Additional Targets for ADC and Novel Therapeutic Development Emerge in Urothelial Cancer

Although the combination of enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) has emerged as the new first-line standard of care (SOC) for the treatment of patients with advanced urothelial cancer, additional effective treatment targets are still needed, especially for patients who may experience disease progression after treatment with this combination, according to David B. Solit, MD.

“[The FDA approval of EV plus pembrolizumab] was a watershed moment and it changed the way those of us in the laboratory are [approaching care],” Solit said in a presentation during the 19th Annual New York GU Cancers Congress®, an event hosted by Physician’s Education Resource (PER®), in New York, New York.^1,2 “Everything needs to now be [done] with an eye towards the resistance mechanisms of EV plus pembrolizumab and what we do next for those patients who unfortunately progress [on this regimen].”

In the presentation, Solit recounted how the approval of EV plus pembrolizumab has reshaped the treatment landscape in urothelial cancer, and detailed antibody-drug conjugates (ADCs) and other novel treatment approaches that are being developed for the treatment of specific patient populations for whom the combination has been ineffective.¹

Solit is the Geoffrey Beene Chair and director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

How has the introduction of EV plus pembrolizumab altered the treatment paradigm in urothelial cancer?

The December 2023 approval of EV plus pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial cancer built on the combination’s April 2023 accelerated approval for patients with this disease who are not eligible for cisplatin-containing therapy.³ The approval for the all-comers indication was supported by data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856).²

Findings from KEYNOTE-A39 published in the New England Journal of Medicine demonstrated that patients who received EV plus pembrolizumab (n = 442) experienced a median overall survival (OS) of 31.5 months (95% CI, 25.4-not evaluable [NE]) compared with 16.1 months (95% CI, 13.9-18.3) among patients treated with chemotherapy (n = 444; HR, 0.47; 95% CI, 0.38-0.58; P < .001).⁴

Moreover, in November 2025, the FDA approved pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck) with EV as perioperative therapy after cystectomy for adult patients with MIBC who are ineligible for cisplatin.⁵ Data from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895), which supported the regulatory decision, demonstrated that patients who received EV plus pembrolizumab (n = 170) achieved a median OS that was not reached (NR; 95% CI, NR-NR) compared with 41.7 months (95% CI, 31.8-NR) for patients who received surgery alone (n =174; HR, 0.50; 95% CI, 0.33-0.74; P < .001).

Solit also highlighted data from the phase 3 EV-304/KEYNOTE-B15 trial (NCT04700124) that were presented during the 2026 Genitourinary Cancers Symposium.⁶ KEYNOTE-B15 examined perioperative EV plus pembrolizumab in patients with MIBC who were eligible for cisplatin-containing therapy and radical cystectomy. Findings from the study showed that the median event-free survival in the investigational arm (n = 405) was NR (95% CI, NR-NR) compared with 48.5 months (95% CI, 43.3-NR) among patients who received cisplatin plus gemcitabine (n = 403; HR, 0.53; 95% CI, 0.41-0.70; 1-sided P < .0001), meeting the primary end point of the study.

“[We saw] dramatic changes in both progression-free survival and OS in the metastatic setting, in the platinum-refractory, neoadjuvant setting, and, most recently, in patients with cisplatin-eligible disease,” Solit commented.

What new ADCs and novel approaches are being developed?

Solit noted that to date, kinase inhibitors have been mostly disappointing for the treatment of patients with bladder cancer. “[In a 2018 basket study], we looked at neratinib [Nerlynx], a HER2 kinase inhibitor, in patients with HER2 kinase mutations. Bladder cancer is the disease where HER2 kinase mutations are most common, so it was a potentially exciting approach in that disease. Unfortunately, we saw no responses in the bladder group of patients on this study,” he added.

Solit explained that the kinase domain mutations frequently observed in bladder cancer are not the same as those seen in lung or breast cancers, where drugs such as neratinib have shown efficacy. Instead, kinase mutations in bladder cancer are mostly extracellular domain mutations which induce dimer formation and they are less sensitive to kinase inhibitors compared with kinases domain mutations, he said.

Additionally, significant heterogeneity of kinase domain mutations is observed in bladder cancer, Solit said. “Approximately 40% of our patients that have a HER2 alteration in either the primary [tumor] or [metastasized disease display] discordance of that HER2 alteration. It’s either only in the primary tumor or it’s only in the metastasis, so sequencing archival tissue to identify patients for treatment with metastatic disease is very challenging in bladder cancer,” he explained.

However, data from the phase 2 DESTINY-PanTumor02 trial (NCT04482309) revealed that patients with bladder cancer (n = 41) who received the HER2-directed ADC fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) achieved an overall response rate (ORR) of 39.0% (95% CI, 24.2%-55.5%).⁷ Patients with a HER2 expression level per immunohistochemistry (IHC) of 3+ experienced an ORR of 56.3% (95% CI, 29.9%-80.2%).

“[We saw] sufficient activity with T-DXd in patients with 3+ HER2 overexpression to allow this to be the first tumor agnostic FDA authorization that’s not based upon next-generation sequencing [NGS],” Solit said. “Because it’s based upon IHC, and most patients are getting NGS in the metastatic setting, this is sometimes forgotten. There are many patients with advanced metastatic bladder cancer who simply have not had IHC assessment of HER2 expression who are maybe missing out on an option that could be effective. In our real-world experience, we see what I would consider to be exceptional responses to T-DXd.”

Another HER2 ADC, disitamab vedotin, has shown promise in combination with toripalimab-tpzi (Loqtorzi) in patients with HER2-expressing advanced urothelial cancer in a phase 3 study (NCT05302284).⁸ Findings from the study revealed that the median PFS among patients who received this combination (n = 126) was 13.1 months (95% CI, 11.1-16.7) compared with 6.5 months (95% CI, 5.7-7.4) in the chemotherapy control arm (n = 149; HR, 0.36; 95% CI, 0.28-0.46; log-rank P < .001).

Solit concluded his presentation by highlighting data from preclinical studies designed to identify new targets for drug development in bladder cancer. He emphasized that patients with urothelial cancer can express high target expression with low ADC sensitivity, underscoring the need for better patient identification to deconvolute clinical practice. He also noted that Nectin-4 could be a potentially attractive treatment target in urothelial cancer, although additional research in this area is needed.

“We’ve launched an RNA sequencing clinical assay at Memorial Sloan Kettering [Cancer Center],” Solit said. “We’ve run approximately 1000 patients so far…and probably will have data in 6 or 12 months. Our hope is to use RNA sequencing to identify these alternative ADC targets that we validate by IHC before a patient goes onto a clinical trial [in order to] drive enrollment to novel ADC targets by specific cellular therapies based upon expression found in individual patients.”

Disclosures: Solit has served as a consultant for Pfizer, Scorpion Therapeutics, BridgeBio, FORE Therapeutics, Function Oncology, Elise Biotechnologies, Meilora Pharma, and Virchow Medical.

References

1. Solit DB. Beyond EV-pembro: ADCs and novel approaches. Presented at: 19th Annual New York GU Cancers Congress; March 13-14, 2026. New York, NY.
2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed March 16, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
3. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed March 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/
4. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
5. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. November 21, 2025. Accessed March 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
6. Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. J Clin Oncol. 2026;44(suppl 7):LBA630. doi:10.1200/JCO.2026.44.7_suppl.LBA630
7. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
8. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin plus toripalimab in HER2-expressing advanced urothelial cancer. N Engl J Med. 2025;393(23):2324-2337. doi:10.1056/NEJMoa2511648