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Enfortumab Vedotin and Pembrolizumab for Untreated Advanced Urothelial Cancer
TAKE-HOME MESSAGE
- This phase III randomized trial showed that enfortumab vedotin (EV) plus pembrolizumab therapy was associated with significantly longer progression-free and overall survival than chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. The most common treatment-related adverse events of any grade in the EV–pembrolizumab group were peripheral sensory neuropathy, pruritus, and alopecia. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the EV–pembrolizumab group and in 69.5% of those in the chemotherapy group.
- Treatment with EV and pembrolizumab resulted in median durations of progression-free and overall survival that were nearly double those observed with chemotherapy, with no new safety signals identified.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.
METHODS
We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival.
RESULTS
A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group.
CONCLUSIONS
Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).
Additional Info
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Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer
N. Engl. J. Med 2024 Mar 07;390(10)875-888, T Powles, BP Valderrama, S Gupta, J Bedke, E Kikuchi, J Hoffman-Censits, G Iyer, C Vulsteke, SH Park, SJ Shin, D Castellano, G Fornarini, JR Li, M Gümüş, N Mar, Y Loriot, A Fléchon, I Duran, A Drakaki, S Narayanan, X Yu, S Gorla, B Homet Moreno, MS van der HeijdenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Despite radical surgical treatment, tumor-specific survival in patients with advanced and metastatic urothelial carcinoma (mUC) is poor. The use of systemic treatment has been unable to fundamentally change these results so far. Regarding classical platinum-based chemotherapy, perioperative treatment only marginally contributes to tumor-specific survival,1 and, in patients with mUC, long-term survival is rarely observed, despite up to 50% of patients showing an objective response.2 Overall survival in patients with mUC has been improved by the introduction of immune checkpoint inhibitors in the treatment algorithms.3-6 However, the improvements are rather due to a significant stabilization of disease progression with a markable duration of response in some patients than an improvement in oncological efficacy in the general patient population.
In this context, Powles and co-investigators recently presented the results of the EV-302/KEYNOTE-A39 trial. Here, in patients with previously untreated mUC, combinatorial treatment with the PD-1 inhibitor pembrolizumab (P) and the antibody–drug conjugate enfortumab–vedotin (EV) resulted in a doubling of both progression-free (HR, 0.45; 95% CI, 0.38–0.54; P < .001) and overall survival (HR, 0.47; 95% CI, 0.38–0.58; P < .001) as compared with standard platinum-based first-line therapy (gemcitabine + cisplatin or carboplatin). Objective responses were observed in 67.7% of patients (including 29.1% complete responses) in the EV plus P arm as compared with 44.4% in the chemotherapy arm (12.5% complete remission). In addition to the impressive improvement in survival outcomes in general, a key aspect is that, in contrast to previous therapies, not only individual subgroups but all subgroups (eg, upper vs lower tract, cisplatin-eligible vs -ineligible) benefited from treatment with EV plus P.
Although some critical points may be raised (eg, only approximately 30% of patients in the control arm have been treated with maintenance avelumab), and the financial toxicities of this novel treatment approach cannot be ignored, this trial's results define, in my opinion, the new standard of care for the first-line treatment of mUC.
References