stay ranged from 6.1 to 14 d. Intraoperative complications were reported in only two studies: one case of obturator nerve damage [10] and one case of aortic injury [37]. The estimated blood loss ranged from 428 to 444 ml, and the major perioperative complications were reported in 1.8–19% of cases. It is worth noting that most studies did not report perioperative outcomes, highlighting an important area for improvement in future research.

Perioperative surgical outcomes—including intraoperative complications, operative time, need for conversion, surgical approach, and postoperative complications—remain largely under-reported in trials evaluating ICIs in MIBC. Given the increasing integration of ICIs in the neoadjuvant setting, dedicated prospective studies are needed to assess its impact on surgical feasibility and safety. This includes potential changes in tissue characteristics, inflammation, fibrosis, and perioperative morbidity that may influence surgical complexity and patient recovery. Improved understanding of these factors is critical to guide multidisciplinary decision-making and optimize the timing of cystectomy following ICI therapy.

3.7. Oncological outcomes

A minority of the studies reported oncological outcomes, with only 15 out of the 35 studies analyzing such data. Nivolumab was the most frequently studied drug for oncological outcomes [16,29,35,38,39], followed by durvalumab [8,10,40,41]. The studies reporting the highest OS at 12 mo included the following: NEMIO [41], which achieved an OS rate of 97% in patients treated with durvalumab combined with tremelimumab and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); AURA [42], which presented an OS rate of 95% in patients receiving avelumab plus dose-dense MVAC,; and LCCC1520 [32], which reported an OS rate of 91% in patients treated with pembrolizumab, cisplatin, and gemcitabine. For studies reporting OS at 24 mo, the highest OS was observed in the NEBULA [37] study, with a 100% rate of OS in patients who received three doses of atezolizumab, and the PrECOG PrE0807 [38] study, which used nivolumab combined with lirilumab, achieving an OS rate of 89%.

The study with the most robust evidence to date, the NIAGARA [8] trial, adopted event-free survival (EFS) as its primary oncological endpoint, defined as the time from randomization to progressive disease precluding radical cystectomy, the first recurrence of disease after radical cystectomy, the expected date of surgery, or death from any cause. At 24 mo, an EFS rate of 67.8% and an OS rate of 82.2% were reported in patients treated with neoadjuvant durvalumab associated with cisplatin and gemcitabine followed by adjuvant durvalumab. In contrast, the cohort treated with cisplatin and gemcitabine only presented 59.8% EFS rate and 75.2% OS rate.

3.8. Immune- and treatment-related adverse events

The safety and tolerability of treatment are critical factors in determining the success of neoadjuvant regimens for patients undergoing curative-intent therapies. For neoadjuvant approaches incorporating ICIs to become a standard of care, they must demonstrate a safety profile that is comparable to, or better than, the neoadjuvant chemotherapy while also achieving similar or superior efficacy. ICIs, while promising, can lead to irAEs, which are off-target inflammatory effects that may impact multiple organ systems. The characteristics, frequency, and timing of these irAEs vary depending on the specific ICI utilized. While most irAEs tend to be mild to moderate and respond effectively to corticosteroid treatment, severe and clinically significant cases can occur, necessitating careful monitoring and management [43].

The regimens associated with the highest incidence of irAEs were avelumab in the BL-AIR [17] study (100%), durvalumab combined with tremelimumab in the MDACC [10] study (100%), and nivolumab combined with ipilimumab in the NABUCCO [31] study (100%). The lowest rates of irAEs were observed with durvalumab and tremelimumab in the NEMIO [41] study (0%) and with pembrolizumab in the LCCC1520 [32] study (2.5%). For grade 3 and 4 irAEs, the highest rates were reported with nivolumab combined with ipilimumab in the NABUCCO [31] study (54%) and with durvalumab combined with tremelimumab [64%]. Hepatitis was the most frequently reported irAE, cited in 16 studies, with incidences ranging from 2% to 27%. Kidney injury was reported in 11 studies, with rates ranging from 2% to 100%. Skin rash was reported in 15 studies, with incidence ranging from 1.1% to 41%. The regimen most associated with delays in radical cystectomy was durvalumab combined with tremelimumab, with a 13% delay rate in the DUTRENEO [11] study. The irAEs are summarized in Table 3.

