2. UroToday Home
  3. Clinical Trials
  4. From the Editor
Back to Clinical Trials    

Nectin-4, A Validated Target for Urothelial Cancer; Opening the Door for Novel Imaging and Therapeutic Development

We have had enfortumab vedotin for use in the clinic for patients with metastatic bladder cancer for many years now. The more recent FDA approval for enfortumab vedotin in combination with pembrolizumab on December 15, 20231 has yielded impressive results, essentially doubling the median overall survival for patients with previously untreated metastatic or locally advanced urothelial cancer.2

The unique thing about enfortumab vedotin, as an antibody-drug conjugate (ADC), is that it specifically targets Nectin-4, representing the only regulatory approved antineoplastic agent that targets this protein. Nectin-4 has biological functions completely unrelated to its role in this situation. Nectin-4 is a type I transmembrane cell adhesion protein that can serve as an entry receptor for viruses.3 However, important for ADC targeting, is the fact that Nectin-4 is highly expressed in urothelial carcinoma.4

Although enfortumab vedotin is clearly highly efficacious, it still carries potential toxicities. The most common treatment emergent adverse events were rash, peripheral neuropathy, fatigue, alopecia, and nausea.5 Rash may be challenging to avoid, as Nectin-4 is expressed in the skin; however, most of the other toxicities are related to monomethyl auristatin E (MMAE), which is the payload used on enfortumab vedotin. The obvious hope for the future is to switch up the ADC and use a different payload, with a unique mechanism of action and distinct toxicities. Although logical, there are many potential methods to use a similar payload on an ADC with different pharmacokinetic (pk) properties. Therefore, the development of novel ADCs that have ability to concentrate payload in the malignant cell and tumor microenvironment, with less free-floating payload, is not only desirable, it may be a very realistic option in the near future.

There may be many methods to accomplish the above goal. For example, antibody binding and faster internalization may lead to greater intracellular payload delivery. Improved linker stability can also be important to ensure the ADC reaches the target without breaking apart early, resulting in less free-floating payload that would have potential to increase systemic toxicity. Another common misconception is that a higher drug-antibody ratio (DAR) is a favorable quality. DAR describes the number of payload molecules linked to the ADC. Yet, in general, a higher, more heterogeneous DAR in production may lead to greater off-target effects of the ADC.

One example of such an agent is CRB-701, which uses a novel nectin-4 IgG1 antibody that offers a longer half-life with high affinity and selectivity. The payload is also MMAE, however, it is conjugated to a cathepsin B-sensitive cleavable linker using a new site-specific transglutaminase conjugation technology. The result is a homogenous ADC, with a stable DAR of 2.0.6 In pre-clinical studies, CRB-701 has demonstrated lower free MMAE and longer half-life in plasma in both rats and non-human primates. CRB-701 has already shown promising efficacy, safety, and pk in a phase 1/2 dose-escalation trial. Specifically, both nectin-4 positive urothelial and cervical cancers have had responses with extended ADC half-life (dosed once every 21 days) and decreased free MMAE, with limited adverse events and no drug-related peripheral neuropathy or rash.7

Measuring nectin-4 in the laboratory is another significant challenge since commercially available antibodies generally are not ideal for detection, lacking sensitivity. The antibody component against nectin-4 from the enfortumab vedotin construct has previously been used for immunohistochemistry with high detection rates. However, that antibody is proprietary and not available for commercial use, and it was not conducive to biomarker marker development or utilization for patient selection due to fairly uniformly high detection. Therefore, the development of novel PET imaging nectin-4 radiotracers is another potentially fruitful area of investigation, and I outline a couple of ongoing trials below.

The above qualities of ADC development are currently being manipulated in many laboratories with many pre-clinical studies ongoing. Besides the example I provided with CRB-701, many of these other novel nectin-4 targeting ADCs have also made their way into clinical trials, and we eagerly await results to see whether the novel ADC constructs accomplish the goal of greater tumor concentration and less free-floating payload. Most important, is whether those qualities will lead to superior efficacy and decreased toxicity outcomes for patients. If the results from these actively accruing clinical trials are promising, one could envision targeting other tumor histologies that harbor much less nectin-4 expression than urothelial carcinomas. Potentially greater efficacy with fewer adverse events might lead to many future successes for various types of cancer patients in the future.

Actively Accruing Therapeutic or Imaging Trials Targeting Nectin-4 in Urothelial and other Cancers

  • Phase 1/2 study of CRB-701 in solid tumors (NCT06265727)
  • Phase 1 study of ADRX-0706 in selected advanced solid tumors (NCT06036121)
  • Phase 1 study of LY4052031 in advanced or metastatic urothelial cancer or other solid tumors (NEXUS-01) (NCT06465069)
  • Phase 1/2 study of BT8009-100 in patients with nectin-4 expressing advanced malignancies (NCT04561362)
  • Phase 1 study of LY4101174 in patients with recurrent, advanced or metastatic solid tumors (includes prostate cancer) (NCT06238479)
  • Phase 1 study of 9MW2821 in high-risk non-muscle-invasive bladder cancer (NCT06551233)
  • Nectin-4 specific LMW PET imaging for urothelial carcinomas (NCT05321316)
  • 18F-LN1 PET/CT imaging for urothelial carcinomas (NCT06120413)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
  2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024; 390:875-88.
  3. Liu Y, Han X, Li Y, et al. Role of Nectin‑4 protein in cancer (Review). Int J Oncol 2021; 59:93.
  4. Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. J Clin Oncol 2020; 38:1041-9.
  5. Wong RL and Yu EY. Enfortumab Vedotin in the Treatment of Urothelial Cancers and Beyond. Future Oncol 2022; 18:3067-84.
  6. Brake R, Sun Z, Dan M, et al. Development of CRB-701 (SYS6002): A novel site-specific, Nectin-4 targeting ADC. Mol Cancer Ther 2023; 22 (12 Suppl):C121-C.
  7. Ye DW, Zhang J, Yang H, et al. Phase 1 dose escalation of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate (ADC). J Clin Oncol 42 (4_suppl):622.