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Evaluating the efficacy and safety of bladder-sparing regimen with Disitamab Vedotin combined with Toripalimab and pelvic lymph node dissection in muscle-invasive bladder cancer patients: study protocol of a multicenter single-arm phase II trial

BMC Cancer volume 25, Article number: 868 (2025) Cite this article

Abstract

Background

Muscle invasive bladder cancer (MIBC) is a malignancy with high recurrence and metastasis rate. Radical cystectomy and lymph node dissection are the current standard cares for MIBC. The demand for bladder preservation in MIBC patients is growing daily; however, the recognized trimodal bladder-sparing regimen has been shown to have substantial radiation damage and inconsistent efficacy in numerous investigations. In order to address these issues, a secure and efficient bladder preservation program is desperately needed. Therefore, a novel bladder-sparing modality that employing antibody-drug conjugates and immune checkpoint inhibitors combined with pelvic lymph node dissection is worth investigating further in this setting.

Methods

In this multicenter, single-arm clinical trial, subjects who were diagnosed with muscle-invasive bladder cancer with human epidermal growth factor receptor-2 expression ≥ 2 + will be enrolled. Eligible subjects will receive 12 cycles Disitamab Vedotin combined with Toripalimab treatment and pelvic lymph node dissection after completed transurethral bladder tumor resection, efficacy evaluation would be performed in all of them, patients who achieved clinical complete response will receive 1-year bladder-sparing therapy with Toripalimab immune maintenance treatment. The primary endpoint is 2-year Bladder-intact disease-free survival, and the secondary endpoints include clinical complete response rate, over survival, quality of life, safety and exploratory objectives that biomarkers will be evaluated.

Discussion

Disitamab Vedotin combined with Toripalimab therapy and pelvic lymph node dissection is a promising bladder-sparing treatment option that has the potential to improve the rate of bladder-intact disease-free survival and may become a novel modality of bladder-sparing regimen if the study endpoints are met.

Trial registration

This study was registered at Chinese Clinical Trial Registry (ldentifer: ChiCTR2400081555) on March 5, 2024.

Peer Review reports

Introduction

Bladder cancer, the 10th most frequent malignancy globally, is categorized into non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [1, 2]. Currently, the standard management for MIBC is radical cystectomy (RC) coupled with Pelvic lymph node dissection (PLND) [3,4,5]. However, RC has a high rate of postoperative complications that the early complications rate is around 20%, and the late complications rate can reach up to 45–66% [6, 7]. As a supplementary treatment to RC or an alternative therapeutic option in select cases, the efficacy of the established trimodal therapy (TMT) for bladder preservation has shown inconsistent outcomes, with clinical response (CR) rates ranging from 66 to 88% [8]. Furthermore, the radiation component of this approach is associated with significant toxicity profiles that may substantially compromise patients’ quality of life [9]. Therefore, there remains an urgent clinical need to develop novel bladder-preserving strategies characterized by enhanced therapeutic efficacy and reduced toxicity.

Over the past decade, it has been demonstrated that the blockade of the programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) pathway is an effective approach in inducing durable anti-tumor responses [10,11,12]. Immune checkpoint inhibitors (ICIs) have been incorporated into several bladder preservation studies with promising initial results. There were 76 patients with MIBC accepted 4 cycles of gemcitabine and cisplatin in combination with Nivolumab treatment in the HCRN16-257 study, those who achieved clinical complete response (cCR) were performed a minimum of 8 cycles of immune maintenance therapy. According to the study, there are 33 (43%) subjects achieved cCR and the 2-year bladder-intact metastasis free survival in the cCR population was approximately 65% [13]. In another study, 54 subjects with cT2N0M0 staging underwent one cycle of pembrolizumab followed by complete transurethral bladder tumor resection (cTURBT) and radiotherapy, and then accepted 3 cycles of pembrolizumab. This research revealed that 80% of patients in intention-to-treat (ITT) population reported CR after 12 weeks and 71% of patients had bladder-intact disease-free survival after two years [14].

