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.