In patients with metastatic urothelial cancer who received previous therapy, as well as in cisplatin-ineligible patients with this cancer, enfortumab vedotin-ejfv (Padcev) improved overall survival (OS), according to new data presented at the virtual 2021 ASCO Genitourinary Cancers Symposium. The data come from the phase 3 EV-301 study and cohort 2 of the phase 2 EV-201 study. Experts believe this antibody–drug conjugate will become a new standard of care in the treatment of patients with advanced urothelial cancer.
“Enfortumab vedotin is the first drug beyond chemotherapy and immune therapy to show a significant survival advantage in previously treated advanced urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited,” said EV-301 lead investigator Thomas Powles, MD, PhD, FRCP, Director, Barts Cancer Centre, Queen Mary University of London, England.
In December 2019, the FDA accelerated the approval of enfortumab vedotin for the treatment of patients with advanced or metastatic urothelial cancer who have received platinum-based chemotherapy and PD-1/PD-L1 therapy. This approval required additional confirmatory studies.
The open-label phase 3 EV-301 study randomized 301 patients to receive enfortumab vedotin and 307 patients to investigator’s choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). All patients had radiographic evidence of disease progression or relapse during or after PD-1/PD-L1 therapy and had received a previous platinum-containing regimen.
“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, [and] therapeutic options are also limited. In this setting, new therapeutic agents supported by randomized trials are needed,” Dr Powles said.
Demographic and disease characteristics were well-balanced between the 2 treatment arms. Geographic regions of enrolled patients included Western Europe (42%), the United States (14%), and other areas (44%).
The median OS was 12.88 months with enfortumab vedotin compared with 8.97 months with chemotherapy, a 30% improvement for enfortumab vedotin (P = .00142). At the time of data cutoff, 134 deaths occurred among the 301 patients in the enfortumab vedotin arm versus in 167 of the 307 patients in the chemotherapy arm.
The OS benefit of enfortumab vedotin was consistent across subgroups.
Progression-free survival (PFS) was also improved with enfortumab vedotin: a median of 5.55 months versus 3.71 months with chemotherapy (P <.00001), a 38% improvement with enfortumab vedotin. The confirmed response rate was 40.6% for enfortumab vedotin versus 17.9% with chemotherapy (P <.001). The disease control rates in the 2 groups were 71.9% and 53.4%, respectively (P <.001).
The rate of grade 3 or 4 treatment-related adverse events was similar in both arms: 51% in the enfortumab vedotin arm and 50% in the chemotherapy arm. Events leading to treatment withdrawal occurred in 14% of the patients in the enfortumab vedotin group and in 11% of those in the chemotherapy group.
EV-201: Platinum-Ineligible Patients
Approximately 50% of patients with advanced urothelial cancer are platinum-ineligible, most often because of poor performance status, renal impairment, and other comorbidities.
“We know that the majority [of cisplatin-ineligible patients] still will not respond to immunotherapy, and after progression on immunotherapy, these patients have limited treatment options,” said lead investigator Arjun V. Balar, MD, Director, Genitourinary Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health, New York, NY, who presented results of the EV-201 study.
Cohort 2 of this study included 89 platinum-naïve and cisplatin-ineligible patients who had previously received a PD-1/PD-L1 inhibitor. The median patient age was 75 years; 74% were male; and 79% had visceral metastases, including 24% with liver metastases. A total of 22 (25%) patients had previously responded to checkpoint inhibitor therapy and their disease progressed. In addition, 50% were obese, 66% had some decrease in kidney function, and upper-tract lesions were overrepresented.
The confirmed overall response rate in cohort 2 was 52%, with complete responses in 20% of patients; 30% of the patients had stable disease as the best response; 9% of patients had progressive disease, and 9% were not evaluable.
Of 77 assessable patients, 88% had some tumor shrinkage from baseline, as seen on a waterfall plot. Responses were observed across all patient subgroups, including patients with upper-tract primary tumor (61% response rate), liver metastases (48%), and patients whose disease previously was unresponsive to PD-1/PD-L1 inhibition (48%).
The median time to response to enfortumab vedotin was 1.8 months, and the median duration of response was 10.9 months. The median PFS in the cohort was 5.8 months, and the median OS was 14.7 months.
“These results are promising, but they must be interpreted with caution in a single-arm study,” Dr Balar said.
Overall, 55% of patients had a grade 3 or 4 treatment-related adverse event. Four treatment-related deaths were reported, all in people aged ≥75 years and with comorbidities.
Treatment-related adverse events of special interest, such as skin reactions, peripheral neuropathy, and hyperglycemia, were manageable in the EV-201 and EV-301 studies.
“The response rates to enfortumab vedotin in the EV-201 study are the highest numerically observed for any regimen in cisplatin-ineligible patients with advanced disease,” Dr Balar said. “These data support a potential new option for this patient population with an unmet need.”