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Clinical Trial
. 2021 Mar 25;384(12):1125-1135.
doi: 10.1056/NEJMoa2035807. Epub 2021 Feb 12.

Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma

Thomas Powles  1 , Jonathan E Rosenberg  1 , Guru P Sonpavde  1 , Yohann Loriot  1 , Ignacio Durán  1 , Jae-Lyun Lee  1 , Nobuaki Matsubara  1 , Christof Vulsteke  1 , Daniel Castellano  1 , Chunzhang Wu  1 , Mary Campbell  1 , Maria Matsangou  1 , Daniel P Petrylak  1
Affiliations
Clinical Trial

Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma

Thomas Powles et al. N Engl J Med. .

Abstract

Background: Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment.

Methods: We conducted a global, open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight on days 1, 8, and 15 of a 28-day cycle) or investigator-chosen chemotherapy (standard docetaxel, paclitaxel, or vinflunine), administered on day 1 of a 21-day cycle. The primary end point was overall survival.

Results: A total of 608 patients underwent randomization; 301 were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. Overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The incidence of treatment-related adverse events was similar in the two groups (93.9% in the enfortumab vedotin group and 91.8% in the chemotherapy group); the incidence of events of grade 3 or higher was also similar in the two groups (51.4% and 49.8%, respectively).

Conclusions: Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. (Funded by Astellas Pharma US and Seagen; EV-301 ClinicalTrials.gov number, NCT03474107.).

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Figures

Figure 1.
Figure 1.
CONSORT Flow Diagram.
Figure 2.
Figure 2.. Overall Survival in the Intention-to-Treat Population and Analysis in Key Subgroups.
The primary endpoint of overall survival was defined as the time from randomization to the date of death, analyzed in the intention-to-treat population that included all patients randomized to treatment. The Kaplan-Meier estimate of overall survival according to treatment group is shown in Panel A. A forest plot displays the subgroup analyses, shown in Panel B, of prespecified key subgroups also examined in the intention-to-treat population. In all subjects, the hazard ratio is reported for all patients based on stratified analysis with the following factors: ECOG performance-status score, geographic region, and presence of liver metastasis recorded at randomization. In each subgroup, the hazard ratio was estimated using unstratified Cox proportional hazards model with treatment. Assuming proportional hazards, a hazard ratio of <1 indicates reduction in the hazard ratio favoring enfortumab vedotin treatment. CI denotes confidence interval, and HR hazard ratio. CI denotes confidence interval, CPI checkpoint inhibitor, ECOG PS Eastern Cooperative Oncology Group Performance-Status Score, HR hazard ratio, US United States, and W western.
Figure 2.
Figure 2.. Overall Survival in the Intention-to-Treat Population and Analysis in Key Subgroups.
The primary endpoint of overall survival was defined as the time from randomization to the date of death, analyzed in the intention-to-treat population that included all patients randomized to treatment. The Kaplan-Meier estimate of overall survival according to treatment group is shown in Panel A. A forest plot displays the subgroup analyses, shown in Panel B, of prespecified key subgroups also examined in the intention-to-treat population. In all subjects, the hazard ratio is reported for all patients based on stratified analysis with the following factors: ECOG performance-status score, geographic region, and presence of liver metastasis recorded at randomization. In each subgroup, the hazard ratio was estimated using unstratified Cox proportional hazards model with treatment. Assuming proportional hazards, a hazard ratio of <1 indicates reduction in the hazard ratio favoring enfortumab vedotin treatment. CI denotes confidence interval, and HR hazard ratio. CI denotes confidence interval, CPI checkpoint inhibitor, ECOG PS Eastern Cooperative Oncology Group Performance-Status Score, HR hazard ratio, US United States, and W western.
Figure 3.
Figure 3.. Progression-Free Survival in the Intention-to-Treat Population.
The Kaplan-Meier estimate of progression-free survival according to treatment group is shown. The secondary endpoint of investigator-assessed progression-free survival was defined as the time from randomization until the date of radiological disease progression (per RECIST v1.1) or until death due to any cause, analyzed in the intention-to-treat population that included all patients randomized to treatment. If the patient neither progressed nor died, the patient was censored at the date of last radiological assessment. Patients who received any further anticancer therapy for urothelial carcinoma before radiological progression were censored at the date of the last radiological assessment before the anticancer therapy started. CI denotes confidence interval, and HR hazard ratio.
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