Editor’s Note: In the field of bladder cancer management, treatment strategies for non–muscle-invasive bladder cancer (NMIBC) are undergoing major transformation. With the development of novel immunotherapies and precision medicine technologies, therapeutic options for NMIBC are expanding rapidly. At the same time, clinicians are facing new challenges, including how to evaluate efficacy and how to select individualized treatments. At the 2025 Pujiang Urologic Oncology Academic Conference, Professor Zhisong He from Peking University First Hospital delivered an in-depth presentation on the latest advances and persistent challenges in NMIBC treatment. UroStream invited Professor He for an exclusive interview to discuss treatment paradigms, strategies after BCG failure, and emerging immunotherapy approaches. Drawing on real-world clinical practice, Professor He systematically analyzed the limitations of current strategies and outlined future directions, providing valuable insights for clinicians.UroStream : You presented a keynote lecture entitled “Advances and Challenges in NMIBC Treatment.” Could you first outline the current main treatment paradigms for NMIBC and their limitations?
Professor Zhisong He: For this presentation, I deliberately adjusted the title from “Challenges and Advances” to “Advances and Challenges,” because in the NMIBC field there are actually more unresolved questions that need discussion. Newly diagnosed bladder cancer can be classified into non–muscle-invasive bladder cancer, muscle-invasive bladder cancer, and locally advanced disease, with NMIBC accounting for about 70% of cases. A key feature of NMIBC is its high postoperative recurrence and progression rates.
According to traditional standards of care, patients usually undergo intravesical chemotherapy first, followed by intravesical Bacillus Calmette–Guérin (BCG) therapy. Once BCG treatment fails, however, subsequent options are extremely limited, and many patients are left with radical cystectomy as the only choice. For a patient population with a 10-year progression risk of only around 20%, radical cystectomy imposes a substantial burden on quality of life and involves significant surgical trauma. This represents a major unmet clinical need.
Over the past five years, the U.S. FDA has consecutively approved three intravesical or systemic therapies for patients with BCG-unresponsive NMIBC. These approaches differ substantially and include intravesical therapy alone, intravesical therapy combined with BCG, and systemic treatment. Specifically, these include the adenoviral gene therapy nadofaragene firadenovec (recombinant interferon alfa-2b gene therapy), N-803 (an IL-15 superagonist combined with BCG), and systemic pembrolizumab, a PD-1 inhibitor. All three agents were approved based on multicenter, phase III, single-arm studies showing clinical benefit compared with historical outcomes, leading to accelerated FDA approval driven by the large unmet clinical need.
At the same time, many additional strategies are under investigation, including oncolytic viruses, novel intravesical agents, innovative immunotherapies, non-viral gene delivery systems, and drug–device combination products. For example, gemcitabine, a commonly used intravesical chemotherapy agent, is now being studied with specialized delivery devices that allow sustained drug release in the bladder to maintain prolonged drug exposure. The sheer number of ongoing studies reflects the diversity of future treatment options. However, which approach will ultimately demonstrate the best outcomes and pass regulatory approval remains to be seen.
Another challenge is trial design. Most existing studies are single-arm and non-comparative because historically there was no appropriate control arm. Now that three agents have been approved, the question arises as to whether future trials must include active control groups. If so, trial complexity and difficulty will increase substantially.
A third area of uncertainty lies in efficacy endpoints. For intravesical therapy in NMIBC, should complete response rate, disease-free survival, recurrence-free survival, or overall survival serve as the primary endpoint? These are critical considerations in trial design. Although the FDA released guidance documents in 2018 and 2022 addressing these issues, it remains unclear whether such standards will be fully accepted and adopted by regulatory authorities in China.
In summary, while progress in NMIBC treatment is undeniable, the number of unresolved questions is even greater. Addressing these challenges will require close collaboration among domestic experts to design high-quality clinical studies, ultimately generating answers that benefit the large population of NMIBC patients in China.
UroStream: BCG failure remains a major clinical dilemma. With increasing exploration of immunotherapy and other novel strategies, which approaches do you consider most promising, and how should treatment strategies be optimized based on current evidence?