Table 3.

Immune-related adverse events

Trial	Treatment	Number of patients	Any irAE, n (%)	G3/G4 irAE, n (%)	Most common (G3/G4)	RC withheld because of TRAEs	Treatment discontinuation
ABACUS [53]	Atezolizumab	87	6 (6.8)	6 (6.8)	Hepatitis (4.5%)/skin rash (1.1%)/myocarditis (1.1%)	3 (3.5%)	Yes (3%)
ABACUS-2 [19]	Atezolizumab	23	3 (13)	1 (4.3)	Hepatitis (9%)/kidney injury (4%)	No	No
ANTICIPATE [60]	Tislelizumab and APL-1202 (nitroxoline)	9	–	–	Hepatitis (11.1%)	–	No
ANTICIPATE II [61]	A: Tislelizumab and APL-1202 (nitroxoline) B: Tislelizumab	32 total A: 18 B: 14	2 (11) 2 (14.3)	– –	Kidney injury (5.5%)/hepatitis (5.5%) Immune hyperthyroidism (14.3%)	Yes Yes	Yes (11.1%) Yes (7.2%)
AURA [42]	A: Avelumab + ddMVAC B: Avelumab + GC C: Avelumab + paclitaxel + gemcitabine D: Avelumab	137 total A: 39 B: 40 C: 29 D: 29	– – – –	– – – –	–	2 (1.4%)	–
BL-AIR [17]	Avelumab	1	1 (100)	0	Kidney injury (100%)	–	Yes (100%)
BLASST-1 [16]	Nivolumab + GC	41	28 (68)	0	Skin rash (30%)/hepatitis (27%)/kidney injury (7%)	No	No
BLASST-2 [18]	A: Durvalumab B: Durvalumab + oleclumab	20 total A: 10 B: 10	– –	– –	– –	– –	No
ChiCTR2100050763 [13]	A: Cisplatin + gemcitabine + tislelizumab B: Carboplatin + gemcitabine + tislelizumab	21 total	– –	– –	–	No No	–
DUTRENEO [11]	A: Cold group—standard cisplatin-based CT (GC or ddMVAC) B: Hot group—standard cisplatin-based CT (GC or ddMVAC) C: Hot group—durvalumab + tremelimumab	61 total A: 16 B: 22 C: 23	0 2 (12.5) 5 (21)	0 1 (4.5) 1 (4.3)	Absent Skin rash (4%) Skin rash (8%)/hepatitis (2%)	1 (6%) 2 (9%) 3 (13%)	No
HCRN GU14-188 [15]	A: GC + pembrolizumab B: Gemcitabine + pembrolizumab	82 total A: 42 B: 40	– –	10 (11.2) – –	Hepatitis (3.7%)/skin rash (2.5%)/pneumonitis (2.5%)/colitis (2.5%)	– –	–
HCRN GU16-257	GC + nivolumab	76	70 (92)	1 (1.3)	Kidney injury (50%)/hepatitis (25%)/skin rash (17%)	–	–
LCCC1520 [32]	Pembrolizumab + GC	39	1 (2.5)	1 (2.5)	Diabetes mellitus (2.5%)	No	Yes (2%)
MDACC [10]	Durvalumab + tremelimumab	28	30 (100)	18 (64)	Skin rash (29%)/amylase increased (29%)/hepatitis (21%)/lipase increased (18%)/colitis (11%)	2 (7%)	Yes (7%)
NABUCCO [31]	Nivolumab + ipilimumab	24	24 (100)	13 (54)	Lipase increased (33%)/diarrhea (21%)/hepatitis (21%)/skin rash (21%)/colitis (12%)	1 (4%)	Yes (25%)
NCT00362713 [12]	Ipilimumab	6	–	–	–	–	–
NCT02989584 [54]	Atezolizumab + GC	39	47 (100)	7 (18)	Pancreatitis (9%)/hepatitis (2%)/kidney injury (2%)/skin rash (2%)	No	No
