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Targeting Nectin-4 and HER2 in Urothelial Cancer: The Evolving Role of ADCs
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Key Takeaways
- ADCs combine chemotherapy's potency with targeted therapy's precision, offering a selective approach to cancer treatment with minimized off-target toxicity.
- Enfortumab vedotin (EV) targets nectin-4, showing superior response rates and survival outcomes in urothelial cancer compared to chemotherapy.
Enfortumab vedotin, trastuzumab deruxtecan, and disitamab vedotin were highlighted at the 2025 ASCO Genitourinary Cancers Symposium.
Antibody drug conjugates (ADCs) have shown significant clinical impact as monotherapies for treatment of patients with urothelial cancer (UC), leading to the development and approval of novel agents such as enfortumab vedotin (EV, Padcev; Pfizer Inc). At the 2025 ASCO Genitourinary Cancers Symposium, experts gathered to discuss the mechanisms of ADCs, key agents and emerging biomarkers, toxicity management, and future directions for ADC therapy in UC.
Antibody drug conjugate molecules | Image Credit: © Love Employee - stock.adobe.com
An ADC consists of 3 essential parts: an antibody that binds to the tumor antigen and aids internalization into the tumor cell; a linker for payload release; and a cytotoxic payload that delivers strong cytotoxins directly to tumor cells, causing death. By combining the potency of chemotherapy with the precision of targeted therapy, ADCs provide a highly selective approach to cancer treatment, minimizing off-target toxicity while maximizing therapeutic efficacy.1
“ADCs aim to improve efficacy, reduce toxicity, and expand the therapeutic index,” explained Di Maria Jiang, MD, MSc, FRCPC, from Princess Margaret Hospital, University Health Network. “Many ADCs exhibit bystander effects, where release payloads reach and kill neighboring tumor cells. Regardless of their target expression, ADCs can also engage with the immune system and promote immunogenic cell death via the antibody and also the payload activity.”1
In UC, there are 4 key ADCs including EV, sacituzumab govitecan (SG, Trodelvy; Gilead Sciences), trastuzumab deruxtecan (T-DXd; Enhertu; Daiichi Sankyo), and disitamab vedotin (DV, Aidixi; RemeGen), and each targeting a key biomarker in UC treatment. EV, T-DXd, and DV remain on the market; however, the SG indication was withdrawn by the FDA following phase 3 data that reported 4% to 5% of patients in the SG arm experienced treatment-related deaths due to neutropenic complications. Additionally, the trial did not mandate the use of prophylaxis.1
EV is a novel agent comprised of a humanized anti-nectin-4 antibody, a cleavable linker, and the cytotoxic payload monomethyl auristatin E (MMAE). Nectin-4 is a cell adhesion molecule that is highly expressed in 97% of UCs and associated with a poorer prognosis. In 2019, EV became the first FDA-approved nectin-4 targeting agent for adult patients with locally advanced or metastatic UC (mUC) as a monotherapy or in combination with pembrolizumab (Keytruda; Milliman, Inc). The EV 301 trial (NCT03474107) results supported the agent’s approval, demonstrating its superior response rates, progression-free survival, and overall survival compared to chemotherapy in the pre-treated setting.1,2
Similar to many other agents, EV has a toxicity profile that includes skin toxicity, peripheral neuropathy, and hyperglycemia, which require careful monitoring and management. It is being further evaluated in combination with immunotherapy, such as in the EV 103 (NCT03288545) and EV 302 trials (NCT04223856), which have shown promising results in terms of response rates and survival outcomes.1,3,4
“EV 103 was an early phase multi-cohort study that enrolled cisplatin-ineligible patients with metastatic [UC]. The dose escalation cohort and cohort A tested EV plus pembrolizumab and showed an impressive response rate of 73% with durable responses at longer follow-up," said Jiang. “Data recently showed that more than 40% of patients remained alive at 5 years, which is unprecedented for this disease. Cohort K randomized patients to EV plus pembrolizumab or EV monotherapy in the first line; while there was no formal statistical comparison, EV plus [pembrolizumab] showed a higher response rate of 64.5% with durable benefit. This led to FDA approval of EV plus [pembrolizumab].”1
Human epidermal growth factor receptor 2 (HER2)-targeting agents, including T-DXd and DV have also gained FDA approval for their safety and efficacy in treatment of UCs. HER2 amplifications and mutations are found in 8% to 12% of bladder cancers, making them a promising target for some patients. Additionally, research suggests that HER2 mutations may enhance ADC internalization and activity.1
Monoclonal antibody binding to the HER2 receptor on a cancer cell | Image Credit: © Man888 - stock.adobe.com
T-DXd is a humanized anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload that showed remarkable activity in the DESTINY-Breast03 trial (NCT03529110), with high response rates and durable responses. These positive results led to its accelerated approval for HER2 IHC 3+ solid tumors, representing the first tumor-agnostic approval for an ADC. T-DXd was also explored in the DESTINY-PanTumor02 trial (NCT04482309) in a cohort of 41 patients with pre-treated mUC.1,5,6
“Here we accrued a variety of different tumor types, including bladder cancer. Across patients, the [ORR] was 29.4%. The patients [with UC] were a more limited cohort, but there was a clear activity signal, suggesting that we need to keep an eye on this as an opportunity,” explained Funda Meric-Bernstam, MD, FASCO, from the University of Texas MD Anderson Cancer Center. “In conclusion, HER2 amplified, expressed, and mutated [UC].”1
DV is another HER2-targeting ADC that consists of a humanized anti-HER2 antibody, a cleavable linker, and the cytotoxic payload MMAE. In a phase 2 study, DV showed an objective response rate of 50.5% in patients with HER2-positive solid tumors, including a 62% response rate in patients with high HER2 expression. When used in combination with immunotherapy, DV had higher response rates compared with other HER2-targeted ADCs like T-DXd. DV is being further evaluated in phase 3 trials in the first line setting for mUC.1
Clinical research is constantly advancing and introducing new opportunities for use of HER2- and nectin-4-targeting agents. For example, use of these agents in combination with immunotherapy or chemotherapy may allow optimization of synergistic effects while simultaneously overcoming resistance. There are also emerging therapies, such as BT 8009, a novel nectin-4 targeting ADC that uses a bicycle peptide conjugate and a different payload, potentially with less neuropathy than EV.1
Molecular model of an antibody | Image Credit: © catalin - stock.adobe.com
Efforts are ongoing to develop the next-generation ADCs with novel bispecific targets to overcome resistance, linkers to improve stability and reduce off-target toxicity, and payloads, such as degraders and STING agonists, beyond traditional cytotoxins. There is also the potential for application of ADCs in earlier stages, including in combination with neoadjuvant chemotherapy and immunotherapy or intravesical use for non-muscle invasive bladder cancer. The next generation of ADCs is focused on improving cure rates for patients with bladder-sparing approaches.1
Beyond the development of novel agents, optimizing patient selection and sequencing of ADC-based therapies requires a deeper understanding of resistance mechanisms to improve treatment outcomes. Identifying reliable biomarkers and refining selection criteria beyond target antigen expression are critical to maximizing efficacy. Additionally, determining the optimal sequencing of ADC therapies while considering cross-resistance and toxicity profiles remains a key area of investigation.1
With emerging agents and next-generation ADCs in development, the field is rapidly evolving toward more effective, personalized, and potentially curative treatment options. By addressing resistance mechanisms and enhancing therapeutic precision, ADCs hold the promise of further improving outcomes and expanding the reach of targeted therapy in UC.