Disitamab Vedotin (RC48 or DV) as an antibody-drug conjugate (ADC) was approved for the first-line therapy of advanced urothelial carcinoma in January 2022. In the RC48-C005 study, DV was applied to treat human epidermal growth factor receptor-2 (HER-2) overexpressing inoperable locally progressive or metastatic urothelial carcinoma. The study demonstrated that 59.1% of patients experienced progression-free survival and 51.2% encountered objective response [15]. The 2022 American Society of Clinical Oncology updated the latest data of RC48-C005 and RC48-C009 study that an objective response rate (ORR) of 50.5%, with a median progression-free survival and over survival of 5.9 and 14.2 months, respectively. Moreover, 54.2% of grade ≥ 3 treatment-related adverse events (TRAEs) were reported [16]. In the RC48-C014 study, DV combined with Toripalimab resulted in an ORR of 75% in ITT population, with a 100% ORR in patients with HER2 expression (3+) and a 77.8% ORR in patients with HER2 expression (2+) [17]. And there was no grade 4 or 5 TRAEs in either study (C005 and C014).

Collectively, DV and Toripalimab have demonstrated promising therapeutic efficacy in the management of MIBC. Their synergistic combination therapy may potentially enhance the success rate of bladder-preserving strategies. Furthermore, the presence of lymph node metastases is a significant predictor of poor prognosis MIBC patients [18]. PLND and complete transurethral bladder tumor resection (cTURBT), as effective local treatments, can effectively remove tumor lesions and are worth considering as part of bladder conserving therapy. Therefore, we are supposed to construct a novel bladder-preserving regimen that evaluating the efficacy and safety of bladder-sparing regimen with Disitamab Vedotin combined with Toripalimab and PLND in MIBC patients after cTURBT.

Methods

Objectives

The study aims to investigate the safety and effectiveness of cTURBT in patients with cT2-4aN0M0 staging bladder urothelial carcinoma with HER-2 expression ≥ 2+, followed by DV in combination with Toripalimab and PLND.

Participants

63 MIBC subjects will be diagnosed by imaging examination, transurethral bladder tumor resection (TURBT) or cystoscopy at Sun Yat-sen Memorial Hospital and other research centers. And the principal inclusion and exclusion criteria is showed in Table 1.

Table 1 Principal inclusion and exclusion criteria
Full size table

NOTE

HER-2 Immunohistochemistry (IHC) Classification System HER-2 IHC Classification System is relying on a clinical pathological expert consensus, which a slight modification from Breast Cancer HER-2 IHC Classification [19]. HER-2 positive is considered as IHC score ≥ 2+. The scoring system is as follows:

  • Score 0: No staining or incomplete, faint membrane staining in < 10% of invasive tumor cells.

  • Score 1+: Incomplete, faint membrane staining in ≥ 10% of invasive tumor cells.

  • Score 2+: Weak to moderate complete membrane staining in ≥ 10% of invasive tumor cells or Complete, intense circumferential membrane staining in < 10% of invasive tumor cells.

  • Score 3+: Complete, intense circumferential membrane staining in ≥ 10% of invasive tumor cells.

Primary endpoint

2-year Bladder-intact disease-free survival (2-yr BI-DFS) rate

Defined as the proportion of subjects who had no muscle-invasive recurrence, regional lymph node recurrence or distant metastasis, bladder cancer related death and retained intact bladder at the 2-year follow-up assessed by imaging, urinary cytology, and cystoscopy.

Second endpoints

Clinical complete remission (cCR) rate

Defined as the proportion of subjects with no evidence of malignant tumors in imaging, cystoscopy or TURBT biopsy, and negative urine cytology after treatment (if the subjects underwent PLND, no evidence of lymph node metastasis is required), with evaluation nodes at 12 weeks, 24 weeks, and 1 year.

Over survival (OS)

Defined as the survival of subjects from screening enrollment to death for any reason stage.

5-year over survival (5-yr OS)

Proportion of patients who did not die from any cause from screening enrollment at 5-year survival follow-up.

