SUMMARY: The American Cancer Society estimates that in 2021, approximately 83,730 new cases of Bladder Cancer will be diagnosed and 17,200 patients will die of the disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.
PADCEV® (Enfortumab vedotin-ejfv) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, PADCEV® becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. The FDA in 2019 granted accelerated approval to PADCEV® for adult patients with locally advanced or metastatic urothelial cancer, who have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand1 (PD-L1) inhibitor, and a Platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. This approval was based on the results from the pivotal Phase II EV-201 study which concluded that treatment with PADCEV® demonstrated a clinically meaningful 44% Objective Response Rate (ORR) in this patient group. EV-301 study was designed to confirm the clinical benefit of PADCEV® as compared with standard chemotherapy, by assessing Overall Survival in patients with advanced urothelial carcinoma, who had previously received treatment.
EV-301 is a global, open-label, randomized, Phase III trial, that evaluated the efficacy of PADCEV®, as compared with chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received treatment with a platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. A total of 608 patients were randomly assigned 1:1 to receive either PADCEV® 1.25 mg/kg IV on days 1, 8, and 15 of a 28-day cycle (N=301), or investigator choice of chemotherapy (Docetaxel 75 mg/m2 IV, Paclitaxel 175 mg/m2 IV, or Vinflunine 320 mg/m2 IV, administered on day 1 of a 21-day cycle (N=307). Both treatment groups were well balanced. The median patient age was 68 years, about 79% of patients had visceral metastases, and 69% of patients had no response to previous treatment with checkpoint inhibitor. The Primary end point was Overall Survival (OS). Secondary end points included Progression Free Survival (PFS) and Overall Response Rate (ORR) and Safety. At the prespecified interim analysis, the median follow up was 11.1 months.
The median OS was 12.88 months in the PADCEV® group versus 8.97 months in patients treated with chemotherapy (H= 0.70; P=0.001), suggesting a 30% reduction in the risk of death with PADCEV®. The PFS was also longer in the PADCEV® group, and was 5.6 months versus 3.7 months with chemotherapy (HR=0.62; P<0.001). The confirmed ORR was higher in the PADCEV® group than in the chemotherapy group (40.6% versus 17.9%; P<0.001), and a Complete Response was observed in 4.9% of the patients in the PADCEV® group and in 2.7% of the patients in the chemotherapy group. Disease Control Rate was 71.9% and 53.4%, respectively (P<0.001). Treatment-related Adverse Events were similar in the two treatment groups.
The authors concluded that treatment with PADCEV® resulted in significantly longer Overall Survival, Progression Free Survival and a higher Overall Response Rate, than 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.
Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. Powles T, Rosenberg JE, Sonpavde GP, et al. N Engl J Med 2021; DOI: 10.1056/NEJMoa2035807