Clinical benefits, tolerability, and risk factors of adjuvant nivolumab for muscle-invasive bladder cancer

Introduction

Radical cystectomy (RC) was previously the standard treatment procedure for bladder cancer; however, the development of minimally invasive surgery (MIS) has progressed with the advancement of surgical robot systems over the last two decades (1). Especially, robot-assisted surgery has played a central role in urological surgery. Regarding bladder tumor surgery, Menon et al. first reported robot-assisted radical cystectomy (RARC) for bladder cancer patients (2). RARC is more favorable than ORC regarding: minimizing blood loss and blood transfusions, promoting a shorter hospital stay, and reducing the risk of thromboembolic events (3). However, postoperative survival outcomes have not been influenced by the evolution of surgical methods (4).

Recently, the necessity of neoadjuvant or adjuvant therapy has been highlighted in patients with bladder cancer, as it improves disease-free survival (DFS) and overall survival (OS) for patients who undergo radical cystectomy. Especially, adjuvant therapy has been markedly influenced by the CheckMate 274 trial (5). In this trial, adjuvant nivolumab improved DFS and OS of patients with urothelial carcinoma, with a more significant impact on bladder cancer compared with upper-tract urothelial carcinoma (UTUC). Adjuvant nivolumab was approved in April 2022 for insurance coverage in Japan, and it is now widely used for urothelial carcinoma patients who have undergone radical cystectomy or nephroureterectomy; however, there is limited real-world evidence in this setting.

The purpose of the present study was to compare the clinical benefits for patients with muscle-invasive bladder cancer (MIBC) who underwent RARC followed by adjuvant nivolumab versus those who did not. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0346/rc).

Methods

To research the feasibility, safety and risk factors of adjuvant nivolumab, we analyzed the bladder cancer patients who received RARC in Hamamatsu University School of Medicine (HUSM). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Hamamatsu University School of Medicine (approval No. 21–090). Informed consent for study involvement was obtained from all included patients.

Patients

The 162 patients have received RARC in HUSM. In this study, we focused these patients to analyze adjuvant therapy. This retrospective study included 60 patients with MIBC who underwent RARC and were eligible for nivolumab between January 2017 and July 2025 at HUSM. Thirty patients did not receive nivolumab before marketing approval (~July/2021) (n=15) or did not receive it due to the decision-making process (July/2021~) (n=15). While the remaining 30 patients received nivolumab (Figure 1). In this cohort, we excluded “salvage or palliative cystectomy” as a definitively positive surgical margin. As for cases with positive surgical margins that were included in the study, these include minor CIS in the urethra, exposure of a tumor measuring a few millimeters, and the possibility of a ureteral tumor based on intraoperative rapid pathology examination results.

Figure 1 Flow chart of indications for adjuvant treatment in the study population. Nivo, nivolumab.

We analyzed prognostic outcomes and adverse events to compare the two groups.

Eligibility criteria for nivolumab

Based on the CheckMate 274 trial, eligible patients either had a history of receiving neoadjuvant platinum-based chemotherapy (ypT2–ypT4a or ypN1), had not received neoadjuvant platinum-based chemotherapy, were ineligible for or declined adjuvant cisplatin-based chemotherapy (ypT3–ypT4a or ypN1), and underwent radical cystectomy (5).

Evaluation

We assessed patients using clinicopathological diagnosis according to the tumor-node-metastasis (TNM) classification on cancer staging, jointly developed by the American Joint Commission on Cancer (AJCC) (6). All patients underwent computed tomography (CT) of the chest to pelvis for evaluation every three months after surgery. The presence of recurrence was evaluated using the Response Evaluation Criteria in Solid Tumors guidelines (version 1.1) as: appearance of the new lesion (local in the urothelial tract, local outside the urothelial tract, or distant recurrence) (7).

Endpoints

The endpoint of interest was DFS, determined as the time between the date of surgery and date of first recurrence or death from cancer-specific causes, whichever occurred first. The second endpoint was cancer-specific survival (CSS), determined as death from urothelial carcinoma.

Statistical analysis

All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, ver. 1.40). P values <0.05 or standardized mean difference (SMD) >0.2 were considered imbalanced. Differences between the two groups were assessed using χ² or Fisher’s exact tests. CSS and DFS were estimated using the Kaplan-Meier method, and differences and hazard ratios (HRs) were determined with the Cox proportional hazards regression model. In addition, inverse probability of treatment weighting (IPTW) was used to determine adjusted HR (aHR). Nonlinear terms for predictors, using restricted cubic splines, were incorporated into the multivariable analysis for distinct risk factors. And we estimated CSS each risk factors. Sensitivity analysis was conducted to generate E-values, which were used to verify the robustness of results. An E-value ≥2.0 was considered significant. Although missing data planned to be omitted by pairwise deletion, there were no missing data in baseline characteristics and outcomes.

