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.)
Generating level 1B evidence is the true game changer for any medical specialty involved in cancer care. This becomes even harder when it comes to locally advanced and/or metastatic setting due to (and luckily) the relative rarity of disease prevalence. However, such evidence-based medicine is the sole driver for the so highly desired paradigmatic shifts in the updating process of Uro-Oncology Guidelines to standardise the care of our oncologic patients and therefore any state-of-the-art advancements should be celebrated.
Specifically, when it comes to locally advanced or metastatic urothelial cancer, we should take a moment to highlight the challenges and importance of the success from the recently published results of the EV-302 trial from Powels et al. regarding the adoption of enfortumab vedotin and Pembrolizumab in primary advanced urothelial diseases.
As we previously covered the preliminary results shown at ASCO GU 2024 in January, we are now able to summarise the full publication advocated with enthusiasm by the uro-oncology communities recently published in the New England Journal of Medicine.
The EV-302 trial is a Phase III study comparing the efficacy and safety of enfortumab vedotin and pembrolizumab with platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic urothelial carcinoma. The background for the adoption of such ‘anticipation and intensification’ therapeutic criterion, now well received for example in the cure of prostate cancer, derives indeed form preclinical studies suggesting enhanced antitumour activity with lasting immunity when enfortumab vedotin is combined with a PD-1 inhibitor. This combination received accelerated approval in the US for patients ineligible for cisplatin-containing chemotherapy, based on promising phase 1b–2 study results.
The trial included adult patients with unresectable locally advanced or metastatic urothelial carcinoma, regardless of biomarker expression. Key exclusion criteria included previous PD-1 or PD-L1 inhibitor therapy, uncontrolled diabetes, and previous autoimmune disease requiring systemic treatment within the last 2 years. In the enfortumab vedotin–pembrolizumab group, patients received enfortumab vedotin (1.25 mg/kg intravenous infusion on days 1 and 8) and pembrolizumab (200 mg intravenous infusion on day 1 of each 3-week cycle). Chemotherapy group patients received gemcitabine (1000 mg/m² intravenous infusion on days 1 and 8) and either cisplatin (70 mg/m² intravenous infusion on day 1) or carboplatin (dose calculated by Calvert formula on day 1).
The trial's primary endpoints were progression-free survival and overall survival, with secondary endpoints including overall response and safety assessments.
The trial enrolled n=886 patients with n=442 patients assigned to enfortumab vedotin and Pembrolizumab, and n=444 patients to chemotherapy. The median age was 69 years and with predominant male representation (76.7%). The study included as primary disease origin a majority of bladder cancer lesions and 27% from the upper tract. Patients receiving enfortumab vedotin–pembrolizumab had a median treatment duration of 9.4 months, with 94% receiving protocol-specified platinum-based therapy, compared to 4.1 months in the chemotherapy group.
Enfortumab vedotin–pembrolizumab demonstrated significantly longer progression-free survival compared to chemotherapy, with a 55% lower risk of disease progression or death (HR 0.45, 95% CI 0.38 to 0.54; p<0.001). Median progression-free survival was 12.5 months versus 6.3 months with chemotherapy. These results were consistent across subgroups based on cisplatin eligibility and PD-L1 expression status.
The trial showed a significant overall survival benefit with Enfortumab vedotin–pembrolizumab over chemotherapy, with a 53% lower risk of death (HR 0.47, 95% CI 0.38 to 0.58; p<0.001). Median overall survival was 31.5 months versus 16.1 months, respectively.
Overall response rates were higher in the enfortumab vedotin–pembrolizumab group (67.7%) than in the chemotherapy group (44.4%), with more complete responses (29.1% vs. 12.5%). Responses were durable, with a majority ongoing at 12 and 18 months in the enfortumab vedotin–Pembrolizumab group.
Median time to pain progression was 14.2 months with enfortumab vedotin–Pembrolizumab versus 10 months with chemotherapy, though the difference was not significant. Subsequent therapies favoured the enfortumab vedotin–Pembrolizumab group, with fewer patients receiving subsequent anti–PD-1 or anti–PD-L1 therapy (0% vs. 58.6%) and a higher proportion continuing trial treatment (32.6%).
Safety profiles were consistent with previous findings, with fewer grade 3 or higher treatment-related adverse events in the enfortumab vedotin–Pembrolizumab group (55.9% vs. 69.5%). Notably, the incidence of adverse events of special interest was manageable, with no new safety signals identified.
In summary
The EV-302 trial provides compelling evidence of the significant survival benefit of enfortumab vedotin and pembrolizumab over chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. The combination therapy offers improved progression-free survival, overall survival, and overall response rates compared to standard chemotherapy, with manageable safety profiles. These findings definitively underscore the potential of enfortumab vedotin and pembrolizumab as a preferred first-line treatment option, highlighting its clinical relevance and impact on patient care in this challenging disease setting.