Educational content on VJOncology is intended for healthcare professionals only. By visiting this website and accessing this information you confirm that you are a healthcare professional.

Nectin-4 Trop-2 HER2

Nectin-4-directed ADCs: enfortumab vedotin

 

Enfortumab vedotin, an antibody-drug conjugate targeting Nectin-4, has significantly advanced the treatment landscape for locally advanced or metastatic urothelial carcinoma (la/mUC). The Phase III EV-302/KEYNOTE-A39 trial (NCT04223856) assessed enfortumab vedotin (EV) with pembrolizumab versus standard platinum-based chemotherapy in patients with treatment-naïve la/mUC. The combination demonstrated a median overall survival of 31.5 months compared to 16.1 months with chemotherapy (95% CI: 0.38-0.58), and a median progression-free survival (PFS) of 12.5 months versus 6.3 months, respectively (95% CI: 0.38-0.54).1

 

These compelling findings led to the FDA approval of EV combined with pembrolizumab for la/mUC on December 15, 20232, which ultimately resulted in the combination therapy becoming the standard of care in patients with untreated la/mUC. Findings presented at GU Cancers 2025 additionally demonstrate the efficacy of ​EV and pembrolizumab in the real-world setting, where a cohort of German patients across 19 centers reported a median PFS of 13 months (95% CI: 5.2-20.8) and a safety profile consistent with what was reported in the aforementioned trial.3

Ongoing research is exploring novel combinations to further enhance treatment efficacy. The Phase Ib ETCTN 10483 trial (NCT04963153) is investigating the combination of enfortumab vedotin with erdafitinib, an FGFR inhibitor, in patients with mUC harboring FGFR3/2 genetic alterations who have progressed following platinum-based and PD-1/L1 inhibitor therapies. The study aims to determine the safety, tolerability, and preliminary efficacy of this regimen, potentially offering a targeted approach for this subset of patients.4

The integration of enfortumab vedotin into combination therapies marks a significant advancement in urothelial carcinoma management. Ongoing trials and emerging data will further assess its role and optimal use in diverse patient populations, potentially leading to more personalized and effective treatment strategies.

Trop-2-directed ADCs: sacituzumab govitecan

 

Trop–2–directed ADCs have also been in development, with sacituzumab govitecan (SG) being explored as a therapeutic option for mUC. However, SG has not been as successful as its nectin-4 counterpart, as results from the Phase III TROPiCS-04 trial (NCT04527991) resulted in its withdrawal.5 The study compared sacituzumab govitecan (SG) to standard chemotherapy in patients with pretreated advanced urothelial carcinoma. The trial did not meet its primary endpoint of overall survival (OS) improvement, where patients receiving SG had an OS of 10.3 months versus 9.0 months in the chemotherapy arm (95% CI: 0.73-1.02).6

Despite these results, SG may have promise in combination therapies. The TROPHY-U-01 Cohort 3 study (NCT03547973) evaluated SG with pembrolizumab in patients with mUC who progressed after platinum-based chemotherapy. This combination demonstrated an objective response rate of 41% after a median follow-up of 14.8 months (95% CI: 26.3 – 57.9) suggesting potential synergistic effects warranting further exploration.7 Additionally, the DAD-IO trial is assessing a triplet regimen of SG, EV, and pembrolizumab in patients with treatment-naïve mUC. The ongoing trial aims to determine the efficacy and safety of this triplet

 

combination and builds upon the DAD trial (NCT04724018) of the two ADCs.8

While monotherapy with SG has faced challenges in mUC, its role within combination regimens remains under active investigation. Future studies will elucidate its potential in enhancing treatment outcomes, particularly when paired with other therapeutic agents.

HER2-directed ADCs: disitamab vedotin

 

Disitamab vedotin (DV), a HER2-targeted ADC, has also emerged as a promising therapeutic agent in the management of urothelial carcinoma (UC). In a pooled analysis of the Phase II RC48-C005 (NCT03507166) and RC48-C009 (NCT03809013) studies involving patients with HER2-positive locally advanced or metastatic UC who had progressed on prior chemotherapy, DV demonstrated an objective response rate (ORR) of 50.5% (95% CI: 40.6 – 60.3), with a median progression-free survival (PFS) of 5.9 months (95% CI: 4.3 0 7.2) and median overall survival (OS) of 14.2 months.9

 