Quality of life (QoL)

The European Organization for Research and Treatment of Cancer QoL thirty item score questionnaires will be used for health-related QoL.

Safety

Including evaluation of adverse events (AEs), Serious adverse events (SAEs), vital signs, physical examinations, laboratory tests, imaging examinations, and some special examinations.

Ethics statements and approvals

The study was approved by Medical Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (Ethical approval number: SYSKY-2024-134-03). Written informed consent will be obtained from all objects prior to enrollment. This study adheres to all relevant ethical guidelines.

Study design

After cTURBT, the subjects are about to receive treatment with DV in combination with Toripalimab for 6-cycle (12 weeks), followed by the first assessment after undergoing TURBT and PLND. Patients who achieved cCR and partial response (PR) would be accepted treatment with DV combination with Toripalimab for another 6-cycles (12 weeks); Comprehensive treatment (not limited to chemotherapy, radiotherapy, immunotherapy, targeted treatment, surgical treatment, etc.) or salvage cystectomy for patients with progressive disease (PD).

Re-assessment at 24 weeks post-treatment, if cCR is achieved, the patients are going to be conducted Toripalimab immune maintenance for 1 year or until the tumor recurrence. However, if cCR is not achieved, the endpoint event will be reached. Follow-up diagnosis and treatment will be carried out based on clinical practice, and only survival follow-up will be performed. The process chart of the trial is exhibited in Fig. 1.

Fig. 1
figure 1

The research process chart. cTURBT, complete transurethral bladder tumor resection; IV, intravenous injection; Q2W, once every 2 weeks; TURBT, transurethral bladder tumor resection; PLND, pelvic lymph node dissection; CR, complete response; PR, partial response; PD, progressive disease; Q3W, once every 3 weeks

Full size image

Intervention scheme

Medicine

Combination therapy period

Subjects will be received 6 cycles of treatment with DV combination with Toripalimab after completed cTURBT at the first combination therapy period; For patients with initial efficacy evaluation of cCR or PR, DV combination with Toripalimab will be administered for another 6 cycles at the second combination therapy period. Among them, the dosage of Toripalimab is 3 mg/kg, once every two weeks (Q2W), intravenous infusion. And the dosage of DV is 2 mg/kg, Q2W, intravenous infusion.

Immune maintenance period

Patients who achieved cCR after re-evaluation will be received maintenance treatment with Toripalimab for one year or until the tumor recurrence. In addition, the dosage of Toripalimab is 240 mg, once every three weeks (Q3W), intravenous infusion.

Surgery

cTURBT should be performed two weeks before the beginning of the first combination therapy period. And the first assessment should be conducted with TURBT and PLND, which should be occurred after the first combination therapy period, before the period of immune maintenance therapy, or before starting another new anti-cancer treatment, whichever occurs first.

Follow-up

Based on the study protocol, subjects are supposed to accept regular examination at the baseline and the whole period of treatment, including the treatment stage of medication and surgery, and each follow-up visit. Vital signs, physical examinations and laboratory examinations should be performed before every therapy of medication or surgery. Detailed follow-up is displayed in Table 2.

Table 2 Follow-up schedule of five years
Full size table

Sample size considerations

Sample size consideration for this study is based on the primary outcome of 2-year BI-DFS rate. Based on previous results, the 2-year BI-DFS rate of patients with TMT was of approximately 62% [20]. Given that longer treatment cycles and application of DV and Toripalimab in our study, we hypothesize that 2-year BI-DFS rate can be improved from 62 to 75% in this trial. Using a one-sided alpha of 2.5% and a study power of 80%. In total, 63 subjects will be enrolled to test the null hypothesis with a power of 80% at a one-sided significance level of 0.25 (one-sample log-rank test).

Statistical analysis

Regularly, standard descriptive methods will be performed in the ITT set. Distribution parameters will be used to describe continuous variables according to the data distribution and counts and percentages for categorical data. Multivariate analyses may be performed using appropriate regression models. For tests and confidence intervals, a two-sided significance level α = 5% will be used except for the primary endpoint and unless otherwise specified.

