On October 20, 2025 Remegen reported a Phase III clinical study on disitamab vedotin plus toripalimab versus chemotherapy as first-line treatment for HER2-expressing locally advanced or metastatic urothelial carcinoma (RC48-C016) was presented at the Presidential Symposium by Professor Jun Guo from Beijing Cancer Hospital at the 2025 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress. It’s the first time a research led by Chinese scholars in the field of urological oncology has ever been selected in this honorable session. The full manuscript was simultaneously published online in The New England Journal of Medicine (NEJM). This marks the first time that the results of a Chinese evidence-based medical research in the field of urothelial carcinoma have been recognized by both an authoritative international academic conference and a top-tier journal.
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The results showed that the RC48-C016 study met the dual primary endpoints of Progression-Free Survival (PFS) and Overall Survival (OS). The Blinded Independent Central Review (BICR)-assessed median PFS reached 13.1 months, and the median OS reached 31.5 months, demonstrating both statistical and clinical significance.
The RC48-C016 trial is by now the only randomized controlled study from China providing high-level evidence for HER2-ADC as a first-line treatment of HER2-expressing (IHC 1+/2+/3+) locally advanced/metastatic urothelial carcinoma (la/mUC). The results garnered high attention and sparked lively discussion among global scholars upon release.
Comprehensive Superiority: Meeting Both PFS and OS Primary Endpoints
On the afternoon of October 19 (local time), a pivotal moment arrived at the ESMO (Free ESMO Whitepaper) Congress: Professor Guo Jun, the principal investigator of the RC48-C016 study, delivered a featured oral presentation at the Presidential Symposium, unveiling the breakthrough results globally for the first time.
The RC48-C016 study is a randomized controlled, multi-center, phase III clinical trial. It compares the efficacy and safety of disitamab vedotin combined with toripalimab versus gemcitabine combined with cisplatin or carboplatin in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who have not received systemic treatment and have HER2 expression (HER2 IHC 1+/2+/3+). The study was initiated in June 2022, with 76 clinical research centers across the country participating, and a total of 484 patients were enrolled. The dual primary endpoints of the study are PFS and OS, and the secondary endpoints include objective response rate (ORR), disease control rate (DCR), and safety, etc.
Results as of March 31, 2025, showed:
Regarding PFS, the median PFS in the disitamab vedotin combination group reached 13.1 months, more than doubling the 6.5 months in the chemotherapy group and reducing the risk of disease progression or death by 64% (Hazard Ratio [HR] =0.36, 95% CI: 0.28 – 0.46, P < 0.0001).
The OS data were equally exciting. In this interim survival analysis, the median OS in the disitamab vedotin combination group was 31.5 months, compared to 16.9 months in the platinum-based chemotherapy group. The delayed disease progression has been well translated into long-term survival benefit as the overall survival time almost doubled as compared to chemotherapy, with a 46% reduction in the risk of death (HR = 0.54, 95% CI: 0.41 – 0.73, P < 0.0001).
Regarding tumor response, the ORR assessed by BICR reached 76.1% in the disitamab vedotin combination group, far exceeding the 50.2% in the chemotherapy group. For disease control, the DCR in the disitamab vedotin combination group reached 91.4%, significantly higher than the 77.6% in the chemotherapy group.
In key subgroup analyses, significant improvements in median PFS and median OS were observed in the disitamab vedotin combination group compared to the platinum-based chemotherapy across subgroups, regardless of cisplatin eligibility, HER2 expression status, or primary tumor site.
Furthermore, the combination regimen demonstrated a better safety profile. The overall incidence of Grade ≥3 treatment-related adverse events was only 55.1% in the disitamab vedotin combination group, significantly lower than the 86.9% in the chemotherapy group.
"This is the world’s first large-scale Phase III randomized controlled clinical study in the first-line treatment of HER2-expressing Chinese mUC patients, which demonstrated that HER2-ADC combined with immunotherapy was superior to standard platinum-based chemotherapy, potentially establishing the combination therapy of disitamab vedotin and immunotherapy as the standard of care in the first-line treatment of advanced HER2-expressing mUC. This not only signifies that China’s innovative drug development is leading transformations in cancer treatment globally but also provides critical rationale for exploring similar combination strategies in treating other cancers." As Professor Guo Jun commented, the result of the RC48-C016 study confirmed that the efficacy of disitamab vedotin + toripalimab combination regimen surpassed that of traditional chemotherapy as first-line treatment for advanced mUC, potentially marking a major shift in the treatment landscape for urothelial carcinoma. It promotes innovation in Chinese diagnostic and treatment pathways while providing valuable evidence for global clinical practice.
During the subsequent expert commentary session, Professor Andrea Necchi from Italy’s IRCCS San Raffaele Hospital spoke highly of RC48-C016 study. He pointed out that the study represents a significant breakthrough in the treatment of HER2-positive urothelial carcinoma. Compared to chemotherapy, the combination therapy of disitamab vedotin and toripalimab significantly improves patients’ PFS and OS, demonstrating substantial statistical significance and clinical value, thereby offering a novel treatment option for this patient population.