In the neoadjuvant setting, the Phase II RC48-C017 trial (NCT05297552) investigated DV combined with perioperative toripalimab in patients with HER2-expressing muscle-invasive bladder cancer (MIBC). Updated results from GU Cancers 2025 revealed encouraging safety signals, where a pCR rate of 63.6% (95% CI: 45.1-79.6) and a pathological response rate of 75.8% (95% CI: 57.7-88.9) were recorded.10

To further assess the efficacy of DV in combination with immunotherapy, the Phase III DV-001 trial is underway. This open-label, randomized, controlled study compares DV with pembrolizumab against standard chemotherapy in previously untreated patients with HER2-expressing la/mUC. The trial aims to provide definitive evidence regarding the potential of this combination as a first-line treatment option.11​

Whilst DV has only been approved in China for platinum-refractory patients with metastatic UC9, the incremental integration of disitamab vedotin into UC treatment regimens represents a significant advancement in personalized oncology. Ongoing and future studies will be crucial in defining its optimal role across various stages of bladder cancer, potentially leading to improved patient outcomes.

References

  1. Powles T, Valderrama BP, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(Suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106.
  2. S. Food and Drug Administration. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer [Internet]. 2023 Dec 15 [cited 2025 Mar 31]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
  3. ​Zschäbitz S, Casuscelli J, Büttner T, Darr C, et al. Enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma: First results on outcomes and safety in a German multicenter real-world patient cohort (GUARDIANS). J Clin Oncol. 2025;43(5_suppl):715. doi:10.1200/JCO.2025.43.5_suppl.715. ​
  4. Jain RK, Ong F, Faltas BM, et al. ETCTN 10483: Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR3/2 genetic alterations (GAs). J Clin Oncol. 2025;43(5_suppl):808. doi:10.1200/JCO.2025.43.5_suppl.808.
  5. ​Benjamin DJ, et al. Implications and Lessons from the Withdrawal of Sacituzumab Govitecan for Treating Advanced Urothelial Carcinoma. Eur Urol Oncol. 2025 Jan 23:S2588-9311(25)00003-3. doi:10.1016/j.euo.2025.01.003. ​
  6. ​Grivas P, Powles TB, Vulsteke C, Goupil MG, Park SH, Voog E, Demey W, Fong PC, Garcia JA, Jacob N, et al. LBA9 TROPiCS-04, a randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (CT) in pretreated advanced urothelial carcinoma (aUC): Overall survival (OS) and safety analysis. Ann Oncol. 2024;35(Suppl 4):S1505-S1507. doi:10.1016/j.annonc.2024.10.830.
  7. Grivas P, Pouessel D, Park CH, et al. Sacituzumab govitecan in combination with pembrolizumab for patients with metastatic urothelial cancer that progressed after platinum-based chemotherapy: TROPHY-U-01 cohort 3. J Clin Oncol. 2024;42(12):1415-1425. doi:10.1200/JCO.22.02835.
  8. ​McGregor BA, Sonpavde GP, Kwak L, Regan MM, Gao X, Hvidsten H, Mantia CM, Wei XX, Berchuck JE, Berg SA, Ravi P, Michaelson MD, Choueiri TK, Bellmunt J. The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. Ann Oncol. 2024 Jan;35(1):91-97. doi:10.1016/j.annonc.2023.09.3114.
  9. ​Sheng X, Wang L, He Z, et al. Efficacy and safety of disitamab vedotin in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic urothelial carcinoma: A combined analysis of two phase II clinical trials. J Clin Oncol. 2023;41(12):2570-2580. doi:10.1200/JCO.22.02912.
  10. ​Sheng X, Wang L, He Z, et al. Updated efficacy and safety results from the phase II RC48-C017 trial: neoadjuvant disitamab vedotin plus perioperative toripalimab in HER2-expressing muscle-invasive bladder cancer. J Clin Oncol. 2025;43(5_suppl):665. doi:10.1200/JCO.2025.43.5_suppl.665.
  11. ​Galsky MD, Grande E, Necchi A, Drakaki A, Loriot Y, Franco S, Ichimaru M, Zhang W, Powles T. Phase 3 study of disitamab vedotin with pembrolizumab vs chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (DV-001). J Clin Oncol. 2024;42(16_suppl):TPS4616. doi:10.1200/JCO.2024.42.16_suppl.TPS4616.

Written by Simon Ng

The content of VJOncology is intended for healthcare professionals