Editor's Note: Research has shown that nearly 50% of patients with muscle-invasive urothelial carcinoma (MIUC) will experience recurrence with distant metastases. Therefore, exploring perioperative treatments for muscle-invasive bladder cancer (MIBC) is crucial to improving patient outcomes. The 2024 European Society for Medical Oncology (ESMO) Congress, held from September 13 to 17 in Barcelona, Spain, highlighted several advances in perioperative immunotherapy and combination immunotherapy for MIUC patients. Dr. Wei Yu and Dr. Qi Tang from Peking University First Hospital shared their insights on this important topic.

In recent years, with the emergence of immune checkpoint inhibitors and antibody-drug conjugates (ADCs), perioperative treatment for urothelial carcinoma has gained renewed attention. At this year’s ESMO Congress, several studies on perioperative treatment for MIBC/MIUC were presented and updated. Below is a brief summary of four key studies, including three on neoadjuvant therapies and one on adjuvant therapy.

For MIBC patients, platinum-based neoadjuvant chemotherapy has been confirmed by high-level evidence studies and is widely recommended by both national and international treatment guidelines. However, in the era of immunotherapy, there is still a lack of high-level evidence supporting immunotherapy-based neoadjuvant treatments for MIBC. The NIAGARA study, released at this conference, aims to fill this gap. This Phase 3 randomized controlled trial included MIBC patients (cT2-T4aN0/1M0) who were cisplatin-tolerant and scheduled for radical cystectomy (RC). Patients were randomized 1:1 to receive neoadjuvant durvalumab (1500 mg IV Q3W) plus chemotherapy (cisplatin + gemcitabine IV Q3W) for four cycles, followed by RC, and eight cycles of durvalumab adjuvant therapy (1500 mg IV Q4W). The control group received neoadjuvant chemotherapy followed by RC. The co-primary endpoints were event-free survival (EFS) and pathologic complete response rate (pCR), with overall survival (OS) as a secondary endpoint. A total of 533 patients were enrolled in the durvalumab group and 530 in the control group. In the pre-planned interim analysis, with a median follow-up of 42.3 months, the EFS and OS were significantly longer in the durvalumab group compared to the control group (EFS HR 0.68 [95% CI 0.56–0.82], P < 0.0001; OS HR 0.75 [95% CI 0.59–0.93], P = 0.0106). A total of 88% of patients in the durvalumab group and 83% in the control group completed RC. Of the 469 postoperative patients, 383 (82%) began durvalumab adjuvant therapy. Grade ≥3 adverse events occurred at similar rates in both groups (41%), and 8% of patients in the trial group discontinued durvalumab adjuvant therapy due to adverse events. This study may potentially change the landscape of traditional MIBC neoadjuvant chemotherapy and provide a more comprehensive perioperative treatment option.

Beyond chemotherapy/chemotherapy combined with immunotherapy, the use of immune therapy combined with ADCs is also being explored in the neoadjuvant treatment of MIBC. The VOLGA study, released at this conference, enrolled cisplatin-intolerant MIBC patients (T2-4aN0-N1M0/T1N1M0) who received three cycles of neoadjuvant combination therapy (durvalumab + enfortumab vedotin + tisotumab vedotin) Q3W, followed by RC, and nine cycles of durvalumab (Q4W) and a single dose of tisotumab vedotin as adjuvant therapy. The study evaluated the correlation between baseline (C1D1) and post-neoadjuvant therapy (C3D1 and pre-RC) circulating tumor DNA (ctDNA) status with pathologic response and EFS. Among the 16 patients with baseline plasma samples, the ctDNA positivity rate was 62.5% (10/16). Of the 13 patients who underwent RC with pre-RC samples, the ctDNA positivity rate at C3D1/pre-RC was 23% (3/13), and 7 patients achieved ctDNA clearance, which was associated with pathologic response and EFS (EFS HR 0.18, 95% CI 0.016–2.1). ctDNA detection status at C3D1/pre-RC was also correlated with pathologic response. This study preliminarily validated the safety of dual immune therapy combined with ADCs in the neoadjuvant treatment of MIBC and suggested that ctDNA might serve as a predictive marker for neoadjuvant treatment efficacy. The value of ctDNA is gaining attention as a potential research focus in the future.

