Treatment with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) continues to show promise in patients with locally advanced or metastatic urothelial carcinoma, according to an exploratory analysis from the phase 3 EV-302 study. The study found that the combination yields benefits in progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) regardless of the level of Nectin-4 expression. These findings were presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain, by Thomas B. Powles, MBBS, MRCP, MD, director of the Barts Cancer Centre at St. Bartholomew’s Hospital in London, United Kingdom.
EV-302 Trial Details
The EV-302 trial is a global, open-label, randomized study involving 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. Participants were randomized 1:1 to receive either enfortumab vedotin plus pembrolizumab or chemotherapy (cisplatin or carboplatin plus gemcitabine). The trial's dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints included overall response rate (ORR) per RECIST 1.1 by BICR and investigator assessment, as well as safety.
Survival and Response Rates
Previous data from the EV-302 trial, published in The New England Journal of Medicine, demonstrated that the combination of enfortumab vedotin and pembrolizumab significantly extended both OS and PFS. At a median follow-up of 17.2 months, treatment with the combination reduced the rate of death by 53% compared to chemotherapy. Patients in the combination arm had a median OS of 31.5 months compared to 16.1 months in the chemotherapy arm (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001).
The median PFS with enfortumab vedotin plus pembrolizumab was 12.5 months versus 6.3 months with chemotherapy, representing a 55% reduction in the rate of disease progression or death (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).
Impact of Nectin-4 Expression
The recent exploratory analysis involved a retrospective assessment of Nectin-4 expression using a CAP/CLIA-validated Nectin-4 IHC assay in primary or metastatic tumor tissue. Nectin-4 expression data were available for 800 of the 886 randomized patients (394 in the enfortumab vedotin plus pembrolizumab arm and 406 in the chemotherapy arm). Investigators assessed clinical efficacy (PFS, OS, and ORR) in Nectin-4 expression subgroups.
The median H-score for Nectin-4 expression was 280 (out of a possible 300; IQR, 230-298) in the enfortumab vedotin plus pembrolizumab arm versus 270 (IQR, 215-297) in the chemotherapy arm. Powles noted that regardless of the Nectin-4 expression level, the hazard ratios for progression-free survival remained consistent, in the 0.4 to 0.5 range. Similar findings were observed for overall survival.
Consistent Benefits Across Subgroups
Powles reported that the overall response rate (ORR) showed a consistent benefit with enfortumab vedotin plus pembrolizumab across all Nectin-4 subgroups. Consistent PFS and OS benefits were also seen with the combination therapy across all Nectin-4 subgroups.
In his concluding remarks, Powles stated, "What we’ve shown is [enfortumab vedotin/pembrolizumab] outperforming chemotherapy in all subgroups, no matter how you slice and dice it: for progression-free survival, for overall survival, and response rate... irrespective of PD-L1 or Nectin-4, it looks like [enfortumab vedotin/pembrolizumab] outperforms chemotherapy. I think it further establishes [enfortumab vedotin/pembrolizumab] as standard of care."
