Enfortumab vedotin plus pembrolizumab significantly outperforms chemotherapy in the first line treatment of patients with advanced urothelial carcinoma

November 2023 Cancer trials
Human bladder cancer, computer illustration.

Decades of reliance on platinum-based chemotherapy for locally advanced metastatic urothelial carcinoma (la/mUC) have yielded suboptimal long-term survival outcomes. In the EV-302/KEYNOTE-A39 study, the combination of the antibody-drug conjugate (ADC) enfortumab vedotin with pembrolizumab (EV+P) significantly outperformed first-line chemotherapy, with a doubling of the median progression-free (PFS) and overall survival (OS). As such, these results strongly support EV+P as a new standard of care in the first line treatment of patients with la/mUC.

For decades, platinum-based chemotherapy has been the standard first-line treatment for patients with la/mUC. While this treatment approach yields some responses, it fails to provide lasting remissions. As a result, the prognosis for these patients remains to be poor with a median OS of 12-14 months. Unfortunately, trials evaluating immune checkpoint inhibition as monotherapy or in combinations with chemotherapy have failed to improve the survival in la/mUC patients. In the phase III EV-302/KEYNOTE-A39 study, the combination of enfortumab vedotin (EV), an ADC directed against nectin-4 directed, and pembrolizumab (EV+P), was compared to chemotherapy as first line therapy for patients with previously untreated la/mUC regardless of cisplatin eligibility and PD-L1 expression status.


The phase III EV-302/KEYNOTE-A39 trial enrolled a total of 886 patients with previously untreated la/mUC who were eligible for a treatment with platinum-based chemotherapy, pembrolizumab, and EV, with a GFR≥30mL/min and no prior exposure to a PD-(l)1 inhibitor. Patients were randomly assigned (1:1) to receive 3-week cycles of EV (1.25 mg/kg; IV) on days 1 and 8 and pembrolizumab (200 mg; IV) on day 1 (N= 442) or gemcitabine with cisplatin or carboplatin (N= 444). Dual primary endpoints included progression-free survival (PFS) and overall survival (OS), with key secondary endpoints including overall response rate (ORR), duration of response (DoR) and safety.


After a median follow-up of 17.2 months, EV+P significantly prolonged the PFS compared to chemotherapy, with a median PFS of 12.5 and 6.3 months for EV+P and chemotherapy, respectively. This corresponds to a 55% reduced the risk of disease progression or death for patients treated with EV+P (HR[95%CI]: 0.45 [ 0.38-0.54]; p< 0.00001). The subgroup analysis favoured EV+P across all subgroups, irrespective of PD-L1 expression, cisplatin eligibility or the presence of liver metastases. Strikingly, this delayed disease progression also translated into a significantly longer OS, marking this trial as the first in history to demonstrate a benefit in OS compared to chemotherapy. Compared to patients in the chemotherapy arm, patients treated with EV+P had a 53% lower death risk, corresponding to a median OS of 31.5 months for EV+P as compared to 16.1 months for chemotherapy (HR[95%CI]: 0.47 [0.38-0.58]; p< 0.00001). Interestingly, this significant OS benefit was observed, regardless of cisplatin eligibility, with a HR for OS of 0.53 and 0.43 in cisplatin-eligible and ineligible patients, respectively. Similarly, the OS benefit was seen irrespective of the PD-L1 status, with HRs of 0.49 and 0.44 for PD-L1 high (CPS≥10) and low (CPS<10) patients. EV+P also came with a significantly higher ORR than chemotherapy (67.7% vs. 44.4%), including a complete response in 29.1% and 12.5% for EV+P and chemotherapy treated patients, respectively.. Finally, responses to EV+P also proved to be more durable than with chemotherapy, with a median DoR that was not reached for EV+P as compared to7.0 months with chemotherapy.

Grade ≥3 treatment-related adverse events (TRAEs) occurred in 55.9% of patients treated with EV+P and 69.5% treated with chemotherapy. The most common grade ≥3 events in patients receiving EV+P consisted of maculopapular rash (7.7%), neutropenia (4.8), peripheral sensory neuropathy (3.6%), diarrhoea (3.6%) and fatigue (3%). Most common grade ≥3 TRAEs of special interest for EV+P included skin reactions (15.5%), peripheral neuropathy (6.8%), and hyperglycemia (6.1%).


The EV-302/KEYNOTE-A39 study represents a groundbreaking achievement in the treatment of  previously untreated la/mUC patients, with a significant OS benefit for EV+P over platinum-based chemotherapy. Compared to chemotherapy, EV+P, nearly doubled the median PFS and OS in this setting. Moreover, the safety profile was generally manageable without unexpected safety signals. These compelling findings firmly support EV+P as a new standard of care for the first line treatment of patients with la/mUC.


Powles TB. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Presented at ESMO 2023; Abstract LBA6.