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EV/pembrolizumab yields PFS, OS, ORR benefits regardless of Nectin-4 level

“What we’ve shown is [EV/pembrolizumab] outperforming chemotherapy in all subgroups," says Thomas B. Powles, MBBS, MRCP, MD.

Treatment of locally advanced or metastatic urothelial carcinoma with enfortumab vedotin-ejfv (Padcev, EV) plus pembrolizumab (Keytruda) yields benefits in progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) regardless of the level of Nectin-4 expression, according to an exploratory analysis from the phase 3 EV-302 study (NCT04223856).

Thomas B. Powles, MBBS, MRCP, MD

Thomas B. Powles, MBBS, MRCP, MD

The 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.1

EV-302 is a global, open-label, randomized study. The intent-to-treat population consists of 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned 1:1 to either EV plus pembrolizumab or chemotherapy (cisplatin or carboplatin plus gemcitabine). The dual primary end points were progression-free survival by blinded independent central review (BICR) and overall survival. Select secondary end points included overall response rate per RECIST 1.1 by BICR and investigator assessment as well as safety.

Data from the EV-302 trial have been published in The New England Journal of Medicine,2 showing that the combination of EV and pembrolizumab extended OS and PFS.

At a median follow-up of 17.2 months, treatment with EV plus pembrolizumab reduced the rate of death by 53% vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months compared with 16.1 months among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001).2

Additionally, the median PFS with EV/pembrolizumab was 12.5 months vs 6.3 months with chemotherapy, translating to a 55% reduction in the rate of disease progression or death (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).2

The current study consisted of a “retrospective assessment of Nectin-4 expression by a CAP/CLIA-validated Nectin-4 IHC assay in primary or metastatic tumor tissue,” according to the authors. “Nectin-4 expression and Nectin-4/PD-L1 expression were available for 800 of 886 randomized patients (EV/pembrolizumab, n=394 patients; chemotherapy, n=406),” they added. The investigators assess clinical efficacy (PFS, OS, and ORR in Nectin-4 expression subgroups.

Regarding Nectin-4 expression, the median H-score was 280 (out of a possible 300; IQR, 230-298) in the EV/pembrolizumab arm vs 270 (IQR, 215-297) in the chemotherapy arm. Thirty-eight (9.6%) of patients in the EV/pembrolizumab arm had an H-score of less than 150 vs 50 (12.3%) patients in the chemotherapy arm. Fifty (12.7%) patients in the EV/pembrolizumab arm had an H-score of between 150 and less than 225 vs 56 (13.8%) patients in the chemotherapy arm, and 306 (77.7%) patients in the EV/pembrolizumab arm had an H-score of 225 or higher vs 300 (73.9%) patients in the chemotherapy arm.

“When we look at that median score [of] 275, you can see the hazard ratios for progression-free survival [are] in the 0.4s and 0.5s, so Nectin-4 doesn’t seem to make a big difference for PFS,” Powles observed. The findings were similar for OS, he added.

Regarding ORR, Powles reported a consistent benefit with EV/pembrolizumab across all Nectin-4 subgroups. Similarly, consistent PFS and OS benefits were seen with EV/pembrolizumab across all Nectin-4 subgroups.

“What we’ve shown is [EV/pembrolizumab] outperforming chemotherapy in all subgroups, no matter how you slice and dice it: for progression-free survival, for overall survival, and response rate. The relationship with PD-L1 doesn’t seem concordant, and actually irrespective of PD-L1 or Nectin-4, it looks like [EV/pembrolizumab] outperforms chemotherapy. I think it further establishes [EV/pembrolizumab] as standard of care,” Powles said in his concluding remarks.

REFERENCES

1. Powles TB, van der Heijden MS, Gupta S, et al. EV-302: Exploratory analysis of nectin-4 expression and response to 1L enfortumab vedotin (EV) + pembrolizumab (P) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC). A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). Presented at: 2024 European Society for Medical Oncology Congress. September 13-17, 2024. Barcelona, Spain. Abstract 1966MO. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/1966MO.html.pdf

2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

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