NCT03520491 [35]	A: Nivolumab B: Nivolumab + ipilimumab	30 total A: 15 B: 15	– –	– –	Myocardites (1.7%) Lipase increase (20%)/hepatitis (33%)	1 (6.6%) 2(13%)	Yes (6.6%) Yes (13%)
NCT03912818 [57]	A: Durvalumab + ddMVAC B: Durvalumab + GC C: Durvalumab, carboplatin, and gemcitabine	6 total A: 3 B: 0 C: 3	0 – 1 (33)	0 – 0	Absent – Kidney injury (33%)	No – No	No – No
NCT04430036 [58]	AGEN1884 (anti–CTLA-4 antibody) + AGEN2034 (anti–PD-1) + GC	4	2 (50)	0	Hepatitis (25%)/skin rash (25%)	No	No
NCT04610671 [59]	Nivolumab + CG0070	21	1(5)	0	Thyroiditis (5%)	No	No
NCT04861584 [34]	Toripalimab + GC	16	5 (30)	0	Thyroiditis (18.75%)/skin rash (12.5%)	–	No
NEBULA [37]	A: Atezolizumab (single dose) B: Atezolizumab (2 doses) C: Atezolizumab (3 doses)	20 total A: 6 B: 5 C: 9	2 (33) 1 (20) 6 (66)	0 0 0	Kidney injury (33%) Skin rash (20%) Kidney injury (27%)/skin rash (18%)/hepatitis (9%)	No No No	No No No
NEMIO [41]	A: Durvalumab + ddMVAC B: Durvalumab, tremelimumab + ddMVAC	120 total A: 60 B: 59	0 0	0 0	Absent Absent	– –	No No
NEODURVARIB [56]	Durvalumab + olaparib	28	–	–	–	–	–
NIAGARA [8]	A: Durvalumab + GC →durvalumab B: GC	1063 total A: 533 B: 530	98 (18.5) 77 (14.6)	11 (2) 4 (0.75)	Kidney injury (18.5%) Kidney injury (14.6%)	9 (1.7%) 6 (1.1%)	Yes (21.1%) Yes (15.1%)
NURE-COMBO [39]	Nivolumab + nab-paclitaxel	31	7 (22.6)	1 (3.2)	Hepatitis (22.6%)	–	Yes (16.1%)
PANDORE [55]	Pembrolizumab	39	–	–	–	–	–
PIVOT IO 009 [29]	A: Nivolumab + B B: Nivolumab C: Radical cystectomy	114 total A: 37 B: 37 C: 40	10 (27) 10 (27) 0	– – 0	Kidney Injury (13.5%)/skin rash (10.81%)/amylase increased (5.4%) Kidney injury (10.81%)/skin rash (10.81%)/arthritis (5.4%)/0	– – –	Yes (21.6%) Yes (21.6%) No
PrECOG PrE0807 [38]	A: Nivolumab B: Nivolumab and lirilumab	43 total A: 13 B: 30	1 (8) 3 (10)	0 0	Skin rash (8%) Skin rash (10%)	No No	No No
PURE-01 [36]	Pembrolizumab	155	11 (7.1)	2 (1.2)	Hepatitis (3.9%)/skin rash (3.2%)	No	No
SAKK 06/17 [40]	Durvalumab + cisplatin-gemcitabine	58	29 (50)	7 (12)	Hepatitis (14%)/diarrhea (12%)/lipase or amylase increased (11%)	No	No
SunRise-4 [62]	A: TAR-200 (intravesical gradual release of gemcitabine) and cetrelimab B: Cetrelimab	122 total A: 80 B: 42	– –	– –	– –	No No	Yes (8.9%) Yes (7.6%)
TRUCE-01 [33]	Tislelizumab + nab-paclitaxel	47	26 (55)	4 (8.4)	Skin rash (41%)/kidney injury (14%)	–	Yes (6.3%)