Results

Patient characteristics

Table 1 summarizes the characteristics of the 60 enrolled patients with bladder cancer who underwent RARC followed by observation (no-Nivo) or adjuvant nivolumab (Nivo). The median age, body mass index, sex (male), and performance status =0 were: 71 vs. 74 years (SMD =0.36), 22.3 vs. 22.2 (SMD =0.15), 80 vs. 83.3% (SMD =0.09), and 56.7 vs. 60.0% (SMD =0.07), respectively. A total of 83.3 vs. 93.3% (SMD =0.33) of patients received cisplatin- or carboplatin-based neoadjuvant chemotherapy, respectively. All patients underwent RARC; there were no marked differences between the two groups regarding the operative time, number of urethrectomies, domain of lymph node dissections (LNDs), or post-surgical complications. Furthermore, there were no significant differences in the histological type, ypT stage, or ypN stage between the two cohorts; however, positive surgical margins differed between the groups (13.3 vs. 3.3%, SMD =0.37).

Treatment outcomes

Table 2 shows the treatment outcomes. In the no-Nivo group, only four patients (13.3%) received adjuvant platinum-based chemotherapy. The number of recurrences tended to be higher in the no-Nivo group compared with the Nivo group.

Disease-free and cancer-specific-free survival

Figure 2 shows Kaplan-Meier curves for DFS and CSS. DFS in the Nivo group was significantly longer than in the no-Nivo group [median, 26.0 vs. 9.4 months, respectively; aHR: 0.44 (95% confidence interval (CI): 0.22–0.88); P=0.02; E-value =3.97] (Figure 2A). Only one patient was urothelial tract recurrence. Absolute recurrence ratio at 24 months were 42.7% and 31.9%, respectively. There were no significant differences in CSS between the two groups [median, NR vs. NR; aHR: 0.40 (95% CI: 0.14–1.10); P=0.08; E-value =4.57] (Figure 2B). Absolute cancer-specific death ratio at 24 months were 83.6% and 62.6%, respectively. In this cohort, we considered proportional hazards to be met based on a parallel log-log plot of Kaplan-Meier curves (Figure S1). We applied IPTW to balance baseline characteristics (adjusted for age, NAC type, and surgical margin) between the no-Nivo and Nivo groups. Figure S2 shows the Love Plot, which demonstrates that each parameter is balanced on SMD <0.2. As presented in Table 3, the following factors were significantly correlated with poor DFS in multivariable analyses: ≥ pT3, pN+, and no nivolumab therapy.

Figure 2 Survival outcomes of patients with muscle-invasive bladder cancer who underwent robot-assisted radical cystectomy. (A) Kaplan-Meier curves for DFS. Median DFS: 26.0 vs. 9.4 months; aHR: 0.44 (95% CI: 0.22–0.88); P=0.02. (B) Kaplan-Meier curves for CSS. Median CSS: NR vs. NR; aHR: 0.40 (95% CI: 0.14–1.10); P=0.08. Significance was assessed using univariable Cox proportional hazards modeling. In addition, IPTW was used to adjust for age, neoadjuvant chemotherapy type, and surgical margin. aHR, adjusted hazard ratio; CI, confidence interval; CSS, cancer-specific survival; DFS, disease-free survival; IPTW, inverse probability of treatment weighting; Nivo, nivolumab; NR, not reported.

Based on the three factors identified by the multivariable analysis, we assessed DFS for ≥ pT3 or pN+ using Kaplan-Meier curves (Figure 3). We found no significant difference between ≥ pT3 and < pT3 groups in the nivolumab cohort (aHR: 0.98; 95% CI: 0.25–3.90; E-value =1.16); however, pN+ remained a high-risk factor even in this cohort (aHR: 4.22; 95% CI: 1.19–15.1; E-value =7.90).

