At the 2023 ESMO Congress, the field of urothelial carcinoma (UC) witnessed a major breakthrough. The global multicenter Phase III CheckMate-901 study showed that in the first-line treatment of unresectable or metastatic urothelial carcinoma (mUC), nivolumab combined with cisplatin-based chemotherapy achieved dual positive results in the co-primary endpoints of overall survival (OS) and progression-free survival (PFS), compared to standard cisplatin chemotherapy (Abstract LBA7). This is the first regimen in nearly 30 years to demonstrate significantly superior survival benefits over cisplatin chemotherapy in this field. Urology Frontier invited Academician Xu Zhang, the Chair-elect of the Urology Branch of the Chinese Medical Association (CUA) and from the Chinese PLA General Hospital, to discuss the general incidence, current diagnosis and treatment status, and recent advances in UC. He also provided an interpretation of the significant immunotherapy study results.

Urology Frontier: As the Chair-elect of CUA, could you first give us an overview of the incidence of UC in China and the overall level of diagnosis and treatment?

Academician Xu Zhang: Urothelial carcinoma includes bladder cancer, renal pelvis cancer, ureteral cancer, and some urethral cancers. Among the Chinese population, bladder urothelial carcinoma accounts for approximately 83% of all UC cases, with the majority of UC tumors occurring in the bladder. Bladder cancer is the tenth most common cancer globally, with 573,000 new cases and 212,500 deaths worldwide in 2020, giving an incidence rate of 5.6/100,000 and a mortality rate of 1.6/100,000.

In China, UC is one of the three most common urological tumors. In 2020, the number of new bladder cancer cases in China was approximately 85,700, with an incidence rate of 3.6/100,000, and the number of deaths was around 39,400, with a mortality rate of 1.6/100,000. The incidence and mortality rates among men are significantly higher than in women, with a male-to-female ratio of 3.7 and 3.75, respectively.

Urology Frontier: Regarding surgical treatment, what are the current general treatment principles for UC? What new technologies have been applied in recent years?

Academician Xu Zhang: Surgical treatment for UC can be divided into non-muscle-invasive urothelial carcinoma (NMIUC) and muscle-invasive urothelial carcinoma (MIUC). NMIUC is a localized tumor confined to the bladder mucosa or subepithelial connective tissue without muscle layer invasion. It can be treated with transurethral resection of bladder tumor (TURBT) or laser resection, followed by intravesical instillation of chemotherapy or BCG (Bacillus Calmette-Guerin) to achieve curative effects. Resectable MIUC is characterized by tumor extension or invasion into the muscle layer, possibly involving microscopic lymph node involvement. Laparoscopic or robot-assisted radical cystectomy, combined with neoadjuvant cisplatin chemotherapy and adjuvant immunotherapy based on tumor staging and malignancy, aims to prevent tumor recurrence, progression, or metastasis.

As a surgeon, I am closely following the advancements in UC surgery. In terms of NMIUC surgical treatment, urological techniques have advanced rapidly. For example, TURBT used to fragment tumors with an electric knife, but now plasma knives can remove the entire tumor in one piece, reducing the likelihood of positive margins and tumor seeding. The clinical application of laser resection has also made tumor removal more precise, complete, and less prone to bleeding. For operable MIUC, traditional radical cystectomy is a major invasive procedure with significant trauma and a high complication rate. Over the past two decades, the widespread use of laparoscopic surgery and the introduction of robotic-assisted technology have made MIUC surgery more minimally invasive, with more thorough tumor removal. These techniques also preserve organ structure and function (such as urinary control and partial sexual function), improving postoperative quality of life.

Urology Frontier: In recent years, immunotherapy has been one of the most significant advances for MIUC patients. Earlier this year, nivolumab became the first approved adjuvant immunotherapy for UC in China, based on the results of the CheckMate-274 study. How do you evaluate the significance of incorporating immunotherapy into the comprehensive surgical treatment of UC?

