ESMO Virtual Congress 2020: EV-302: Enfortumab Vedotin plus Pembrolizumab and/or Chemotherapy, vs Chemotherapy Alone, in Untreated Locally Advanced or Metastatic Urothelial Cancer

( Platinum-based chemotherapy is the mainstay of first-line treatment for medically eligible patients with advanced urothelial carcinoma (UC). Unfortunately, up to 50% of patients are unable to receive cisplatin, and disease progression often develops even for patients who receive cisplatin. Immunotherapy with checkpoint blockade is a standard of care option for platinum-ineligible patients or those who have progressed on platinum therapy. Antibody-drug conjugates that are targeted to a highly expressed tumor protein and conjugated to a chemotherapy payload, such as enfortumab vedotin, are emerging as effective therapies for subsequent lines of treatment. 

Enfortumab vedotin (EV) consists of an antibody against Nectin-4, a transmembrane adhesion molecule that is highly expressed in urothelial carcinomas, conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. As monotherapy in patients who had received prior platinum therapy and immunotherapy, cohort 1 of the EV-201 trial demonstrated a 55% confirmed objective response rate. Based on this response and safety data, the United States Federal Drug Administration (FDA) granted accelerated approval for EV in this context. 

Other antibody-drug conjugates have been shown in preclinical studies to induce immunogenic cell death that may enhance antitumor immunity. The EV-103 study of EV in combination with pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced UC has demonstrated a 73.3% objective response rate, with activity seen regardless of PD-L1 expression. To further study the combination of EV with pembrolizumab, the authors present the design of the EV-302 (NCT04223856) global randomized phase 3 study as first-line therapy advanced UC. While initially created with two intervention arms (EV + pembro OR EV + pembro + platinum) as compared to platinum + gemcitabine chemotherapy, the triple therapy arm was discontinued based on encouraging EV-103 data and limited clinical benefit from triplet platinum + gemcitabine + checkpoint blockade from the KEYNOTE-361 and IMvigor130 trials. EV-302 is therefore a randomized study of platinum-eligible patients with advanced UC comparing Arm A (EV + pembrolizumab with Arm B (cisplatin or carboplatin + gemcitabine). The study schema is shown below.


The primary objectives of the study are progression-free and overall survival. Secondary endpoints are objective response rate, duration of response, disease control rate., quality of life, and safety.  Key inclusion criteria are advanced UC (unresectable, metastatic), measurable disease, no prior systemic therapy except neoadjuvant or adjuvant treatment with cystectomy, and medically eligible for treatment with study drugs in either arm. Key exclusion criteria include other active malignancy or prior malignancy within past three years, prior treatment with any immunotherapy, Grade 2+ sensory or motor neuropathy, active CNS metastases, and uncontrolled diabetes. The study plans to randomize 760 patients.

Presented by: Michiel S. van der Heijden, MD, PhD, Medical Oncologist at The Netherlands Cancer Institute, Amsterdam, the Netherlands

 Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.