Figure 3 Survival outcomes by pathological risk of patients with muscle-invasive bladder cancer who underwent robot-assisted radical cystectomy. (A) Kaplan-Meier curves for DFS and adjusted hazard ratio against ≥ pT3 vs. < pT3. Median DFS for Nivo group: 26.0 months vs. NR. Median DFS for no-Nivo group: 5.8 vs. 16.5 months. (B) Kaplan-Meier curves for DFS and adjusted hazard ratio against pN+ vs. pN−. Median DFS for Nivo group: 12.5 months vs. NR. Median DFS for no-Nivo group: 3.2 vs. 16.4 months. Significance was assessed using univariable Cox proportional hazards modeling. In addition, IPTW was used to adjust for age, neoadjuvant chemotherapy type, and surgical margin. aHR, adjusted hazard ratio; CI, confidence interval; DFS, disease-free survival; IPTW, inverse probability of treatment weighting; N, node; Nivo, nivolumab; NR, not reported; T, tumor.

Safety outcome

Table 4 presents immune-related adverse events (irAEs) in the Nivo group. Overall, 36.7% of patients experienced at least one grade 1 or higher adverse event, 13.3% experienced grade 3 or higher, and 3 patients (10%) discontinued treatment due to toxicity.

First life-prolonging therapy

The first subsequent therapy is shown in Table 5. In the no-Nivo group, 18 patients (82%) received some form of treatment, and 4 (19%) received best supportive care (BSC). In the Nivo group, 11 patients (85%) received some form of treatment, and 2 (15.3%) received BSC. The most commonly selected agent in the no-Nivo group was pembrolizumab (38%); in contrast, enfortumab vedotin (EV) + pembrolizumab was the most commonly selected in the Nivo group (54%). Notably, 4 of 8 patients in the no-Nivo group who received pembrolizumab subsequently received EV.

Discussion

In recent years, significant changes have been made in therapeutic strategies for patients with muscle-invasive and high-grade non-muscle invasive bladder cancer. Notably, several novel systemic therapies, including neoadjuvant platinum-based therapy combined with simultaneous or adjuvant immunotherapy, have been adopted in real-world practice (5,8,9).

In accordance with the CheckMate 274 study, adjuvant therapy for patients with muscle-invasive urothelial carcinoma who had undergone radical surgery followed by nivolumab was first accepted, some real-world data were published (10); however, few comparative studies have been reported.

In addition, the response to adjuvant nivolumab in UTUC patients is controversial (5). Therefore, at HUSM, we restrict the use of adjuvant nivolumab for UTUC to limited purposes. Furthermore, HUSM is a high-performance center for RARC. Collectively, we have focused on bladder cancer patients and planned a comparative study of adjuvant nivolumab versus no adjuvant nivolumab.

Previously, open radical cystectomy (ORC) was the standard treatment procedure for patients with bladder cancer; however, the development of MIS has progressed with surgical robot system advancement over the last two decades (1). There are no significant differences in survival outcomes between patients receiving ORC and RARC (4), although we consider that MIS allows more effective introduction of perioperative drug administration.

In our cohort, the relatively high proportion of patients who received carboplatin-based neoadjuvant chemotherapy (approximately 40–50%) is noteworthy. While some publications have explored this approach and reported encouraging results in selected settings, particularly among cisplatin-ineligible patients (11), the available evidence continues to support cisplatin-based neoadjuvant chemotherapy as the recommended standard of care, whereas carboplatin-based regimens have not demonstrated equivalent levels of evidence in the neoadjuvant setting. However, in clinical practice, we select carboplatin due to factors such as renal function, advanced age, comorbidities, and the waiting period before surgery. We apply carboplatin for patients who are older (80~ years), have chronic kidney disease, and/or cardiovascular disease. Indeed, the number of patients who matched those criteria in carboplatin group is significantly more than those in cisplatin group (67% vs. 23%, P<0.05).

In the present series, differences in patient characteristics were observed; therefore, we used the IPTW method to evaluate DFS and CSS in the two groups. DFS was significantly longer in the Nivo than no-Nivo group (median, 26.0 vs. 9.4 months, respectively). In the CheckMate 274 extended follow-up, median DFS of bladder cancer patients was 25.6 and 8.5 months in the nivolumab and placebo groups, respectively (12). These results are comparable to our findings. Barragán-Carrillo et al. reported a retrospective, multi-institutional study of 253 patients who received adjuvant nivolumab, with the following data: bladder cancer patients comprised 94.5%, the median follow-up was 12.7 months, DFS was not reached, and 15.8% (40/253) of patients experienced recurrence (13). These findings suggest that adjuvant nivolumab for bladder cancer in real-world practice may have a meaningful impact rather than a phase 3 trial.