B = bempegaldesleukin; CT = chemotherapy; CTLA-4 = T-lymphocyte–associated protein 4; ddMVAC = dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin; G = grade; GC = cisplatin + gemcitabine; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; RC = radical cystectomy; TRAE = treatment-related adverse event.

The irAEs are related to immunotherapeutic agents, particularly the ICIs. In contrast, treatment-related adverse events (TRAEs) refer to the side effects or complications that arise directly from any medical treatments, including both chemotherapy and immunotherapy [43]. Among the clinical trials comparing neoadjuvant immunotherapy and chemotherapy, the NIAGARA [8] and DUTRENEO [11] studies provided a comparative analysis of TRAE incidences. The NIAGARA [8] trial reported a similar frequency of grade 3–4 TRAEs in both the ICI group (40.6%) and the chemotherapy group (40.9%), showing no significant difference. However, the DUTRENEO [11] trial highlighted a higher incidence of grade 3–4 TRAEs—including neutropenia, thrombocytopenia, asthenia, and mucosal inflammation—among patients receiving neoadjuvant chemotherapy.

3.9. Biomarkers

The identification of reliable predictive biomarkers for an ICI response is crucial to minimize treatment-associated toxicities and reduce the financial strain on health care systems caused by ineffective therapies. Among the most extensively studied biomarkers are PD-L1 expression (evaluated through immunohistochemistry), tumor mutational burden (reflecting the median number of mutations per megabase), and microsatellite instability [[44], [45], [46]]. The FDA has approved tumor mutational burden testing for patients with unresectable or metastatic solid tumors as a criterion for pembrolizumab treatment following progression after prior therapies [44]. PD-L1 expression by immunohistochemistry is a widely adopted predictive tool for assessing the response to anti–PD-1 and anti–PD-L1 therapies across various tumor types [45]. PD-L1 expression can be quantified through methods such as the tumor proportion score, which measures PD-L1 in tumor cells, or the combined positive score, which includes staining in tumor cells as well as immune cells [46]. However, significant limitations exist in the predictive power of PD-L1 expression. Some patients with low or undetectable PD-L1 expression have experienced durable responses to ICI treatment, raising concerns about the assay's sensitivity [47]. On the contrary, cases of PD-L1–positive patients who fail to respond to ICI therapy further highlight the need for improved predictive methods [48]. This underlines the necessity for the development of more robust and accurate biomarkers to predict ICI responses.

4. Discussion

4.1. The future of neoadjuvant immunotherapy: ongoing trials and biomarkers

The three largest ongoing phases 3 studies, with awaited results, involve patients with clinical staging T2-T4aN0M0 and predominant (>50%) urothelial histology. The KEYNOTE-866 [49] trial, initiated in 2019, includes two arms: one with neoadjuvant pembrolizumab and the other with platinum-based neoadjuvant chemotherapy. The trial has an actual enrollment of 907 patients, and the primary endpoints are pCR and EFS. The CA017-078 [50] trial launched in 2018 includes two arms: one with neoadjuvant gemcitabine and cisplatin, and another with the same chemotherapy agents combined with neoadjuvant nivolumab, followed by adjuvant nivolumab postoperatively. The trial has recruited 861 patients so far, with a target enrollment of 1200 patients. Its primary endpoints are pCR and EFS. Lastly, the KEYNOTE-905 [51] trial, which began in 2019, has three arms: one arm receiving neoadjuvant and adjuvant pembrolizumab, a second arm receiving only radical cystectomy, and a third arm involving neoadjuvant enfortumab vedotin combined with pembrolizumab, followed by adjuvant enfortumab vedotin and pembrolizumab. The study has currently enrolled 595 patients, with a target of 610 patients, and its primary endpoint is EFS.

The integration of magnetic resonance imaging with radiomics and circulating tumor DNA (ctDNA) to detect residual disease after neoadjuvant therapy cycles may further refine treatment strategies, and in the future, new trials exploring less invasive strategies, including bladder preservation approaches, could benefit from immunotherapy advancements [52].

Histological variants of urothelial carcinoma, including micropapillary, plasmacytoid, and sarcomatoid subtypes, exhibit aggressive clinical behavior, early dissemination, and limited responsiveness to conventional neoadjuvant chemotherapy. The NIAGARA trial [8] included patients with variant histologies: squamous differentiation was present in 7.1% of patients in the durvalumab arm and 9.2% in the control arm; glandular variants were present in 1.9% and 2.8%, respectively; and other variants were present in 5.3% and 4.7%, respectively. In a prespecified subgroup analysis, patients with variant histologies demonstrated a favorable response to perioperative immunotherapy, with a hazard ratio for EFS of 0.52 (95% confidence interval, 0.32–0.84), exceeding that of patients with pure urothelial carcinoma. These findings may signal a paradigm shift, positioning ICI therapy as a neoadjuvant option not only for cisplatin-ineligible patients, but also for those harboring aggressive variant subtypes. However, further analyses with larger cohorts and trials specifically designed to evaluate histological variants are warranted to substantiate this potential change in clinical practice.

