Editor's Note: At a recent international oncology conference, Professor Tom Powles from the Barts Cancer Centre in London presented the latest results from the RC48-G001 study. This global, multicenter Phase 2 trial evaluated disitamab vedotin (RC48) in patients with HER2-expressing, previously treated advanced urothelial carcinoma (UC). As a HER2-targeted antibody-drug conjugate (ADC) utilizing a monomethyl auristatin E (MMAE) payload, RC48 has previously demonstrated efficacy in biomarker-selected cohorts in China. This global study further validates its clinical utility across a broader, international patient population.01. Treatment Landscape and HER2 Expression: Addressing Unmet Needs
There remains a significant unmet medical need for advanced UC in the second-line setting. HER2 is widely expressed in urothelial carcinoma tissues, with immunohistochemistry (IHC) showing expression in approximately 80% of samples. Specifically, 20%–25% of patients are classified as HER2-positive (IHC 3+ or IHC 2+/FISH+), while approximately 50% are categorized as HER2-low (IHC 1+ or IHC 2+/FISH-). With its optimized antibody design and potent bystander effect, RC48 provides a novel precision therapy for this substantial HER2-expressing population.
02. RC48-G001 Study Design: Focused on Both HER2-Positive and HER2-Low Cohorts
RC48-G001 is a global, multicenter, open-label Phase 2 study. The trial enrolled patients with advanced UC who had progressed after 1–2 lines of prior systemic therapy. Patients were divided into two cohorts based on baseline HER2 expression levels:
- Cohort A (HER2-Positive): IHC 3+ or IHC 2+ with FISH amplification.
- Cohort B (HER2-Low): IHC 1+ or IHC 2+ with negative FISH.
The primary endpoint was the objective response rate (ORR) as assessed by a Blinded Independent Central Review (BICR). Most enrolled patients had visceral metastases, representing a population with a high disease burden.
03. Clinical Efficacy: Potent Response Across HER2 Expression Intensities
The study results demonstrated consistent and significant antitumor activity regardless of the intensity of HER2 expression:
- Objective Response Rate (ORR): The ORR was 55% in Cohort A (HER2-positive) and 53% in Cohort B (HER2-low). These results are remarkably similar, suggesting that the efficacy of RC48 is not strictly dependent on high-level HER2 expression.
- Complete Response (CR): A striking CR rate of 17% was observed in the global population, which exceeds the data previously reported in Chinese cohorts.
- Disease Control: The rate of progressive disease (PD) was less than 10%, with a median duration of response (DOR) of approximately 6 months.
04. Survival Data and Therapeutic Strategy: Long-Term Benefits and Sequencing
RC48 also showed encouraging survival outcomes:
- Progression-Free Survival (PFS): The median PFS across cohorts was approximately 6 months.
- Overall Survival (OS): The median OS reached 17 to 20 months.
Prof. Powles noted that in the current landscape of advanced UC, these OS figures are highly competitive, even among patients previously treated with platinum-based chemotherapy or immune checkpoint inhibitors (ICIs). Furthermore, the study explored the potential for sequencing RC48 with enfortumab vedotin (EV). Despite both drugs sharing the same MMAE payload, clinical responses to RC48 were observed in patients who had previously failed EV.
05. Safety Profile: Manageable AEs with Precise Management Required
The safety profile of disitamab vedotin was consistent with previous reports. Grade 3 or 4 adverse events (AEs) occurred in 41% of patients.
- Common Toxicities: Primary AEs included fatigue, peripheral neuropathy (PN), and alopecia.
- Neuropathy Management: Peripheral neuropathy was cumulative and was the leading cause of treatment interruption or dose reduction (16% of patients discontinued treatment due to PN).
- Skin Toxicity: Notably, the incidence of skin rash appeared lower with RC48 compared to historical data for EV.
Expert Conclusion and Outlook:
Professor Tom Powles concluded that the RC48-G001 study successfully replicated and validated the clinical activity of disitamab vedotin in a global population of patients with HER2-expressing advanced UC. Whether in HER2-positive or HER2-low subgroups, RC48 achieved an ORR exceeding 50% alongside significant survival benefits. Currently, a global Phase 3 study comparing RC48 plus pembrolizumab against platinum-based chemotherapy as a first-line treatment for HER2-expressing advanced UC has completed enrollment. This combination therapy is expected to bring a profound paradigm shift to clinical practice in the near future.
