ASCO 2020: Study EV-103: New Randomized Cohort Testing Enfortumab Vedotin as Monotherapy or in Combination with Pembrolizumab in Locally Advanced or Metastatic Urothelial Cancer (Trial in Progress)

( Treatment with platinum-based chemotherapy and program death ligand 1 (PD-L1) immune checkpoint inhibitor has been shown to have a modest objective response rate (ORR) and limited durability, emphasizing the critical unmet need in the first-line setting for patients with locally advanced or metastatic urothelial carcinoma.1

To date, cisplatin-based chemotherapy is the standard of care in this disease space and is regarded as the first-line treatment for patients with locally advanced or metastatic urothelial carcinoma. However, approximately half of the patients are excluded from this type of treatment due to several reasons, including renal dysfunction, neuropathy, or poor performance status. 

The recently developed Enfortumab vedotin-ejvf (EV) received FDA accelerated approval based on tumor response rates for adults with locally advanced or metastatic urothelial carcinoma, who have previously received a PD-1/PD-L1 inhibitor and platinum-containing therapy. In this ongoing phase 1b/2 study EV-103/KEYNOTE-869 (NCT03288545), the safety and anti-tumor activity of EV are being studied as a monotherapy (for the first time in the first-line setting of this disease space) and combined with the PD-1 inhibitor, pembrolizumab and/or chemotherapy. The combination of pembrolizumab and EV regiment has shown encouraging and durable activity with an ORR of 73.3%, median progression-free survival of 12.3 months, and 93% had a reduction in target lesions. Moreover, it has shown a tolerable and stable safety profile in cisplatin-ineligible patients, in the setting of locally advanced or metastatic urothelial carcinoma, as a first-line treatment (as shown in abstract 5044 presented in the ASCO 2020 virtual meeting). 

Due to these results, on February 18th 2020, the FDA granted breakthrough therapy designation for the combination of EV and pembrolizumab for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma as a first-line treatment setting.

The rationale for the combination of pembrolizumab and EV was described next. EV is an antibody-drug conjugate, which delivers the microtubule disrupting agent monomethyl auristatin E (MMAE) to cells expressing Nectin-4, which is highly expressed in urothelial carcinoma2,3 (Figure 1). EV and Pembrolizumab each have a single agent activity that has been shown in locally advanced or metastatic urothelial carcinoma in advanced lines of therapy. Preclinical studies show that antibody-drug conjugates linked to MMAE induce immunogenic cell death and may enhance anti-tumor immunity. More clinical data suggest that the combination of EV and pembrolizumab may have the potential to induce greater anti-tumor activity in locally advanced or metastatic urothelial carcinoma patients compared with either agent that is used alone4.

Figure 1 – EV mechanism of action: Figure1_EV_mechanism__action.png

Currently, EV-103 cohort K is enrolling cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. Patients will receive either EV monotherapy or EV plus pembrolizumab combination in the first-line setting, to further evaluate this potential platinum-free treatment option in the first-line treatment setting in this disease space. The study design is shown in Figure 2.

Figure 2 – EV-103 study design:

The primary objective of this study is to assess the anti-tumor activity of the treatment combination of EV with pembrolizumab and EV as monotherapy as measured by objective response rate per the RECIST criteria 1.1, by blinded independent central review. Secondary objectives include objective response rate by investigator assessment, duration of response, disease control rate, progression-free survival, overall survival, and safety and tolerability. The study is currently active in 27 sites around the US (Figure 3), and we eagerly await its results.

Figure 3 – Study sites:

Presented by: Nataliya Mar, MD, UC Irvine Medical Center, Orange, CA, USA

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.


  1. Grande E, Galsky M, Arranz Arija JA, et al. IMvigor130: Efficacy and safety from a phase III study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC). Annals of Oncology 2019; 30: v888-v9.
  2. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. Journal of Clinical Oncology 2019; 37(29): 2592-600.
  3. Petrylak DP, Perez RP, Zhang J, et al. A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer. Journal of Clinical Oncology 2017; 35(15_suppl): 106-.
  4. Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Journal of Clinical Oncology 2020; 38(6_suppl): 441-.
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