Efficacy and safety analyses will be conducted in all-treated population, defined as the population of subjects treated with at least one dose of any investigational drug. For the primary analysis, Kaplan Meier method will be used to estimate the 2-year BI-DFS rate and its 95% confidence interval.

For the secondary outcomes, the proportion of patients with the outcome and two-sided 95% confidence intervals will be calculated using two-sided Clopper-Pearson method. Kaplan-Meier analysis will also be applied to the other time-to-event data. The safety analysis contains type, incidence of AEs, vital signs, physical examinations, Eastern Cooperative Oncology Group (ECOG) status, and laboratory test values. AEs and SAEs will be evaluated based on NCI-CTCAE v5.0 [21], and surgical related adverse events will be evaluated based on Clavien-Dindo grading [22].

Discussion

Current clinical guidelines recommend cisplatin-based neoadjuvant chemotherapy followed by RC and PLND as the standard management for MIBC. However, both in the process of clinical practice and in the demands of patients, the need for bladder-sparing treatment is increasing. Patients with bladder cancer frequently forfeit the opportunity to undergo surgery of orthotopic neobladder with retained urinary control function if bladder-sparing therapy fails, this is mainly because the addition of radiotherapy to current bladder preservation treatments, which is able to cause abdominal adhesions, bowel damage, and other radiotherapy-related complications. As a result, we designed a novel bladder-sparing treatment model that utilizes surgical approach rather than localized radiotherapy, allowing patients maintain their own urine control function even when bladder preservation treatment fails. It is worth noting that the absence of radiation may result in the efficacy of bladder preserving treatment. Therefore, systemic medication with significant therapeutic effects is also required.

A meta-analysis study demonstrated that HER-2 positive with a pooled positive rate of 41.2% in bladder cancer patients [23], while HER-2 overexpression has been found to be associated with tumor progression and poor prognosis [24, 25], and patients with HER-2 overexpressing exhibit therapeutic resistance to conventional chemoradiotherapy compared to HER-2 negative MIBC patients [26]. During the past few years, ADCs have been gaining much attention as potential solutions to figure out the bottleneck, which consist of monoclonal antibody, linkers, and chemotherapeutic agents. The monoclonal antibody recognizes the antigen on the surface of the cancer cells, and the chemotherapeutic drugs are connected to the antibody through the linkers, allowing for precise targeting treatment of the tumor [27]. Currently, ADCs have been illustrated to be effective in the treatment of advanced bladder cancer. For example, in the DESTINY-PanTumor02 study, Trastuzumab deruxtecan (T-DXd) demonstrated significant efficacy in patients with previously treated HER2-expressing advanced solid tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and other tumor types. In the overall study population of 267 patients, the confirmed ORR assessed by the investigators was 37.1% (95% CI: 31.3–43.2). The highest response rates were observed in patients with HER-2 IHC 3 + tumors, with an ORR of 61.3% (95% CI: 49.4–72.4). Notably, in the cohort of bladder cancer patients, patients with HER-2 IHC 3 + bladder cancer (n = 16), the ORR reached 56.3% (95% CI: 29.9–80.2) [28]. This study provides brand new treatment options for patients with HER-2 positive bladder cancer, especially in the subgroup of patients with IHC 3 + expression, where the increase in ORR is more pronounced. DV as another ADC has also been proven safe and effective in studies C005, C009, and C014 as mentioned in the background part earlier. Several current bladder-preserving studies have included DV in their treatment regimens [29, 30]. Taking the Hope-03 study as an example, all four enrolled patients achieved cCR. In terms of safety, DV related-toxicity included transaminase, erythema, sensory abnormalities, which occurred in 3 subjects [29]. ICIs will also be considered as part of bladder-sparing therapy, not only because of its satisfactory anti-tumor effects and generally tolerability, but also owing to the synergistic effect of immunotherapy with ADC drugs [31]. Toripalimab is a specific ICI for human PD-1, it has been proven to have good efficacy and safety in the treatment of bladder urothelial carcinoma [12, 32, 33].