Academician Xu Zhang: Even after standard radical cystectomy, about 50% of MIUC patients, especially those at high risk, will experience postoperative recurrence, which severely affects long-term survival and quality of life. For patients at high risk of recurrence after radical cystectomy, adjuvant cisplatin-based chemotherapy is commonly used to reduce the recurrence rate. Although this approach has some clinical benefits, the actual benefit of adjuvant chemotherapy remains controversial for several reasons: ① The current randomized Phase III clinical trial evidence supporting routine adjuvant chemotherapy is limited; ② Some patients, due to older age and poor renal function, cannot tolerate platinum-based toxicity; ③ Over-treatment may occur as it’s difficult to assess the sensitivity of patients to chemotherapy; ④ Postoperative complications may delay chemotherapy and reduce patient tolerance.

CheckMate-274: A New Dawn for Adjuvant Immunotherapy in UC

Up to half of UC patients who undergo surgery experience recurrence, indicating an urgent need for new adjuvant treatment options. CheckMate-274 is a randomized, double-blind, placebo-controlled, multicenter clinical study that evaluated the efficacy of nivolumab as adjuvant therapy for patients at high risk of recurrence after radical resection of bladder or upper urinary tract UC.

The study results showed that nivolumab significantly improved median disease-free survival (DFS) in the overall population, extending it to more than double that of the control group (22.0 vs. 10.9 months, HR 0.71, P<0.001), reducing the risk of recurrence, progression, or death by 29%. Among PD-L1-positive patients, the DFS benefit was even greater, with a 48% reduction in the risk of recurrence, progression, or death.

The median non-urothelial recurrence-free survival (NUTRFS) in the nivolumab group was nearly double that of the control group (24.6 vs. 13.7 months, HR 0.72), with PD-L1-positive patients benefiting the most.

Recent years have seen an explosion of new technologies and methods in clinical medicine, with transformative advancements in UC surgery and the emergence of new drugs reshaping the approach to comprehensive UC treatment. The CheckMate-274 study is the first global Phase III clinical trial to confirm that immunotherapy significantly reduces the risk of disease recurrence in muscle-invasive urothelial carcinoma. It provides high-level evidence for adjuvant immunotherapy, setting a new standard for adjuvant treatment in UC. It also provides urologists with a new tool for treating bladder and other urothelial tumors, offering patients more treatment options, improving therapeutic outcomes, and extending survival times. We are very grateful to the research teams and the industry for their contributions in bringing this benefit to patients.

Urology Frontier: Regarding drug treatment for mUC, we recently received great news: at this year’s ESMO Congress, the results of the Phase III CheckMate-901 study were announced, with nivolumab becoming the first first-line treatment in nearly 30 years to show significant survival benefits compared to cisplatin chemotherapy for mUC. Why has mUC been so difficult to treat, and what are the main reasons for the lack of breakthroughs in first-line treatment over the long term? How will the CheckMate-901 study results change first-line treatment for mUC?

Academician Xu Zhang: The treatment outcomes for metastatic urothelial carcinoma have been poor, and it has long been a clinical challenge. The reasons can be summarized as follows:

① mUC tumors typically invade the pelvis or abdomen, spread to lymph nodes, or metastasize to distant organs. These patients are at an advanced stage, and surgical removal of the tumor is not feasible, making drug treatment the primary option to control tumor progression and extend survival;

② Current drug therapies are limited. Since the late 1980s, cisplatin-based chemotherapy has been established as the standard first-line treatment for mUC, with an objective response rate (ORR) of over 40%. However, the duration of response is short, resistance and tumor progression are common, and long-term survival rates are difficult to improve;

③ A portion of mUC patients are in poor general health and cannot tolerate chemotherapy, particularly those with impaired renal function, which is required for cisplatin treatment;

④ Targeted therapy has progressed rapidly in recent years, but advances in targeted therapies for UC have lagged, with limited available targets and approved drugs;

⑤ Immunotherapy has been a hot topic, but early clinical trials for UC immunotherapy yielded disappointing results. Several Phase III trials evaluated the efficacy of immunotherapy compared to platinum-based chemotherapy in the first-line treatment of mUC, but they failed to achieve statistically significant differences in long-term survival outcomes such as OS.

