In a groundbreaking advancement for urothelial carcinoma (UC) treatment, recent findings have shed light on the therapeutic potential of RC48-ADC, an antibody-drug conjugate targeting HER2-low and HER2-null expression in advanced stages of the disease. Urothelial carcinoma, a malignancy originating from the lining of the urinary tract, remains a formidable challenge in oncology due to its aggressive nature and limited effective treatment options, particularly in patients exhibiting low or absent HER2 protein expression. This real-world, multicenter retrospective study offers unprecedented insight into the efficacy and safety profile of RC48-ADC both as a standalone treatment and in synergy with immunotherapy.
HER2, or human epidermal growth factor receptor 2, is a protein that plays a significant role in cell growth and differentiation. While HER2 overexpression has been widely studied and effectively targeted in cancers such as breast and gastric cancer, approximately half of UC patients present with low (IHC 1+) or null (IHC 0) levels of HER2 expression, historically limiting the utility of anti-HER2 therapies in this subgroup. The investigation of RC48-ADC (Disitamab Vedotin) — an innovative conjugate that links an antibody directed against HER2 to a potent cytotoxic agent — marks a pivotal shift toward inclusivity in targeted therapy for these patients.
The study enrolled 27 patients diagnosed with locally advanced or metastatic urothelial carcinoma characterized by HER2 low or null expression. With a median patient age of 64 years and a male predominance of 63%, the cohort reflects a typical population burdened by this malignancy. Patients were treated either with RC48-ADC monotherapy or combined with programmed cell death protein 1 (PD-1) inhibitors, a class of immunotherapies designed to unleash the immune system’s potential against cancer cells.
Efficacy outcomes revealed an objective response rate (ORR) of 30.8% across the patient population, with nearly half achieving stable disease, culminating in a disease control rate (DCR) of 76.9%. These results underscore remarkable antitumor activity considering the historically dismal prognosis for UC patients in this setting. Median progression-free survival (PFS) reached 7.4 months, while overall survival (OS) extended to a median of 13.8 months, demonstrating meaningful clinical benefits that could redefine standard of care paradigms.
The stratification of treatment modalities showed that seven patients received RC48-ADC exclusively, whereas twenty received combination therapy alongside PD-1 inhibitors. The combination approach, often hailed for synergistic mechanisms, achieved encouraging control rates with manageable toxicity profiles. Adverse events of grade 3 severity were confined to the combination arm, affecting four individuals, and included anemia, elevated serum creatinine, and a rare instance of autoimmune encephalitis. Importantly, no severe grade 3 or higher toxicities emerged from monotherapy, suggesting a favorable tolerability spectrum for RC48-ADC alone.
Technically, RC48-ADC operates by precisely directing potent chemotherapeutic payloads to HER2-expressing cancer cells, enabling selective cytotoxicity while sparing healthy tissue. This targeted approach mitigates common systemic side effects associated with conventional chemotherapy. When partnered with PD-1 blockade, the dual assault not only inhibits tumor cell proliferation but concurrently modulates the immune microenvironment, potentially overcoming immune escape mechanisms that characterize advanced urothelial carcinoma.
This investigation is notable for its real-world design, encompassing multiple centers and thereby ensuring data relevance beyond controlled clinical trial settings. Such studies are crucial to capturing the complexities of patient heterogeneity and treatment responsiveness encountered in everyday oncology practice. The retrospective nature, while limiting causal inference, provides valuable hypothesis-generating evidence to propel further prospective research initiatives.
The significance of these findings is underscored by the unmet medical needs within the HER2-low/null UC population. Prior to this study, therapeutic options were severely constrained due to the lack of effective agents tailored to this subgroup. RC48-ADC’s apparent efficacy invites reconsideration of HER2 expression cutoffs in clinical decision-making and supports the expansion of antibody-drug conjugates into broader oncologic contexts.
From a molecular perspective, HER2-low and null tumors may harbor distinct biological behaviors compared to their HER2-overexpressing counterparts. Exploring the mechanisms underpinning RC48-ADC activity in these settings may elucidate novel pathways of tumor vulnerability and resistance. Additionally, such insight could optimize patient selection criteria, enhancing personalized treatment strategies.
The integration of immune checkpoint inhibitors alongside RC48-ADC hints at a promising combinatorial frontier in UC management. Immune evasion is a hallmark of advanced malignancies, and PD-1 inhibitors have revolutionized care by reactivating antitumor immunity. This study’s indication that the combination is both effective and tolerable encourages ongoing exploration of immunotherapy partnerships designed to amplify therapeutic windows.
Despite the encouraging outcomes, limitations inherent to the study’s design mandate cautious interpretation. The relatively small cohort size and retrospective nature necessitate validation in larger, prospective clinical trials to consolidate efficacy signals and establish standardized protocols. Delineating the long-term safety profile, particularly concerning immune-related adverse events, will be critical to ensuring patient safety.
This study’s revelations could have far-reaching implications for clinical oncology, particularly in the evolving landscape of precision medicine. The demonstration that RC48-ADC possesses robust antitumor activity in HER2-low and null urothelial carcinomas challenges existing treatment algorithms and heralds a new era of targeted and immune-based interventions. Such progress exemplifies the power of translational research bridging molecular discoveries with patient-centered outcomes.
In conclusion, the real-world evidence provided by this multicenter retrospective study highlights RC48-ADC as a formidable contender in the therapeutic arsenal against locally advanced and metastatic urothelial carcinoma with low or absent HER2 expression. Its dual potential as monotherapy and in combination with PD-1 inhibitors offers a tailored, efficacious, and manageable treatment paradigm that holds promise for transforming patient prognoses. As future prospective studies unfold, the oncology community awaits further validation that could culminate in regulatory approvals and widespread clinical adoption.
The momentum generated by this research epitomizes the relentless pursuit of novel cancer therapies harnessing the convergence of targeted molecular agents and immunomodulators. RC48-ADC’s success reinforces the necessity to revisit biomarker stratification practices, expanding the scope of targeted treatments to previously underserved patient populations. Such advancements ultimately translate into improved survival and quality of life, cornerstones of modern cancer care.
Ongoing and future research endeavors will need to dissect the mechanistic pathways underlying observed clinical responses, optimize combinatorial regimens, and refine patient stratification models. Collaboration across disciplines and institutions will be essential to accelerate these efforts, driving innovation that transcends traditional therapeutic boundaries. The clinical community eagerly anticipates the dawn of a new treatment era characterized by precision, efficacy, and safety informed by studies like this.
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Subject of Research: Urothelial carcinoma treatment with RC48-ADC in HER2 low and null expression patients
Article Title: RC48-ADC monotherapy or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma with HER2 low and null expression: a multicenter, real-world, retrospective study
Article References: Wang, D., Cao, M., Zhang, Y. et al. RC48-ADC monotherapy or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma with HER2 low and null expression: a multicenter, real-world, retrospective study. BMC Cancer 25, 812 (2025). https://doi.org/10.1186/s12885-025-14154-4
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14154-4
Tags: advanced urothelial cancer therapiesantibody-drug conjugate in oncologycancer immunotherapy synergydisitamab vedotin efficacyeffective treatments for advanced cancerHER2-low expression cancer treatmentHER2-null expression challengesinnovative cancer therapiesRC48-ADC urothelial carcinoma treatmentreal-world cancer treatment studiesretrospective studies in oncologytargeted therapy for urothelial carcinoma