Patients with cT2-T4aN0M0 staging identified by imaging and pathology will be enrolled in this prospective, multicenter, open-label, single-arm study, which is designed to evaluate the efficacy and safety of DV combination with Toripalimab therapy in patients with HER-2 expressing ≥ 2 + bladder cancer. Enrollment is expected to be completed within 2 years with a target enrollment of 63 patients. The trial is intended to identify an optimal bladder-sparing regimen, which is supposed to be further validated in large randomized controlled Phase III clinical trials in the future.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

NMIBC:

Non-muscle invasive bladder cancer

MIBC:

Muscle invasive bladder cancer

RC:

Radical cystectomy

cTURBT:

Complete transurethral bladder tumor resection

TURBT:

Transurethral bladder tumor resection

PLND:

Pelvic lymph node dissection

TMT:

Trimodal therapy

CR:

Clinical response

cCR:

Clinical complete response

PR:

Partial response

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death 1 ligand 1

ICIs:

Immune checkpoint inhibitors

BI-DFS:

Bladder-intact disease-free survival

ITT:

Intention-to-treatment

AEs:

Adverse events

SAEs:

Serious adverse events

TRAEs:

Treatment-related adverse events

irAEs:

Immune related adverse events

RC-48 or DV:

Disitamab Vedotin

ADC:

Antibody-drug conjugate

HER-2:

Human epidermal growth factor receptor-2

ORR:

Objective response rate

OS:

Over survival

QoL:

Quality of life

Q2W:

Once every two weeks

Q3W:

Once every three weeks

ECOG:

Eastern Cooperative Oncology Group

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Acknowledgements

We appreciate Tao Qin, Yong Li, Shoumin Bai, Hong Zeng and Xia Yang for providing vital feedback on the design of this study, and we also thank the participating centers and their local investigators.

Funding

This work was supported and sponsored by Shanghai Junshi Biosciences Co., Ltd, Rongchang Biopharmaceutical (Yantai) Co., Ltd and Beijing Life Oasis Public Service Center. And This study was also funded by the National Key Research and Development Program of China (Grant No. 2023YFC2507003); the National Natural Science Foundation of China (Grant Nos. 82173266); the Guangdong Provincial Clinical Research Center for Urological Diseases (2020B1111170006).

Author information

Author notes

  1. Tianhang Lan, Yingying Zhu and Wenlong Zhong contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang West Road, Guangzhou, Guangdong, 510120, China

    Tianhang Lan, Wenlong Zhong, Qihong Tan, Tianxin Lin, Jian Huang & Wang He

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou, Guangdong, 510120, China

    Wenlong Zhong, Tianxin Lin, Jian Huang & Wang He

  3. Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, 510120, China

    Wenlong Zhong, Tianxin Lin, Jian Huang & Wang He

  4. Clinical Research Design Division, Clinical Research Center, Sun Yat- sen Memorial Hospital, Sun Yat-sen University, Guangdong, 510120, China

    Yingying Zhu

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Contributions

W.H. and J.H. are the general supervisor and responsible for the project. T.H.L., W.H, J.H., W.L.Z., T.X.L., Q.H.T. were responsible for in the design of this study. Y.Y.Z. provided proposal of clinical research design and statistical guidance for this study. All authors participated in the initial protocol writing and approved the final manuscript.

Corresponding authors

Correspondence to Jian Huang or Wang He.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by Medical Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University. Written informed consent will be obtained from all objects prior to enrollment. Participants will be made aware that participation is strictly voluntary. Participants may withdraw from the study at any time.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Lan, T., Zhu, Y., Zhong, W. et al. Evaluating the efficacy and safety of bladder-sparing regimen with Disitamab Vedotin combined with Toripalimab and pelvic lymph node dissection in muscle-invasive bladder cancer patients: study protocol of a multicenter single-arm phase II trial. BMC Cancer 25, 868 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14234-5

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BMC Cancer

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