Enfortumab Vedotin Maintains Long-Term OS Benefit in Advanced Urothelial Carcinoma

Jonathan E. Rosenberg, MD

Enfortumab vedotin-ejfv (Padcev) extended overall survival (OS) by 3.97 months compared with chemotherapy for patients with locally advanced or metastatic urothelial carcinoma (UC), according to long-term follow-up data from the phase 3 EV-301 trial (NCT03474107) presented at the 2022 ASCO Annual Meeting.¹

At a median follow-up of 23.75 months, the median OS was 12.91 months (95% CI, 11.01-14.92) in the experimental arm vs 8.94 months (95% CI, 8.25-10.25) with the control (HR, 0.704; 95% CI, 0.581-0.852; P = .00015). As of July 30, 2021, investigators observed 207 deaths in the experimental arm vs 237 in the control arm.

Enfortumab vedotin, an antibody-drug conjugate (ADC) directed against nectin-4, extended OS for all subgroups except women (HR, 1.201; 95% CI, 0.806-1.789).

In previously reported interim data, the median OS in the investigative arm was 12.88 months (95% CI, 10.58-15.21) vs 8.97 months (95% CI, 8.05-10.74) in the control arm, which translated to a 30% reduction in the risk of death with the ADC (HR, 0.70; 95% CI, 0.56-0.89; P = .001).²

Investigators recruited 608 patients with locally advanced or metastatic UC that had progressed after platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy into the trial. Patients were randomly assigned to 1.25 mg/kg of enfortumab vedotin on days 1, 8, and 15 of each 28-day cycle (n = 301), or investigator’s choice of 75 mg/m² of docetaxel, 175 mg/m² of paclitaxel, or 320 mg/m² of vinflunine on the first day of each 21-day cycle (n = 307).

Key stratification factors included performance status (0 vs 1), geographic region (Western Europe, United States, or rest of the world), and baseline liver metastases (present vs absent).

OS served as the primary end point, and secondary end points included investigator-assessed progression-free survival (PFS), clinical response per RECIST v1.1 criteria, and safety.

Consistent with previous findings, enfortumab vedotin induced superior median PFS (5.55 vs 3.71 months; 95% CI, 0.525-0.762; P <.00001). Investigators observed 231 PFS events in the experimental arm vs 248 in the control arm.

The confirmed overall response rate was 41.3% (95% CI, 35.57%-47.25%) vs 18.6% (95% CI, 14.32%-23.49%) in favor of the ADC. The complete response rate was 6.9% with enfortumab vedotin compared with 3.4% with chemotherapy.

Investigators said rates of treatment-related adverse effects (TRAEs) were comparable between the treatment groups, as was the case at the interim analysis. In the experimental arm, 52.4% of patients experienced grade 3 or higher TRAEs compared with 50.5% with chemotherapy. Investigators observed no new grade 5 TRAEs observed since the interim analysis.

Grade 3 or higher TRAEs that were more common in the experimental arm included maculopapular rash (7.4% vs not reported), fatigue (6.8% vs 4.5%), and peripheral sensory neuropathy (5.1% vs 2.1%). Decreased neutrophil count, decreased white blood cell count, and anemia were among the TRAEs more common with chemotherapy.

In July 2021, the FDA granted a regular approval to the ADC and expanded the agent’s indication to include adult patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy and who have previously received 1 or more lines of therapy.³

The agency granted an accelerated approval to enfortumab vedotin in December 2019 for use in adult patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.⁴ The regulatory decision was supported by findings from the phase 2 EV-201 trial (NCT03219333), which showed that the ADC induced an ORR of 44% in this population.⁵

Additionally, in April 2022, the European Commission approved enfortumab vedotin for use as a single agent in adult patients with locally advanced or metastatic urothelial cancer who have received prior platinum-containing therapy and a PD-1/PD-L1 inhibitor based on previous findings from EV-301.⁶

References

1. Rosenberg JE, Powles T, Sonpavde GP, et al. Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. J Clin Oncol. 2022;40,(suppl 16; abstr 4516). doi: 10.1200/JCO.2022.40.16_suppl.4516
2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807
3. US FDA grants approval and expands indication for PADCEV (enfortumab vedotin-ejfv) for patients with locally advanced or metastatic urothelial cancer. News release. Seagen Inc. and Astellas Pharma Inc. July 9, 2021. Accessed July 1, 2022. https://bit.ly/3r7jzJ2
4. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. News release. FDA. December 18, 2019. Accessed July 1, 2022. https://bit.ly/3nzUipT
5. Petrylak DP, Balar AV, O'Donnell PH, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37(suppl 18):LBA4505. doi:10.1200/JCO.2019.37.18_suppl.LBA4505
6. European Commission approves PADCEV (enfortumab vedotin) for locally advanced or metastatic urothelial cancer. News release. Astellas Pharma, Inc.; April 13, 2022. Accessed July 1, 2022. https://bit.ly/3xrVmlU