Professor Zhisong He: This is a very broad and complex question. As mentioned earlier, current research spans completely different mechanisms of action, including monotherapies and combination regimens, local intravesical treatments and systemic therapies, and even combinations of local and systemic approaches. The key question is which strategy can deliver the greatest benefit to patients.
Among the three currently approved options, although no head-to-head comparisons exist, the IL-15 superagonist combined with BCG appears to provide particularly notable benefit. This suggests that combination therapy may represent an important future direction.
Even in traditional practice, exploratory studies have examined various combinations, such as sequential chemotherapy with BCG, or combinations of different intravesical chemotherapeutic agents, with some degree of success. From this perspective, systemic oncology has long emphasized combining agents with different mechanisms of action. It is reasonable to ask whether intravesical therapy or NMIBC management should also move toward combination strategies, especially combining different routes of administration, such as local therapy plus systemic treatment. Personally, I believe this approach holds significant promise.
At the same time, many of the most promising future strategies are centered on immunotherapy. This extends beyond PD-1 or PD-L1 inhibitors to include oncolytic viruses, adenoviral gene delivery platforms, and ADCs combined with PD-1 inhibitors. There is considerable uncertainty ahead, and only time and mature clinical data will ultimately determine which therapies or combinations are most suitable for this patient population.
UroStream: The emergence of immunotherapy and other novel approaches has created new opportunities for bladder-sparing strategies. How are patient selection criteria evolving, and what might be the optimal combinations and sequencing of multimodal therapy?
Professor Zhisong He: At present, the strongest guideline-supported evidence for bladder-sparing treatment still comes from maximal transurethral resection combined with concurrent chemoradiotherapy, often referred to as trimodality therapy, as its efficacy has been well established in clinical studies. However, with the advent of antibody–drug conjugates and immune checkpoint inhibitors, the treatment landscape for advanced urothelial carcinoma has entered an entirely new phase. Traditional chemotherapy has not been completely abandoned, but it is no longer considered the optimal first-line option, as ADCs combined with PD-1 inhibitors have demonstrated approximately doubled efficacy and survival benefits in advanced disease.
It is therefore inevitable that these regimens will be moved earlier in the disease course, into perioperative and bladder-sparing settings. Ongoing perioperative studies include phase III trials such as KEYNOTE-905 (EV-303) and KEYNOTE-B15/EV-304, which are evaluating pembrolizumab with or without enfortumab vedotin in muscle-invasive bladder cancer. The EV-303 trial, for example, assessed pembrolizumab with or without enfortumab vedotin versus surgery alone in patients who were ineligible for or declined cisplatin-based chemotherapy. The latest results show a statistically and clinically significant improvement in event-free survival in the combination arm compared with surgery alone, along with meaningful improvements in overall survival and pathological complete response rates. These findings signal a fundamentally new era for perioperative treatment.
More importantly, bladder preservation represents a massive unmet clinical need. In practice, there are many patients who should undergo radical cystectomy but either refuse surgery or are medically unfit for it. If ADCs and immune checkpoint inhibitors can deliver robust clinical outcomes, their use in bladder-sparing strategies becomes highly feasible. Relevant studies are already underway. While it remains to be seen when definitive conclusions will be reached and whether outcomes will meet clinical expectations, I am confident in the underlying rationale. In traditional trimodality therapy, chemotherapy plays a central role, and ADCs combined with immunotherapy offer clear advantages over conventional chemotherapy. Introducing these regimens into bladder-sparing approaches should, in theory, be successful.
There is also active discussion among experts about whether future bladder-sparing strategies might move toward “de-escalation of radiotherapy.” From a surgical perspective, if bladder preservation ultimately fails and radical cystectomy is required, prior radiotherapy can increase surgical difficulty and postoperative complication risk. Avoiding radiotherapy in bladder-sparing protocols could greatly facilitate subsequent surgical management. This would reduce surgeons’ concerns and potentially increase confidence in bladder-sparing approaches. Of course, these ideas remain hypothetical at present, and robust evidence is still needed. Ultimately, time and well-designed clinical trials will provide the answers.
Professor Zhisong He
