Frontline Enfortumab Vedotin Plus Pembrolizumab Shows Encouraging Data in Advanced Urothelial Cancer

Gina Columbus

Jonathan E. Rosenberg, MD

Jonathan E. Rosenberg, MD

Enfortumab vedotin-ejfv (Padcev) combined with pembrolizumab (Keytruda) 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, according to updated results of the phase Ib/II EV-103 trial (NCT03288545) that will be presented during the 2020 Genitourinary Cancers Symposium.1,2

Additionally, 45 patients were treated with the combination and were also evaluable for safety and efficacy. 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% complete response (CR) rate and a 57.8% partial response (PR) rate. The median duration of response (DOR) has not yet been reached (range, 1.2-12.9+ months).

"Cisplatin-based chemotherapy is the standard treatment for first-line advanced urothelial cancer; however, it isn't an option for many patients," Jonathan E. Rosenberg, MD, medical oncologist and chief, Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center, stated in a press release. "I'm encouraged by these interim results, including a median progression-free survival of a year for patients who received the platinum-free combination of Padcev and pembrolizumab in the first-line setting."

In the ongoing, multi-cohort, 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 ineligible 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 is 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.

The DOR, PFS, and OS are immature. 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. However, the 1-year OS rate was 81.6% (95% CI, 62%-91.8%).

"These updated data are encouraging and provide support for the recently initiated phase III trial EV-302 that includes an arm evaluating Padcev in this platinum-free combination in the first-line setting," Roger Dansey, MD, chief medical officer at Seattle Genetics, the developer of enfortumab vedotin, stated in a press release.

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% 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.

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.

In December 2019, the FDA granted an accelerated approval to enfortumab vedotin 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.


  1. Seattle Genetics and Astellas announce updated results from phase 1b/2 trial of Padcev (enfortumab vedotin-ejfv) in combination with immune therapy pembrolizumab as investigational first-line treatment for advanced bladder cancer [news release]: Bothell, WA. Seattle Genetics, Inc., and Astellas Pharma, Inc. Published February 10, 2020. Accessed February 11, 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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