Nectin-4 has emerged as one of the fastest-growing targets in the antibody-drug conjugate (ADC) field. Once primarily associated with urothelial carcinoma (UC), it is now evolving into a promising therapeutic platform with broad potential across multiple solid tumors.

This momentum was further reinforced at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, where seven Nectin-4 ADC programs were featured, making it one of the most actively discussed ADC targets except for HER2 at the conference. While the approved Nectin-4 ADC enfortumab vedotin (Padcev®) continues to strengthen its position as the standard of care in urothelial carcinoma, next-generation Nectin-4 ADCs have reported encouraging clinical results in a growing range of malignancies, including cervical cancer, non-small cell lung cancer (NSCLC), and muscle-invasive bladder cancer (MIBC), etc. 

Nectin-4 is a transmembrane cell adhesion protein belonging to the immunoglobulin superfamily. Beyond its physiological role in mediating calcium-independent cell-cell adhesion, Nectin-4 has been implicated in tumor cell proliferation, migration, invasion, and metastasis. It is highly expressed across a wide range of epithelial malignancies, including urothelial, breast, lung, gastric, pancreatic, ovarian, head and neck, and thyroid cancers, while exhibiting limited expression in normal adult tissues.

Padcev: First & Only Approved Nectin-4 ADCs

The clinical success of Nectin-4-targeted ADCs began with Padcev®. As the first Nectin-4 ADC approved worldwide, Padcev plus pembrolizumab has established itself as the standard of care for patients with locally advanced or metastatic urothelial carcinoma (la/mUC), while also demonstrating strong commercial success. In 2025, global sales surpassed US$3.3 billion, making it one of the world's best-selling ADC therapies.

Long-term results from the pivotal EV-302 trial, presented at ASCO 2026, further strengthened Padcev's leadership in this space. With approximately 3.5 years of follow-up, the combination of enfortumab vedotin and pembrolizumab continued to demonstrate durable clinical benefit, achieving a median overall survival (OS) of 33.8 months, compared with 15.9 months for platinum-based chemotherapy (HR 0.51). The nearly 18-month improvement in median OS confirms the regimen's sustained survival advantage and reinforces EV plus pembrolizumab as the preferred first-line standard of care for patients with metastatic urothelial carcinoma.

Beyond metastatic disease, Nectin-4-targeted therapy is rapidly moving into earlier stages of treatment. Results from the KEYNOTE-B15 (EV-304) and KEYNOTE-905 (EV-303) studies presented at ASCO 2026 demonstrated encouraging efficacy for perioperative enfortumab vedotin plus pembrolizumab in patients with muscle-invasive bladder cancer (MIBC), regardless of cisplatin eligibility. The combination significantly improved pathological complete response (pCR) rates and event-free survival (EFS), supporting the expansion of Nectin-4 ADCs into the perioperative setting.

KEYNOTE-B15 (Abstract 4614) in Cisplatin-Eligible Perioperative MIBC: Perioperative EV plus pembrolizumab significantly improved EFS, OS, and pCR rates compared with neoadjuvant gemcitabine plus cisplatin. The study further demonstrated a pCR rate of 55.8%.

KEYNOTE-905 (Abstract 4510) in Cisplatin-Ineligible Perioperative MIBC: The results demonstrated a remarkable pCR rate of 57.1%, along with an approximately 50% reduction in the risk of death.

Although enfortumab vedotin has shown remarkable efficacy, long-term treatment can lead to cumulative toxicity, with about 70%–75% of patients requiring dose reductions or treatment interruptions. This has prompted interest in treatment strategies that reduce EV exposure while maintaining clinical benefit.

The ongoing Phase II IMPROVE trial is evaluating whether patients who achieve a complete or partial response after six cycles of enfortumab vedotin plus pembrolizumab can safely switch to pembrolizumab maintenance therapy, with enfortumab vedotin reintroduced only if the disease progresses. The goal is to maintain efficacy while reducing treatment-related toxicity.

More Nectin-4 Pipelines Under Development

While Padcev maintains its lead, ASCO 2026 highlighted that competition in the Nectin-4 ADC space is accelerating. Multiple candidates worldwide have now entered clinical development.

