FDA Grants Breakthrough Designation to Frontline Enfortumab Vedotin/Pembrolizumab in Bladder Cancer

Gina Columbus

The FDA has granted a breakthrough therapy designation to the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) as a first-line treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy.1

The designation is based on results from the dose-escalation cohort and dose-expansion cohort from the phase Ib/II EV-103 trial. In the study, updated data showed that the combination led to an objective response rate (ORR) of 73% in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy.2

“The FDA’s breakthrough therapy designation reflects the encouraging preliminary evidence for the combination of Padcev and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options,” Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head of Astellas, which jointly develops the antibody-drug conjugate with Seattle Genetics, stated in a press release. “We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.”

The recommended first-line treatment for patients with advanced urothelial cancer is a cisplatin-based chemotherapy. For those who cannot receive cisplatin, such as patients with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens; outcomes are typically poorer versus cisplatin-based regimens, Astellas Pharma stated in the press release.

Currently, enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.

In the ongoing, multicohort, open-label, multicenter, phase Ib/II EV-103 trial, investigators evaluated the efficacy and safety of enfortumab vedotin alone or in combination with pembrolizumab in patients with muscle-invasive, locally advanced, and first- and second-line metastatic urothelial cancer. In the dose-escalation and dose-expansion phases of cohort A, patients enrolled had locally advanced or metastatic urothelial cancer who were eligible for cisplatin-based chemotherapy.

In cohort A, patients received enfortumab vedotin intravenously (IV) on days 1 and 8 and pembrolizumab on day 1 in a 21-day cycle. At the time of the initial analysis, 45 patients (dose-escalation, n = 5; dose-expansion, n = 40) with locally advanced and/or metastatic urothelial cancer were treated with enfortumab vedotin at 1.25 mg/kg plus pembrolizumab in the frontline setting.

The primary endpoint of the analysis is safety; key secondary endpoints, related to efficacy, include ORR, disease control rate (DCR), DOR, progression-free survival (PFS), and overall survival (OS).

The median age was 69 years, and men accounted for 80% (n = 36) of the study population. The primary tumor location was lower tract in 69% (n = 31), and metastatic sites consisted of lymph nodes only in 4 patients, and also of visceral disease in the remaining 41 patients, including liver metastases (n = 15). PD-L1 expression status by combined composite score was <10 in 19 patients, ≥10 in 13, and was not evaluable or not available in 13 patients.

Initial results of this cohort of EV-103 were presented during the 2019 ESMO Congress.3 Here, the combination of enfortumab vedotin and pembrolizumab led to an ORR of 71%, including a 13% complete response (CR) rate. Moreover, the stable disease rate was 22%, leading to a clinical benefit rate of 93%. Two patients were not evaluable for response status; 1 patient had progressive disease as a best response. All but 3 evaluable patients had some degree of tumor shrinkage.

Updated findings were presented during the 2020 Genitourinary Cancers Symposium. At a median follow-up of 11.5 months (range, 0.7-19.2 months), results showed that the 73% ORR (95% CI, 58.1-85.4) included a 15.6% CR rate and a 57.8% partial response (PR) rate. Responses were observed regardless of PD-L1 expression level.

Moreover, 88% of responses were at observed at the first assessment (week 9 + 1 week), and the median time to response was 2 months (range, 1.4-4.2 months). The median duration of response (DOR) has not yet been reached (range, 1.2-12.9+ months) at a 10.4-median follow-up.

Further findings showed that 55% of the 33 responses were ongoing at the time of the analysis, with 83.9% of responses lasting ≥6 months and 53.7% of responses lasting ≥12 months, according to Kaplan-Meier estimates. The median PFS was 12.3 months, and the median OS has not been reached. The 1-year PFS and OS rates were 50.1% and 81.6%, respectively. The DOR, PFS, and OS data remain immature.

Regarding safety, 7 patients had treatment-related adverse events (TRAEs); 6 had resolved, and 1 treatment-related death was reported and due to multiple organ dysfunction syndrome. There were 6 treatment discontinuations (13%) with the combination due to TRAEs, the most common reason being peripheral sensory neuropathy (n = 3). The immune-mediated adverse events were found to be similar to single-agent pembrolizumab.

Additional urothelial cancer cohorts of EV-103 will evaluate enfortumab vedotin: alone or in combination with pembrolizumab or a platinum-based chemotherapy in the first-line setting for patients with metastatic disease; plus pembrolizumab and carboplatin or cisplatin in first-line metastatic disease; alone or in combination with pembrolizumab in muscle-invasive disease; in combination with pembrolizumab in second-line metastatic disease; and plus gemcitabine in first- or second-line metastatic disease.

Moreover, the phase III EV-302 trial (NCT04223856) is evaluating enfortumab vedotin in combination with pembrolizumab with and without chemotherapy versus chemotherapy alone in patients with previously untreated locally advanced or metastatic urothelial cancer.


  1. Astellas and Seattle Genetics Receive FDA Breakthrough Therapy Designation for PADCEV™ (enfortumab vedotin-ejfv) in Combination with Pembrolizumab in First-Line Advanced Bladder Cancer [news release]: Tokyo, Japan and Bothell, WA. Astellas Pharma Inc. and Seattle Genetics, Inc. Published February 19, 2020. https://prn.to/2SXzEQJ. Accessed February 19, 2020.           
  2. 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. J Clin Oncol. 2020;38(suppl; abstr 441).
  3. Hoimes C, Rosenberg J, Srinivas S, et al. EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Ann Oncol. 2019;30(suppl_5):v356-v402. doi: 10.1093/annonc/mdz249.
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