Editor’s note: In recent years, antibody-drug conjugates (ADCs) targeting various molecules and using novel payloads have led to significant breakthroughs in the treatment of metastatic urothelial carcinoma (mUC). The combination of ADCs with immune checkpoint inhibitors (ICIs) has successfully advanced into the first-line setting, yet unmet clinical needs remain. At the 2025 ASCO Annual Meeting, Professor Xinan Sheng from Peking University Cancer Hospital delivered an oral presentation on a phase 1b/2 study of a domestically developed Ncetin-4–targeted ADC (9MW2821) combined with an ICI as first-line therapy in mUC. The results demonstrated promising efficacy and manageable safety. Oncology Frontier invited Prof. Sheng to share his insights.Oncology Frontier: For advanced urothelial carcinoma, platinum-based chemotherapy remains the standard first-line treatment in the current CSCO guidelines. With the release of results from studies like EV-302, how do you see ADC-ICI combinations influencing treatment strategies for advanced UC in China?
Prof. Xinan Sheng: In recent years, we’ve witnessed remarkable progress in the treatment of advanced urothelial carcinoma. Internationally, the EV-302 trial confirmed the clinical benefit of enfortumab vedotin (EV) combined with pembrolizumab for mUC, leading to its approval both globally and in China. Domestically, the phase III trial RC48-C016 investigating disitamab vedotin (RC48) combined with toripalimab also yielded positive results. These developments mark a major step forward in first-line mUC treatment.
Until last year, chemotherapy was still the mainstay. However, with the recent updates to both the CSCO and NCCN guidelines, we now anticipate a shift toward immunotherapy plus ADC-based regimens as the new frontline standard. This shift is backed by strong clinical evidence and increased drug accessibility.
We are undoubtedly entering a new era of immunotherapy–ADC combinations for advanced mUC. The key challenge ahead lies in identifying which patients are best suited for these therapies. We now have two viable options—EV plus pembrolizumab and RC48 plus toripalimab—and further combinations are being explored.
Another issue that arises is how to manage treatment sequencing following frontline ADC use. Traditionally, ADCs were reserved for second-line or later settings, but with their movement to the front line, we now need to consider what comes next. Beyond chemotherapy, are there alternative ADCs with different targets or payloads that could be used? Although several clinical studies are underway, definitive answers are still pending.
That said, biomarker-driven treatment selection is likely to play an increasingly critical role. This year’s NCCN guidelines have already incorporated biomarker-based recommendations for second-line treatment in mUC. We expect biomarkers to guide therapy decisions not only in later lines but also in the frontline setting. As more evidence and treatment options emerge, biomarker selection will become a central pillar of precision treatment in mUC.
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Oncology Frontier: Your presentation was the only oral abstract from China selected in the field of genitourinary oncology at this year’s ASCO. It focused on the novel Nectin-4–targeting ADC, 9MW2821. Could you share more about the efficacy and safety of this regimen?
Prof. Xinan Sheng: At this year’s ASCO, we presented a phase 1b/2 clinical study investigating 9MW2821 in combination with toripalimab for the treatment of patients with locally advanced or metastatic urothelial carcinoma (la/mUC). 9MW2821 is a novel ADC targeting Nectin-4. In this study, we reported outcomes from 40 patients receiving first-line therapy. The confirmed objective response rate (cORR) reached 80.0%, with a disease control rate (DCR) of 92.5%. The median progression-free survival (PFS) was 12.5 months. These results are comparable to those of similar ADC-ICI combinations, both in China and internationally—and in fact, the ORR appears numerically higher. Of course, these findings still require validation through a phase III trial. A randomized, controlled phase III study comparing 9MW2821 plus toripalimab to chemotherapy is already underway in China.
In terms of safety, treatment-related grade ≥3 adverse events occurred in 42.3% of patients. The most common events were neutropenia (11.5%), elevated liver enzymes (5.8%), and leukopenia (5.8%). Compared to other Nectin-4–targeted ADCs used abroad, the skin toxicity of 9MW2821 appears slightly lower, which is a valuable reference point. Although these agents share the same target and payload, differences in linker technology and drug-antibody design may lead to different toxicity or efficacy profiles. While we don’t yet have definitive answers, this underscores the importance of optimizing ADC components—target, linker, and payload—to strike a balance between high efficacy and low toxicity. That remains one of our key goals moving forward.
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Oncology Frontier: The confirmed ORR in this study reached as high as 87.5%, and subgroup analyses showed high response rates even in patients with liver metastases and those who were Nectin-4 negative. What are the clinical implications of these findings? How should we approach patient selection?
Prof. Xinan Sheng: Patients with liver metastases typically have a poorer prognosis. Even when treated with the same regimen, outcomes tend to be worse compared to those without liver involvement. Liver metastasis is one of the greatest challenges in clinical oncology. However, we’ve observed in recent years that ADCs—such as disitamab vedotin and enfortumab vedotin—have demonstrated superior efficacy over traditional systemic therapies in treating visceral metastases, particularly liver metastases.
This raises an important question: Should ADCs be prioritized for patients with liver metastases? In China, disitamab vedotin was recently approved for the treatment of HER2-positive breast cancer with liver metastases. This marks a shift toward precision treatment by selecting specific patient subgroups—like those with liver metastases—and matching them with appropriate ADC therapies. It prompts us to consider whether ADCs might offer superior efficacy in this setting. While further translational research is needed to confirm this, the preliminary evidence is promising.
So far, whether in urothelial carcinoma or breast cancer, patients with otherwise difficult-to-treat liver metastases appear to benefit from ADC therapy. These findings not only offer new therapeutic avenues but also expand the range of options available to patients.