Table 1. Nectin-4 Pipelines - Results disclosed at ASCO 2026

Compared to first-generation products, next-generation Nectin-4 ADCs are differentiating themselves across several areas, including:

• ● Expanding into more solid tumor indications
• ● Pioneering novel structural modalities, such as bicycle peptide drug conjugates
• ● Utilizing novel topoisomerase I (Topo I) inhibitor payloads
• ● Exploring combinations with PD-1/PD-L1 immunotherapies
• ● Reducing skin and neurological toxicities

Industry competition has shifted from simply validating Nectin-4 as a target to a comprehensive race focused on product performance, combination therapies, and indication strategies.

Bicycle Peptide Drug Conjugates

Bicycle Therapeutics's zelenectide pevedotin (BT8009) employs a synthetic bicyclic peptide to deliver an MMAE payload. Its low molecular weight drives rapid tumor penetration and systemic renal clearance, bypassing the slow biodistribution that causes traditional ADCs to accumulate in the skin and salivary glands. This format is engineered to maintain MMAE-driven efficacy while delivering a significantly cleaner systemic safety profile than enfortumab vedotin.

Topo I Payloads Emerge as a Key Direction for Next-Generation Nectin-4 ADCs

Current global R&D trends indicate that next-generation Nectin-4 ADCs are gradually shifting away from traditional microtubule inhibitor (MMAE) payloads toward Topo I inhibitors. This shift is largely driven by their strong bystander effect and potential advantages across various solid tumors.

Currently, assets such as 9MW2821, SHR-A2102, and Eli Lilly's LY4052031 and LY4101174 all incorporate Topo I inhibitor payloads. The goal is to further enhance anti-tumor activity and broaden the scope of indications.

Notably, LY4052031 has demonstrated continued anti-tumor activity in patients who previously progressed on enfortumab vedotin. This suggests that ADC resistance does not necessarily indicate the failure of the Nectin-4 target itself, but may instead be linked to the payload's mechanism of action. The concept of "reusing the target but not the payload," highlighted during ASCO expert discussions, provides a new rationale for sequential ADC therapies in the future.

ADC and Immunotherapy Combinations Represent a Major Future Direction

Across indications ranging from urothelial carcinoma to cervical cancer, NSCLC and MIBC, multiple clinical trials have reported positive efficacy signals for ADCs combined with PD-1/PD-L1 therapies.

As more Phase III trials launch, ADC plus immunotherapy combinations are poised to advance into first-line and perioperative settings, gradually establishing themselves as key treatment strategies across multiple solid tumors.

Outlook

Over the past few years, the development of Nectin-4 ADCs has centered primarily on urothelial carcinoma. However, clinical signals from ASCO 2026 and ESMO Gynae 2026 indicate that this target is entering a new phase of pan-tumor development.

While Padcev continues to secure its position as the standard of care in urothelial carcinoma, next-generation assets such as 9MW2821, SHR-A2102, and CRB-701 are pushing past traditional indication boundaries. These candidates are demonstrating clinical promise in cervical cancer, TNBC, NSCLC, and other Nectin-4-positive solid tumors.

Simultaneously, strategies including the use of Topo I payloads, ADC and immunotherapy combinations, and sequential ADC treatments are advancing Nectin-4 ADCs into their next technological evolution. As more Phase III clinical trial readouts become available and biomarker research deepens, Nectin-4 is positioned to evolve from a specialized target for urothelial carcinoma into a broad ADC platform addressing multiple solid tumors, ultimately offering novel precision medicine options to a wider patient population.

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References:
[1] https://www.urotoday.com/conference-highlights/asco-2026/asco-2026-bladder-cancer/169469-asco-2026-discussant-nectin-4-antibody-drug-conjugates-the-past-present-and-future.html
[2] https://ascopubs.org/doi/10.1200/JCO.2026.44.16_suppl.4506
[3] https://ascopubs.org/doi/10.1200/JCO.2026.44.16_suppl.4614 
[4] https://www.asco.org/abstracts-presentations/264016
[5] https://www.asco.org/abstracts-presentations/231470 

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