Another important topic that remains under investigation is the optimal timing of systemic immunotherapy in MIBC. Neoadjuvant immunotherapy offers theoretical advantages, such as the preservation of tumor architecture and microenvironment, which may enhance antigen presentation and immune priming. Furthermore, preoperative assessment of a pathological response to immunotherapy may assist in stratifying patients who could benefit from postoperative treatment intensification.

Conversely, adjuvant immunotherapy has yielded mixed results. The IMvigor010 trial failed to demonstrate benefit with atezolizumab, while CheckMate-274 showed improved disease-free survival with adjuvant nivolumab, particularly among patients with PD-L1–positive tumors. These trials enrolled heterogeneous populations, and patient selection may have influenced the outcomes. Additionally, the JAVELIN Bladder 100 trial, although conducted in the metastatic setting, supports the concept of postplatinum immunotherapy and indirectly informs adjuvant strategies in high-risk localized disease.

In the absence of validated predictive biomarkers—such as ctDNA dynamics or immune gene expression signatures—treatment intensification cannot be personalized yet. Therefore, clinical decisions should integrate individual risk profiles, pathological response, and tumor characteristics. Future risk-adapted strategies incorporating molecular profiling, including PD-L1 expression and postoperative ctDNA status, may help optimize therapeutic benefit while avoiding unnecessary systemic exposure.

New studies on neoadjuvant therapy in patients with bladder tumors are numerous, and their results are expected to be published in the coming years, which will allow for a better understanding of immunotherapy in this clinical setting.

5. Conclusions

The phase 3 results of the NIAGARA trial shed light on the survival advantages of perioperative chemoimmunotherapy over traditional neoadjuvant chemotherapy, positioning ICIs as a potential emerging standard for neoadjuvant therapy for MIBC in the coming years. This is particularly relevant for patients who cannot undergo chemotherapy due to comorbidities or poor performance status.

Nevertheless, irAEs pose a significant obstacle, impacting a substantial proportion of patients and, in some cases, leading to treatment discontinuation. Additionally, the financial burden of ICI therapy may limit its accessibility. To address these challenges, future research should prioritize the development of ICIs with reduced adverse effects and explore optimized dosing protocols to enhance treatment safety and efficacy. The outcomes of ongoing studies are anticipated to confirm the role of ICIs as the new gold standard in neoadjuvant therapy for MIBC.



Author contributions: Caio Vinicius Suartz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.



Study concept and design: Suartz, Fradet.

Acquisition of data: Suartz, de Lima, de almeida, Liebl, Lopes, Sant’Anna, Reis, de Campos.

Analysis and interpretation of data: Suartz.

Drafting of the manuscript: Suartz, de Lima, de almeida, Liebl, Lopes, Sant’Anna, Reis, de Campos, Mota, Melão, Nahas, Shahrour, Shabana, Ribeiro-Filho, Toren, Fradet.

Critical revision of the manuscript for important intellectual content: Suartz, de Lima, de almeida, Liebl, Lopes, Sant’Anna, Reis, de Campos, Mota, Melão, Nahas, Shahrour, Shabana, Ribeiro-Filho, Toren, Fradet.

Statistical analysis: Suartz.

Obtaining funding: Fradet.

Administrative, technical, or material support: Suartz, de Lima, de almeida, Liebl, Lopes, Sant’Anna, Reis, de Campos, Mota, Melão, Nahas, Shahrour, Shabana, Ribeiro-Filho, Toren, Fradet.

Supervision: Fradet.

Other: None.



Financial disclosures: Caio Vinicius Suartz certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.



Funding/Support and role of the sponsor: None.

Associate Editor: M. Carmen Mir

Appendix A. Supplementary material

The following are the Supplementary data to this article: