In recent years, the rapid advancement of antibody-drug conjugates (ADCs) has completely reshaped the treatment paradigm across the entire disease course of urothelial carcinoma. Meanwhile, Chinese investigators and domestically developed innovative agents have gained ever-increasing influence in the global oncology landscape. Recently, we had the exclusive opportunity to interview Prof. Shilpa Gupta, a world-leading expert in urothelial carcinoma, Leading Principal Investigator of multiple pivotal international multicenter clinical trials from Cleveland Clinic. We conducted an in-depth, professional exchange with Prof. Gupta on core topics including the global positioning of China's clinical research in urological oncology, optimized pathways for cross-border research collaboration, the paradigm shift in diagnosis and treatment driven by ADCs, and the future disruptive breakthrough directions in the field. The following is the edited content of this interview.Oncology Frontier: Thank you, Prof. Gupta, for accepting our exclusive interview. First of all, as you have led and been deeply involved in numerous global multicenter clinical trials, in your opinion, what role is China currently playing in the field of clinical research on urological oncology? Meanwhile, there are certain differences between China, the United States and Europe in terms of research systems and patient population characteristics. How can we better promote international collaboration in this field?
Prof. Shilpa Gupta: I have consistently maintained that China has demonstrated exceptional capabilities in drug innovation, novel agent R&D, and efficient patient enrollment in clinical trials. This strength is underpinned by China’s vast patient population and increasingly sophisticated clinical research infrastructure. Of particular note, for the first time, we are witnessing high-quality positive results being continuously generated from China-led, population-specific clinical trials, beyond the traditional international clinical trial system dominated by the US and Europe.
When it comes to global collaboration, its core value is paramount. If we only conduct independent regional trials separately across different continents, the research findings can hardly achieve true clinical translation and widespread application globally. A very typical example here is the clinical trial of disitamab vedotin combined with toripalimab, which has yielded impressive positive results but enrolled exclusively Chinese patients. At the same time, the clinical trial of disitamab vedotin combined with pembrolizumab in other regions of the world has just been initiated, with core results not expected to be published for several years. This undoubtedly causes a lag in global treatment advancement, and prevents more patients from accessing potentially highly effective treatment regimens as early as possible.
Therefore, in my opinion, when pharmaceutical companies collaborate with global investigators to design clinical trials, there are two feasible, optimized pathways to better advance international collaboration. The first is to pre-specify regional cohorts in the trial, with a reasonable cap on patient enrollment for each continent. This not only ensures the global generalizability of the study, but also simultaneously obtains efficacy and safety data across diverse populations, enabling the results to be better adapted to patient groups in different regions. The second pathway, still taking the disitamab vedotin plus toripalimab trial as an example: given that the efficacy of this regimen has been verified in the Chinese population, an expansion cohort of approximately 200 patients can be conducted in European and American populations to further validate the efficacy and safety of this regimen in Western populations, which is a highly feasible approach. Of course, truly efficient global collaboration in clinical research cannot be achieved without the synergy and joint efforts of pharmaceutical companies, global investigators, and regulatory authorities in various countries.
Oncology Frontier: The EV-302 trial has completely reshaped the first-line treatment landscape for advanced urothelial carcinoma, with its subgroup analysis showing that the regimen achieved a significant survival benefit in the pan-Asian population. In your opinion, what are the potential reasons behind this phenomenon?
Prof. Shilpa Gupta: First and foremost, it should be clarified that we can hardly draw absolute and definitive conclusions from subgroup analysis with limited sample size. However, from a mechanistic perspective, this phenomenon is most likely associated with the expression and distribution profile of Nectin-4 in tumor tissues.
It should be noted that we do not consider Nectin-4 expression level as the core determinant of the efficacy of Enfortumab Vedotin (EV) — as confirmed by EV-302 trial data, patients derive significant benefit from the EV plus pembrolizumab combination regimen regardless of their Nectin-4 expression level. Nevertheless, one possibility that cannot be ruled out is that the overall Nectin-4 expression level in tumor tissues from pan-Asian/Chinese patients with urothelial carcinoma is relatively higher, which may be one of the potential drivers of the differential benefit across populations.
Oncology Frontier: At present, ADC agents have achieved milestone success in the field of urothelial carcinoma. In your opinion, which direction is most likely to deliver the next disruptive therapeutic breakthrough in this field?
Prof. Shilpa Gupta: This is an extremely valuable question. The field of urothelial carcinoma is currently in an unprecedented period of robust development: a large number of novel ADC agents are emerging, featuring innovative designs of entirely new targets, next-generation payloads, and optimized linkers. Meanwhile, numerous highly effective combination regimens, bispecific ADCs and other cutting-edge technologies have entered clinical exploration.
However, in my view, the core breakthrough direction in the future cannot focus solely on populations that already benefit from treatment. We all know that the EV plus pembrolizumab regimen achieves an objective response in approximately 70% of patients with advanced urothelial carcinoma, but we must not only focus on this subset of responding patients. More importantly, we need to shift our research focus to the remaining 30% of patients who are primary non-responders to this regimen. We must elucidate the core mechanisms underlying treatment failure in these patients, and explore how to spare them from the potential toxicity of the regimen and transition to precision medicine-based individualized treatment as early as possible.
At the same time, there is an urgent unmet need to identify biomarkers that can accurately predict primary resistance to EV combined with immunotherapy, given the extremely poor prognosis of these non-responding patients. For this population, we must design targeted alternative treatment strategies, such as exploring novel therapeutic targets, or developing novel payload agents with distinct mechanisms of action.
Therefore, I believe that the future treatment of urothelial carcinoma will still take different classes of ADC agents as the core cornerstone. However, we must have the ability to rapidly switch between ADC agents and their combination regimens based on the patient’s response status and biomarker characteristics, to truly deliver precision treatment for the entire patient population.
Oncology Frontier: Looking back at clinical research advances over the past few years, what do you think is the biggest paradigm shift in diagnosis and treatment, the most disruptive “game-changer” in the global urothelial carcinoma field?
Prof. Shilpa Gupta: In my opinion, the biggest paradigm shift in the field of urothelial carcinoma over the past few years is undoubtedly the treatment model of ADC combined with immunotherapy, the most representative of which is the EV plus pembrolizumab regimen.
The core underpinning this conclusion is the EV-302 trial — the first phase III clinical trial in four decades that has comprehensively outperformed the traditional platinum-based standard chemotherapy in the first-line treatment of locally advanced/metastatic urothelial carcinoma. The success of this regimen has also triggered a domino effect across the entire disease course of urothelial carcinoma.
For example, in the neoadjuvant setting for localized bladder cancer, data from the EV-303 trial showed that the neoadjuvant regimen of EV plus pembrolizumab yielded significantly superior efficacy compared to radical cystectomy alone. This result was within our expectations, but what was truly striking was the unprecedented pathological complete response (pCR) rate of up to 57% achieved with this regimen. It is important to note that the majority of these patients are elderly with generally poor underlying physical status. In the previous treatment paradigm, most of these patients would directly undergo radical cystectomy, a major surgery, without preoperative systemic therapy, facing an extremely high risk of postoperative recurrence. Today, this neoadjuvant regimen has been proven to bring a significant overall survival benefit to these patients, which is an unprecedented breakthrough. This is just one of the application scenarios of the EV plus immunotherapy regimen. Recently, we have also seen that this regimen has demonstrated efficacy superior to traditional platinum-based neoadjuvant chemotherapy in the treatment of muscle-invasive bladder cancer (MIBC).
Therefore, I believe that the ADC combined with immunotherapy regimen is the well-deserved “game-changer” in this field. The core change brought by this paradigm shift is that the clinical value of defining a patient’s platinum eligibility has been greatly reduced today. Instead, the core questions we need to focus more on are: Are we overtreating some patients through this “sandwich-style” perioperative treatment model? How can we more accurately screen the population who truly need adjuvant therapy after surgery to avoid unnecessary treatment?
In addition, another core exploration direction in the future is how to leverage highly effective regimens such as EV plus pembrolizumab to enable more patients with MIBC to receive individualized bladder-preserving treatment, significantly improving their quality of life while ensuring durable tumor control.
