Urothelial bladder cancer (UC) ranks the ninth most common cancer worldwide, with an annual incidence of over 500,000 new cases and 200,000 deaths attributable to the disease (Bray et al., 2018). Only 30% of these newly diagnosed cases involve muscle-invasive bladder cancer (MIBC), where the tumor invades the detrusor muscle (Charlton et al., 2014). A combination of Neoadjuvant chemotherapy plus Radical cystectomy (RC) has traditionally been the standard of care for MIBC. Current RC methodologies have achieved 5-year overall survival (OS) rates ranging from 56% to 66% (Grossman et al., 2003; Sherif et al., 2004; Stein et al., 2001; Zehnder et al., 2011).

Over recent decades, there has been a growing trend toward organ-preserving therapies in treating numerous cancers. Within the sphere of bladder cancer, introducing a disciplinary approach has led to the development of bladder-sparing approaches. These approaches combine maximal transurethral resection (TURBT) with radiotherapy and concurrent radio-sensitizing chemotherapy to treat MIBC. While no definitive randomized studies have compared RC and this bladder-sparing trimodal therapy (TMT), multiple series suggest that TMT may produce favorable outcomes for carefully chosen patients (Hoskin et al., 2010; Efstathiou et al., 2012; James et al., 2012a; Mak et al., 2014).

The recent application of immune checkpoint inhibitors (ICIs) has yielded significant clinical outcomes, thereby establishing a role in treating metastatic UC (mUC) and MIBC. This includes inhibitors such as pembrolizumab, nivolumab, avelumab, tislelizumab, and toripalimab. Using neoadjuvant cisplatin-based chemotherapy (NAC) and PD-1/PD-L1-based immunotherapy has demonstrated pathologic complete response rates of approximately 30%–40% and 30%–50%, respectively, (APOLO et al., 2017; SHARMA et al., 2017; Powles et al., 2019; Guptal et al., 2020; Sheng X. et al., 2021; Necchi et al., 2019; Bellmunt et al., 2021; Ye et al., 2021; Christopher et al., 2022). Furthermore, immunotherapy has been linked to a notably high complete response rate (up to 80%) in conjunction with bladder-sparing treatment, an improvement compared to traditional TMT, which achieves 60%–70% (COPPIN et al., 1996; SAUER et al., 1998; JAMES et al., 2012b; Balar et al., 2021; Garcia delMuro et al., 2021). The observed outcomes underscore the need for additional research into the application of ICIs in combination therapies for the curative treatment of MIBC patients.

In bladder cancer, human epidermal growth factor receptor 2 (HER2) overexpression is strongly linked with tumor progression and poor prognosis, although HER2 genomic amplification is not a typical mechanism (Chow et al., 2001; Jimenez et al., 2001; Kruger et al., 2002; Fleischmann et al., 2011). Disitamab vedotin (DV, RC48-ADC) is an innovative humanized anti-HER2 antibody, conjugated with MMAE via a cleavable linker. DV has demonstrated promising antitumor activity and a tolerable safety profile toward mUC, exhibiting an objective response rate (ORR) of 51.2% and median progression-free survival (PFS) of 6.9 months (Sheng Xinan et al., 2021). In the RC48-C014 trial, 32 patients with metastatic UC were treated with DV and toripalimab, resulting in an ORR of 71.8% in the overall population and 73.9% in first-line previously untreated patients (Sheng et al., 2022). Additionally, DV combined with PD-1 inhibitors has yielded satisfactory efficacy in patients with MIBC and non-muscle Invasive Bladder Cancer (NMIBC) (Wen, 2022; Hu et al., 2023; Huang et al., 2023). Nevertheless, real-world studies, which provide crucial information on a drug’s efficacy and safety within the actual patient population, are lacking for the role of DV in MIBC. Therefore, this study aims to explore the use of DV for the treatment of locally advanced bladder urothelial carcinoma, utilizing real-world data.