The third neoadjuvant study explored the value of combining systemic therapy with local treatment for MIBC. The SunRISe-4 study used cetrelimab (a PD-1 inhibitor) combined with TRA-200 (a bladder-targeted delivery system for continuous local release of gemcitabine) as a treatment regimen. The study enrolled cT2-T4a N0M0 MIBC patients who were intolerant to/refused platinum-based neoadjuvant chemotherapy and were scheduled for RC. Patients were randomized 5:3 to receive TAR-200 + cetrelimab (Cohort 1) or cetrelimab alone (Cohort 2). The primary endpoint was pathologic complete response rate (pCR; ypT0N0), with secondary endpoints including overall pathologic response rate (pOR; ≤ ypT1N0) and safety. Cohort 1 included 79 patients, and Cohort 2 included 41 patients. Among evaluable patients, the confirmed pCR rates in Cohort 1 and Cohort 2 were 42% and 23%, respectively, and the pOR rates were 60% and 36%, respectively. TRAEs occurred in 72% of patients in Cohort 1 and 44% in Cohort 2, with most being Grade 1-2. In Cohort 1, 8% of patients discontinued TAR-200 due to TRAEs. This study preliminarily demonstrated that combining systemic therapy with intravesical local therapy could significantly improve local tumor response, offering new ideas for enhancing the efficacy of neoadjuvant treatment in MIBC.

The AMBASSADOR study provided updated follow-up data on adjuvant therapy in MIUC. This study explored the difference in prognosis between MIUC patients receiving adjuvant pembrolizumab (200 mg Q3W for one year) and those under observation post-surgery. Previous reports had already shown a significant improvement in the primary endpoint of DFS. At this conference, extended follow-up DFS data and the distribution of metastatic disease recurrences were updated. The median DFS follow-up time reached 41.3 months. DFS benefits were observed across most analyzed subgroups, including pathological staging, positive margins, neoadjuvant therapy, PD-L1 status, age, and ECOG PS. A trend of DFS benefit was observed in ureteral carcinoma, but not in renal pelvic carcinoma. In the overall analysis, pembrolizumab showed DFS benefits in both N0 and N+ patients, but in upper urinary tract urothelial carcinoma (UTUC), DFS benefits were only seen in N+ patients. Common sites of metastasis included lymph nodes, pelvis, lungs, bones, and liver. Following nivolumab, the AMBASSADOR study also confirmed the effectiveness of pembrolizumab in adjuvant MIUC treatment. The updated follow-up data further confirmed the DFS advantage and showed a trend of benefit for patients with ureteral carcinoma, offering hope for UTUC adjuvant immunotherapy.

As perioperative treatment for urothelial carcinoma continues to receive increasing attention, several high-level evidence studies have been published in recent years. The CheckMate 274 study established the role of immunotherapy in MIUC adjuvant treatment, and the AMBASSADOR study confirmed the efficacy of pembrolizumab, providing more options for clinical treatment. The release of the NIAGARA study results may disrupt the position of traditional MIBC neoadjuvant chemotherapy, offering new options for perioperative comprehensive treatment. Meanwhile, different drug combinations and predictive markers for neoadjuvant therapy efficacy remain hot topics for future research. However, the ultimate goal of perioperative treatment is not only to improve short-term tumor response rates but to achieve long-term recurrence-free survival and even overall survival benefits. These clinical outcomes typically require long observation periods, posing significant challenges for perioperative research. As studies continue and evolve, we hope to see more high-level clinical research results that can change clinical practice in the near future.

Dr. Wei Yu Deputy Director, Department of Urology, Peking University First Hospital Chief Physician, Professor, PhD Supervisor Standing Committee Member, Urothelial Carcinoma Committee, Chinese Society of Clinical Oncology (CSCO) Member, CUA Basic Science Group Vice Chair, Prostate Cancer Committee for Integrated Chinese and Western Medicine, Chinese Anti-Cancer Association Member, Tumor Group, Urology Committee, Chinese Association of Integrative Medicine Vice Chair, Familial Hereditary Tumor Committee, Beijing Anti-Cancer Association Standing Committee Member, Urology Committee, Beijing Cancer Prevention Society Member, Organ Transplantation Committee, Beijing Physician Association Member, Youth Committee, Oncology Branch, Beijing Medical Association

Dr. Qi Tang Associate Chief Physician, Associate Professor, Department of Urology, Peking University First Hospital Vice President, Maotai Hospital, Guizhou Province Outstanding Young Physician, Peking University Member, Sixth Group of Central Government’s “Group-style” Medical Aid Program to Tibet Deputy Leader, CUDA UTUC Collaboration Group Member, Oncology Committee, Chinese Research Hospital Association Member, Palliative Care and Rehabilitation Committee, Beijing Anti-Cancer Association Principal Investigator for multiple provincial and central high-level research projects Has presented research findings at AUA, EAU, and CUA conferences multiple times