Evaluating the Potential New Standard for HER2-Expressing Urothelial Carcinoma

In a pivotal Phase III trial presented at the 2025 ESMO Congress and simultaneously published in The New England Journal of Medicine, researchers reported that the combination of disitamab vedotin, a HER2-directed antibody-drug conjugate (ADC), and toripalimab, a PD-1 immune checkpoint inhibitor, delivered significant survival benefits over standard platinum-based chemotherapy in patients with previously untreated HER2-expressing advanced or metastatic urothelial cancer.

The trial, RC48-C016, marks a key milestone in first-line treatment of HER2-positive bladder cancer, a subgroup that has long lacked tailored therapeutic options despite well-characterized biomarker expression.

Involving 484 patients across multiple centers in China, the open-label study enrolled adults with HER2-expressing urothelial carcinoma—defined by immunohistochemical scores of 1+, 2+, or 3+. Patients were randomized to receive either the disitamab vedotin plus toripalimab regimen or standard chemotherapy with gemcitabine plus cisplatin or carboplatin.

The results were compelling:

• Median progression-free survival (PFS) was 13.1 months with the disitamab vedotin–toripalimab combination vs 6.5 months with chemotherapy (HR: 0.36; P < .001).
• 12-month PFS rates favored the immunotherapy-ADC group by a wide margin: 54.5% vs 16.2%.
• Median overall survival (OS) in an interim analysis reached 31.5 months for the combination arm compared to 16.9 months in the chemotherapy group (HR: 0.54; P < .001).
• Objective response rates (ORR) were also higher: 76.1% vs 50.2%.

Such magnitudes of benefit in both survival and tumor response point to a potentially paradigm-shifting treatment option for a disease where platinum-based chemotherapy has remained the standard first-line therapy for decades.

Disitamab vedotin is a novel HER2-targeting ADC that delivers cytotoxic payloads selectively to HER2-expressing tumor cells, regardless of amplification level. While most HER2-targeted therapies are reserved for HER2-overexpressing cancers, disitamab vedotin has demonstrated activity even in tumors with low to intermediate HER2 expression, expanding the eligible population.

Toripalimab, already approved in China and under global development, inhibits PD-1 to restore T-cell function and promote anti-tumor immunity. Together, these agents offer a dual-pronged attack: direct cytotoxicity via the ADC, and immune activation via PD-1 inhibition.

The trial’s inclusion criteria, which allowed HER2 IHC scores as low as 1+, suggest that even modest HER2 expression is sufficient to benefit from this strategy, broadening its applicability well beyond the small subset of patients with HER2-amplified disease. [h3] [/h3] While any intensification of treatment raises questions about safety, the disitamab vedotin–toripalimab regimen showed a more favorable toxicity profile than chemotherapy:

• Grade ≥3 treatment-related adverse events (TRAEs) occurred in 55.1% of patients on the combination therapy vs 86.9% on chemotherapy.
• Common high-grade toxicities in the combination arm included elevated liver enzymes, neutropenia, and hypokalemia, whereas chemotherapy was associated with myelosuppression—including neutropenia in over 60% of patients.
• Rates of serious TRAEs were lower in the combination arm (28.4% vs 40.5%), with similar rates of treatment-related deaths (1.2% vs 1.4%).

Overall, while adverse events remained common—as expected with both ADCs and checkpoint inhibitors—the combination was better tolerated than standard chemotherapy, and fewer patients required discontinuation due to toxicity.

These findings are especially significant given the high unmet need in advanced urothelial cancer, where the majority of patients are elderly or frail, and many are ineligible for cisplatin. The ability to offer a biomarker-driven, non-chemotherapy regimen with both efficacy and tolerability represents a major clinical advancement.

Moreover, the trial challenges conventional notions about HER2-targeted therapy, suggesting that HER2-directed ADCs can be effective even without high HER2 amplification, and that immunotherapy combinations may amplify this effect.

Whether these results will translate to global practice remains to be seen. Toripalimab and disitamab vedotin are not yet widely approved outside China, and regulatory submissions will likely hinge on expanded global trials. However, with OS exceeding 31 months in a first-line setting, the combination sets a new benchmark in HER2-positive urothelial cancer.

This may signal the emergence of a new standard of care, ushering in an era of biomarker-guided combination therapies in bladder cancer.