This real-world study explores the application of DV combined with PD-1 inhibitors in locally advanced bladder urothelial carcinoma. In this study, DV combined with either tislelizumab or toripalimab demonstrated promising responses in patients with locally advanced urothelial carcinoma. The study enrolled nine patients with locally advanced urothelial carcinoma, of which five achieved confirmed CR and three achieved PR, resulting in an ORR of 88.9%. rCR was entirely consistent with pCR. The median rPFS was 12.0 months (range: 8.0–17.0 months).

An open-label, single-arm, multicenter phase Ib/II clinical trial demonstrated that four patients with locally advanced urothelial carcinoma and HER2 IHC 1+/2+/3+ achieved a cCR rate of 100% after receiving DV plus tislelizumab as neoadjuvant therapy (Wen, 2022). However, our study involved a more diverse patient population: nine patients, including three recurrent cases and one with HER2 (0). In another retrospective study, seven patients with HER2 overexpressing (IHC 2+ or 3+) NMIBC, who could neither have their bladder tumor completely resected nor tolerate surgery, were treated with either DV or a combination of DV and ICIs, showing promising efficacy and an ORR of 85.7% for all patients (Hu et al., 2023). The patient populations in these studies were distinct; the previous study enrolled all NMIBC patients, while our study focused on MIBC, which is associated with poorer survival outcomes for patients with urothelial carcinoma. Overall, this retrospective study represents a successful exploration of neoadjuvant or bladder-preserving therapy in the real-world setting using DV combined with immunotherapy.

Besides short-term efficacy, the safety of DV combined with PD-1 inhibitors during therapy in patients with MIBC is of utmost importance. In this study, no adverse events (AEs) of grades 4 or 5 were observed, with grade 1 or 2 AEs accounting for 88.9% of the total. Anorexia, rash, and fatigue were the most frequently reported AEs. Importantly, these events were of grade 1 or 2 severity, transient, and could be effectively managed in the outpatient setting without necessitating any dose modification or interruption. No new AEs were reported, and all observed AEs were manageable. Furthermore, there were no recorded fatalities during the therapy period.

An essential finding of this study was the anti-tumor activity of DV combined with PD-1 inhibitors in patients with HER2 IHC1+, IHC 0, and PD-L1< 1%. This effect is not solely due to the nonspecific bystander effects of the cytotoxic drugs released by DV. Our data strongly support a T cell-dependent mechanism and the efficacy of the combination therapy. This effect is achieved through non-redundant yet complementary mechanisms. Specifically, DV enhances T cell infiltration into the tumor by inducing tumor-specific, adaptive anti-tumor immunity, while PD-1 blockade rejuvenates exhausted T cells (Huang et al., 2022). Other chemotherapy regimens have had similar therapeutic benefits (Haratani et al., 2020; D’Amico et al., 2019; Wang et al., 2018).

Some limitations to our study should be acknowledged. The most significant was the lack of a mature follow-up period to provide survival outcomes. Extended follow-up was required, particularly focusing on long-term bladder preservation and survival. Another limitation was the small sample size of patients with cT2-T3bN0-2M0 tumors included in our study; we will embark on a prospective, case-control multicenter study, including evaluating the efficacy of the combination therapy in specific subgroups based on HER2 expression levels, to further validate our findings and provide new approaches to guide neoadjuvant therapy or bladder-sparing treatment for bladder cancer. Furthermore, we could not obtain data on survival rates with our limited observation period and sample size; we will include this subset of patients to observe survival data in future studies.

The promising safety profile and anti-tumor activity demonstrated by the combination of DV and PD-1 inhibitors in this real-world study lay a solid foundation for a phase 2 clinical trial exploring DV in combination with PD-1 inhibitors in patients with MIBC. Our study data were the most extended median follow-up time for DV plus immunotherapy to date, and our findings provided a new possibility for DV plus immunotherapy as neoadjuvant therapy or treatment of sparing bladder.

The combination of DV and PD-1 inhibitors demonstrated significant improvements in ORR in patients with MIBC across all HER2 IHC levels (0/1+/2+/3+). This regimen also reported the longest median rPFS to date, solidifying the combination of DV and PD-1 inhibitors as a compelling treatment choice for patients with T2-T4aN0-3M0 staging. Furthermore, this study confirms that the combination treatment maintains a manageable safety profile even with extended treatment duration.