Precision Treatment, Benefiting the Full Spectrum of HER2-Expressing Population (IHC 1+/2+/3+)
Urothelial carcinoma is the most common malignant tumor of the urinary system, representing a significant area of clinical unmet need.
Chinese researchers have been at the forefront of exploring HER2-ADC therapy for UC. The HER2-ADC disitamab vedotin was first approved in China in 2021 for the treatment of HER2-overexpressing (IHC 2+/3+) advanced or metastatic urothelial carcinoma, demonstrating excellent efficacy and consistent safety with that observed in prior clinical trials.
RC48-C016 study prospectively extended its clinical design to the full HER2-expressing population (IHC 1+/2+/3+). Among 765 patients tested for HER2, 632 patients had HER2-expressing characteristics (IHC 1+/2+/3+), accounting for approximately 82.6% of the tested population. The study enrolled 484 patients, who were randomized in a 1:1 ratio to groups. Stratification factors were pre-specified in the study design, primarily including cisplatin eligibility, HER2 expression status (IHC 1+ vs. IHC 2+/3+), and presence of visceral metastasis.
The results showed that the efficacy observed in the disitamab vedotin plus toripalimab regimen were consistent across all pre-specified subgroups. Regardless of HER2 expression status, cisplatin eligibility, or whether the tumor originated in the upper or lower urinary tract, disitamab vedotin combined with toripalimab significantly improved PFS and OS compared to chemotherapy, robustly demonstrating its benefit for the full demonstrating its benefit for the full HER2-expressing population (IHC 1+/2+/3+) with urothelial carcinoma.
"The significant survival benefit achieved by disitamab vedotin combined with toripalimab is not subject to the level of HER2 expression or cisplatin eligibility status, delivering benefit to populations with different characteristics," Professor Guo Jun stated, noting that its benefit for the full HER2-expressing population (IHC 1+/2+/3+) is one of the most groundbreaking findings of this study.
Disitamab Vedotin Combined with Immunotherapy, Establishing a New Benchmark in UC First-Line Treatment
Undoubtedly, RC48-C016 study is a milestone in the global first-line treatment landscape for advanced urothelial carcinoma, signifying a fundamental shift in the treatment paradigm for HER2-expressing patients:
Firstly, RC48-C016 study is the world’s first Phase III head-to-head trial to demonstrate that the combination of HER2-ADC and immunotherapy is significantly superior to traditional platinum-based chemotherapy in the first-line treatment of HER2-expressing (IHC 1+/2+/3+) advanced urothelial carcinoma. The release of its outstanding data on PFS, OS, ORR, and safety provides strong decision-making basis for clinicians, which will promote this combination to become a new first-line treatment standard for Chinese mUC patients and is expected to rewrite clinical guidelines.
Secondly, the study successfully implements the concept of precision medicine in urothelial carcinoma based on significant biomarker characteristics. By extending the beneficiary population from the traditional HER2-high (IHC 2+/3+) to the full HER2-expressing (IHC 1+/2+/3+) population, it enables over 80% of urothelial carcinoma patients to potentially benefit significantly from this treatment regimen. In the current clinical practice in China where HER2 routine detection in urothelial carcinoma has been achieved, the study provides a preferred precise treatment plan for the majority of patients and precise basis for anti-HER2 treatment, promoting a comprehensive upgrade in the global treatment concept and strategy for urothelial carcinoma and leading the continuous exploration of this combination therapy in different disease stages of urothelial carcinoma.
Thirdly, this combination regimen substantially reduces the toxicity associated with traditional platinum-based chemotherapy, significantly improving patient treatment tolerance and compliance, and providing a foundation for subsequent continuous therapy, achieving an optimized balance between tumor control, long-term survival, and quality of life.
Since its marketing four years ago, disitamab vedotin, relying on its outstanding efficacy, has achieved a progress from late-line to first-line treatment in the field of urothelial carcinoma, comprehensively breaking through the bottlenecks of traditional chemotherapy and continuously expanding the boundaries of its clinical value. The revelation of RC48-C016 study data once again demonstrates its huge clinical treatment potential.
Based on the breakthrough results of the RC48-C016 study, RemeGen Co., Ltd. submitted a New Drug Application (NDA) in China in July of this year for the new indication of disitamab vedotin combined with toripalimab for the first-line treatment of HER2-expressing locally advanced or metastatic urothelial carcinoma. This will not only address domestic clinical needs but also holds the potential to become a "Chinese Solution" influencing the global treatment landscape.
It is believed that with extended follow-up, disitamab vedotin will continue to yield clinical benefit data for broader treatment prospects.
(Press release, RemeGen, OCT 20, 2025, View Source;disitamab-vedotin-achieves-major-breakthrough-as-first-line-treatment-for-urothelial-carcinoma-302588752.html [SID1234656833])