Enfortumab vedotin plus pembrolizumab demonstrates sustained survival advantage across subgroups in urothelial carcinoma

Results from the phase III EV-302/KEYNOTE-A39 trial demonstrate improvements in progression-free survival, overall survival and objective response rates with enfortumab vedotin plus pembrolizumab compared with chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. The benefit of enfortumab vedotin plus pembrolizumab in all prespecified subgroups was consistent with the overall patient population.

Despite a few advances to address the high unmet therapeutic need in advanced urothelial carcinoma, the median overall survival has remained low at approximately 13 months. For decades, cisplatin-eligibility has defined the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. However, the primary analysis of the phase III KEYNOTE-A39 (EV-302) study demonstrated a statistically significant and clinically meaningful benefit of enfortumab vedotin plus pembrolizumab compared with platinum-based chemotherapy for the co-primary endpoints – progression-free survival (PFS, HR: 0.45; p< 0.00001) and overall survival (OS, HR: 0.47; p< 0.00001) – in the total study population of previously untreated patients with locally advanced or metastatic urothelial carcinoma. At ASCO GU 2024, Dr. Michiel van der Heijden, presented the results from the prespecified subgroup analyses from this phase III study.

Methods

KEYNOTE-A39 (EV-302) is a global, randomised, open-label phase III study comparing enfortumab vedotin plus pembrolizumab with platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic urothelial carcinoma, regardless of cisplatin eligibility or PD-L1 expression status. Participants were randomised 1:1 to receive 3-week cycles of enfortumab vedotin (1.25 mg/kg IV on day 1 and 8) and pembrolizumab (200 mg IV on day 1) or chemotherapy with gemcitabine, cisplatin or carboplatin. Co-primary endpoints were PFS and OS. One of the secondary endpoints included the objective response rate (ORR). Prespecified subgroups included cisplatin eligibility (eligible, ineligible), PD-L1 expression (low, high), liver metastases (present, absent), and metastatic disease site (visceral metastases, lymph node only metastases).

Results

In total, 886 patients were randomised to receive enfortumab vedotin plus pembrolizumab (n=442) or chemotherapy (n=444). Patient and disease characteristics were balanced between treatment groups. Treatment with enfortumab vedotin plus pembrolizumab prolonged PFS versus chemotherapy among prespecified subgroups, including cisplatin-eligible (HR [95% CI]: 0.48 [0.38-0.62]) or cisplatin-ineligible (HR [95% CI]: 0.43 [0.33-0.55]) patients, patients with high (HR [95% CI]: 0.42 [0.33-0.53]) or low (HR [95% CI]: 0.50 [0.38-0.52]) PD-L1 expression, patients with (HR [95% CI]: 0.53 [0.38-0.76]) or without (HR [95% CI]: 0.43 [0.35-0.52]) liver metastases and patients with visceral (HR [95% CI]: 0.45 [0.37-0.55]) or lymph node only (HR [95% CI]: 0.40 [0.26-0.62]) metastases. Earlier findings also showed an OS advantage with the combination in cisplatin-eligible (HR [95% CI]:0.53 [0.39-0.72]) and -ineligible (HR [95% CI]: 0.43[0.31-0.59]), as well as PD-L1–high (HR [95% CI]: 0.49[0.37-0.66]) and PD-L1–low (HR [95% CI]: 0.44[0.31-0.61]) subgroups. Additionally, the presence of liver metastases did not seem to affect the magnitude of OS benefit seen with the combination (with: HR [95% CI]: 0.47[0.32-0.71]; without: HR [95% CI]: 0.47[0.36-0.61]). Enfortumab vedotin plus pembrolizumab also improved OS regardless of visceral metastases (HR [95% CI]: 0.47[0.37-0.60]) and in lymph node-only patients (HR [95% CI]: 0.46[0.27-0.78]). The ORR was ≥60% for enfortumab vedotin plus pembrolizumab across all subgroups.

Conclusions

In the phase III KEYNOTE-A39 (EV-302) study, enfortumab vedotin plus pembrolizumab significantly improved outcomes versus platinum-based chemotherapy in a broad patient population with previously untreated locally advanced or metastatic urothelial carcinoma. Survival benefits of enfortumab vedotin plus pembrolizumab were observed in all prespecified subgroups and were consistent with results found in the total study population. According to the researchers, the results of these subgroup analyses support the findings of the primary analysis, which showed that enfortumab vedotin plus pembrolizumab is a potential new standard treatment for this patient population.

Reference

Van der Heijden MS, et al. Enfortumab vedotin (EV) in combination with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC): subgroup analyses results from EV-302, a phase 3 global study. Presented at ASCO GU 2024; Abstract LBA530.