Enfortumab vedotin improves survival in previously treated advanced urothelial carcinoma

Enfortumab vedotin improved overall survival (OS) compared with chemotherapy in patients with previously treated, locally advanced or metastatic urothelial carcinoma (UC), according to interim results of the phase III EV-301 study.

“Enfortumab vedotin had superior OS compared with chemotherapy in patients with advanced UC who had previously received platinum-based chemotherapy and a PD-1 or PD-L1* inhibitor,” said study author Professor Thomas Powles from the Barts Cancer Centre, London, UK, at ASCO GU 2021.

Participants in this open-label trial were 608 patients (median age 68 years, 77.3 percent male) with locally advanced or metastatic UC and ECOG performance status 0–1 who had previously received platinum-based chemotherapy and had experienced radiographic progression or relapse during or following PD-1/PD-L1 treatment. They were randomized 1:1 to receive enfortumab vedotin (1.25 mg/kg on days 1, 8, and 15 on 28-day cycles; n=301) or investigator-selected chemotherapy** (n=307).

Thirty-one percent of patients in both groups had liver metastasis, and 87 and 88 percent of those assigned to enfortumab vedotin and chemotherapy, respectively, had received 1–2 prior lines of systemic therapy.

At data cut-off after 301 deaths, patients assigned enfortumab vedotin and chemotherapy had received treatment for a median 5.0 and 3.5 months, respectively, and had been followed up for a median 11.1 months. Eighty-one and 93 percent, respectively, discontinued treatment, primarily due to disease progression (59 percent in each group) and treatment-emergent adverse events (AEs; 14 and 15 percent, respectively).  

OS was significantly longer in the enfortumab vedotin than chemotherapy group (median 12.88 vs 8.97 months; hazard ratio [HR], 0.70, 95 percent confidence interval [CI], 0.56–0.89; p=0.00142). [ASCO GU 2021, abstract 393; N Engl J Med 2021;doi:10.1056/NEJMoa2035807]

Subgroup analysis of the OS findings generally favoured enfortumab vedotin, though some groups were too small to draw definitive conclusions, remarked Powles.

Progression-free survival was also significantly improved with enfortumab vedotin vs chemotherapy (median 5.55 vs 3.71 months; HR, 0.62, 95 percent CI, 0.51–0.75; p<0.00001).

Overall response rate was significantly greater with enfortumab vedotin vs chemotherapy (40.6 percent vs 17.9 percent; p<0.001), with 4.9 and 2.7 percent, respectively, having a complete response (CR), and 35.8 and 15.2 percent, respectively, having a partial response (PR). Disease control rate which comprised CR, PR, and stable disease for ≥7 weeks was also greater with enfortumab vedotin than chemotherapy (71.9 percent vs 53.4 percent; p<0.001).

Grade ≥3 treatment-related (TR) AEs occurred at a comparable rate between enfortumab vedotin and chemotherapy recipients (51 percent vs 50 percent), as did serious AEs (23 percent in each group). The most common grade ≥3 AEs in the enfortumab vedotin group were maculopapular rash (7 percent), decreased neutrophil count, fatigue (6 percent each), and neutropenia (5 percent), while the most common in the chemotherapy group were decreased neutrophil count (13 percent), anaemia (8 percent), decreased white blood cell count (7 percent), and neutropenia (6 percent). AEs led to treatment withdrawal in 14 and 11 percent of enfortumab vedotin and chemotherapy recipients, respectively, while TRAEs led to death (excluding disease progression) in 2.4 and 1.0 percent, respectively.

Grade ≥3 TRAEs of special interest in the enfortumab vedotin group included skin reactions, peripheral neuropathy, and hyperglycaemia, at rates of 15, 5, and 4 percent, respectively. Most TRAEs of special interest were mild to moderate in severity.

“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging,” noted Powles. “OS is limited and disease progression occurs in most patients,” he said.  

“Enfortumab vedotin is the first drug beyond chemotherapy and immune therapy to show a significant survival advantage in previously treated advanced UC. This is a big step in the right direction for patients with advanced UC where treatment options remain quite limited,” he concluded.