We analyzed risk factors for DFS in this cohort, and identified ≥ pT3, pN+, and no nivolumab therapy as significant (Table 3). Furthermore, we evaluated each risk group as ≥ pT3 or < pT3, and pN+ or pN− for the Nivo and no-Nivo groups using Kaplan-Meier curves. Despite receiving nivolumab, pN+ patients had significantly shorter DFS than pN− patients. Nakagawa et al. reported that pN of ≥ 1 is a poor prognostic factor for both DFS and OS, and is one of the definitions of high-risk UC (14). This agreed with our results; more intensive therapy may be necessary for pN+ bladder cancer patients.

There was no significant difference in CSS between our patient groups. This was the most biased and limiting aspect of this study. Given the retrospective nature of the study and the evolution of therapeutic strategies throughout the study period, each group has heterogeneity factors. This may act as a confounding factor when interpreting overall survival outcomes, although its impact on disease-free survival is likely to be less pronounced. The first subsequent therapy varies by treatment timing (Table 5). Pembrolizumab was the most commonly selected agent in the no-Nivo group, while EV + pembrolizumab was the most commonly selected in the Nivo group. However, the no-Nivo group received EV monotherapy as secondary treatment; consequently, 8 patients were administered EV-based therapy. There is general consensus that EV-based therapy is acceptable as first- and late-line therapy for patients with advanced urothelial carcinoma (15,16). This might lead to a turning point for postoperative patients in real-world practice. The two-year CSS rates in our data were 84% (Nivo group) and 63% (no-Nivo group), and aHR was 0.4, suggesting a potential benefit of nivolumab; however, further studies are warranted to confirm this. As a future consideration, the effectiveness of “nivolumab” followed by EV + “pembrolizumab” must be assessed regarding immunotherapy sequences. Nevertheless, ICIs combined with ADCs can lead to synergistic effects in the treatment of urogenital tumor patients through immunogenic cell death (17). Therefore, we will continue to select nivolumab followed by EV + pembrolizumab.

Our Nivo group tended to exhibit fewer irAEs (Table 4). In the phase 3 trial, nivolumab-related adverse events (AEs) occurred in 77.5% of patients (5). In contrast, 20–65% of AEs were observed in real-world practice (10,13,14). We were able to administer nivolumab relatively safely at HUSM.

Recently published phase 3 results from the NIAGARA trial showed that perioperative durvalumab with NAC was associated with improved event-free and overall survival compared with NAC alone (8). In real-world practice, the question is whether to administer adjuvant durvalumab even in cases that achieve pCR. Furthermore, the phase III KEYNOTE-905/EV-303 study (NCT03924895) evaluated perioperative EV + pembrolizumab versus RC alone in cisplatin-ineligible patients with MIBC (18). Recently updated data presented at ESMO 2025 showed that EV + pembrolizumab significantly improved event-free survival (median, NR vs. 15.7 months, respectively; HR: 0.40), OS (median, NR vs. 41.7 months, respectively; HR: 0.50), and the pathological complete-response rate (57.1 vs. 8.6%, respectively) compared with RC alone; however, grade ≥3 AEs occurred in 71.3% of patients. In real-world practice, we have no definitive information on whether these AEs are tolerable for patients in the perioperative phase.

In this regard, adjuvant nivolumab is a reasonable treatment option that can be administered only in high-risk cases and may be associated with a low incidence of adverse events in real-world settings. As we enter an era of multiple treatment options, we hope that our report on bladder cancer will serve as one of the comparison points for future practice, including NIAGARA and EV303.

Several limitations of this study should be noted. First, this was a single-arm retrospective study with a small sample size. In addition, the two groups received different subsequent therapies due to differences in treatment timing; therefore, the meaning of CSS in our study is controversial. A multi-institutional, prospective, and comparative study is needed. Second, we could not assess patients with UTUC. Third, this study may have been subject to selection bias due to physician involvement and real-world practice. Additionally, our trial lacked central review and relied on individual physicians’ assessments of objective responses.

Conclusions

In conclusion, this was a comparative study of 60 patients receiving/not receiving adjuvant nivolumab. DFS was significantly longer in the Nivo group; however, CSS did not differ significantly. As it prolongs DFS, we consider that adjuvant nivolumab provides a benefit for high-risk bladder cancer patients. Furthermore, pN+ was one of the risk factors associated with shorter DFS. In the future, the new regimen will be implemented in real-world practice. To confirm optimal treatment for each patient, further comparative studies involving patients with bladder cancer will be necessary.

Acknowledgments

We thank the Department of Urology, HUSM, for supporting our research efforts.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0346/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0346/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0346/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0346/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Hamamatsu University School of Medicine (approval No. 21–090). Informed consent for study involvement was obtained from all included patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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