Achieving Dual Endpoints of OS and PFS: Nivolumab Combined Therapy Enters First-Line Treatment for mUC

The results of the CheckMate-901 study, presented at the 2023 ESMO Congress, showed that nivolumab combined with chemotherapy significantly improved median OS in untreated, unresectable, or metastatic UC patients compared to chemotherapy alone (21.7 vs. 18.9 months, HR 0.78, P=0.0171), reducing the risk of death by 22%. The two-year OS rates were 46.9% in the nivolumab group versus 40.7% in the chemotherapy group.

The median PFS in the nivolumab plus chemotherapy group reached 7.9 months (vs. 7.6 months in the chemotherapy group, HR 0.72, P=0.0012), with a two-year PFS rate of 23.5%, more than double that of the chemotherapy group (9.6%). These data indicate that the addition of nivolumab significantly improved survival benefits in first-line mUC treatment compared to previous cisplatin chemotherapy.

In the CheckMate-901 study, the ORR of the nivolumab plus chemotherapy group improved by nearly 15% compared to the chemotherapy group (57.6% vs. 43.1%), and the complete response rate (CR) nearly doubled (21.7% vs. 11.8%). The median duration of CR was nearly three times longer in the nivolumab group (37.1 vs. 13.2 months). These data suggest that nivolumab plus chemotherapy as first-line treatment helps reduce tumor burden and provides deep and lasting remission, addressing the clinical challenge of insufficient and non-durable responses to cisplatin chemotherapy.

The success of the Phase III CheckMate-901 trial marks nivolumab as the first immunotherapy drug in nearly 30 years to demonstrate significant survival benefits compared to standard cisplatin chemotherapy in first-line UC treatment, filling a long-standing clinical gap.

Urology Frontier: With the full coverage of Phase III study results for immunotherapy in the UC field, including adjuvant and first-line treatment, how do you see the role of multidisciplinary comprehensive treatment (MDT) in advancing urological oncology care?

Academician Xu Zhang: In summary, based on the CheckMate-901 and CheckMate-274 studies, nivolumab has become the first PD-1 inhibitor globally to show significant clinical benefits in both adjuvant treatment and first-line treatment for urothelial carcinoma. This has brought substantial changes to UC treatment, breaking the barriers in adjuvant therapy and offering a transformative first-line treatment option. These study results provide hope for bladder cancer patients, offering better clinical outcomes, and I look forward to more clinical application results from China.

When it comes to UC MDT, I believe that a multidisciplinary collaborative treatment model should run through the entire process of UC diagnosis and treatment. We now have an increasing number of new treatment options, including new surgical techniques and innovative drugs. Clinicians must seize the opportunities presented by technological advancements, continuously acquire knowledge from multiple disciplines, and collaborate to optimize treatment strategies to achieve better clinical outcomes for patients. I also hope that groundbreaking studies like CheckMate-274 and CheckMate-901 will inspire new ideas and approaches for everyone.

Academician Xu Zhang

• Director, Urology Department, Chinese PLA General Hospital
• Academician of the Chinese Academy of Sciences
• Member of the Chinese Academy of Medical Sciences
• Chair-elect, Urology Branch of the Chinese Medical Association
• Chairman, Urology Branch of the Beijing Medical Association
• Deputy Director, China Human Organ Donation Management Center
• Chairman, Laparoscopy and Robotic Surgery Branch of the Chinese Anti-Cancer Association
• Director, Key Laboratory of Trauma in the Military
• Member, Central Health Committee Expert Group
• Chief Scientist, National High-Tech Research and Development Program and Major Military Logistics Research Projects
• Leading Scientific Talent in the Military
• Recipient of the National Outstanding Youth Fund and the National Science and Technology Progress Award
• Enjoys special government allowances from the State Council
• Pioneer of Urological Laparoscopic and Robotic Surgery in China
• Editor-in-Chief of “Bladder” and “Journal of Minimally Invasive Urology”