Enfortumab Vedotin plus Pembrolizumab Combination Leads to Impressive Responses in Patients with Urothelial Cancer

Combining the antibody drug conjugate, enfortumab vedotin (Padcev) with the immune checkpoint inhibitor pembrolizumab (Keytruda) showed encouraging results in patients with locally advanced or metastatic urothelial cancer who were unable to receive cisplatin-based chemotherapy in the first-line setting.

In an interim analysis of the phase 1b/2 EV-103 clinical trial, the objective response rate (ORR) was 73% in 45 patients who received the combination and tumor shrinkage was observed in 93% of patients.

“Cisplatin-based chemotherapy is the standard treatment for first-line advanced urothelial cancer; however, it isn’t an option for many patients,” said Jonathan E. Rosenberg, MD, Chief, Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, who presented the data at the 2020 Genitourinary Cancers Symposium. “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 enfortumab vedotin and pembrolizumab in the first-line setting.”

Study Results

EV-103 is an ongoing, multicohort, multicenter phase 1b clinical trial. At the 2019 European Society of Medical Oncology annual meeting, the first results of cohort A (N = 45, cisplatin-ineligible patients with metastatic bladder cancer) showed an ORR of 71% (complete response rate, 13%; partial response rate, 58%) and a disease control rate of 93.3%. The updated results of EV-103 presented at the 2020 Genitourinary Cancers Symposium included the first data on durability of response, progression-free survival, and overall survival (OS) in the dose-expansion phase of cohort A.

In this phase, 45 patients in cohort A received enfortumab vedotin intravenously on days 1 and 8 and pembrolizumab on day 1 of a 21-day cycle.

The median age of patients enrolled in the trial was 69 years, and 36 (80%) of the patients were male. The primary tumor site was the lower urinary tract (N = 31; 69%); only 4 patients had metastases in the lymph nodes, and the remaining 41 patients had visceral metastases.

The responses held up at a median follow-up of 10.4 months (range, 1.2-12.9 months). The ORR in the 45 patients in cohort A was 73.3%, including 7 complete responses and 26 partial responses. The median duration of response had not yet been reached.

Overall, 55% of the responses were ongoing at the time of the analysis, 83.9% of responses were ongoing at ≥6 months, and 53.7% lasted ≥12 months. The median progression-free survival was 12.3 months, and the median OS had not been reached. The 1-year OS rate was 81.6%.

“Based on these results, further investigation of enfortumab vedotin plus pembrolizumab as a platinum-free option is warranted in patients with untreated locally advanced and metastatic urothelial cancer,” Dr Rosenberg said.

Of the 45 evaluable patients, 26 (58%) had grade ≥3 treatment-related adverse events. The most common grade ≥3 events were increased lipase (18%), fatigue (9%), maculopapular rash (9%), diarrhea (7%), and anemia (7%).

Dr Rosenberg commented that the cost of treatment with the combination of enfortumab vedotin and pembrolizumab will be “shockingly expensive…even if these are shockingly good results.” Given the high price tag, he noted that studies are needed to show that the regimen is superior to other options for the treatment of metastatic urothelial cancer.

A phase 3 trial will evaluate first-line therapy with enfortumab vedotin plus pembrolizumab with or without chemotherapy versus gemcitabine (Gemzar) plus platinum chemotherapy in patients with metastatic urothelial cancer.

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