Five-year follow-up data from the EV-103 study demonstrates that the combination of enfortumab vedotin (EV) and pembrolizumab provides durable responses and meaningful survival outcomes in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC). The study, presented at the 2024 European Society of Medical Oncology (ESMO) Annual Congress, highlights the potential of this combination as a first-line treatment option, regardless of cisplatin eligibility.
Background and Rationale
Approximately half of patients with la/mUC are ineligible for cisplatin-based chemotherapy due to impaired renal function, poor performance status, or other comorbidities. This limitation has driven the need for alternative first-line treatments. The EV-302/KEYNOTE-A39 trial previously established EV plus pembrolizumab as a superior option compared to platinum-based chemotherapy, leading to its FDA approval and inclusion in treatment guidelines.
The ongoing phase 1b/2 EV-103 study (NCT03288545) assesses EV in combination with pembrolizumab in cisplatin-ineligible patients with previously untreated la/mUC. The latest results reported at ESMO 2024 provide updated efficacy and safety data after five years of follow-up for Cohort A.
Study Design and Patient Characteristics
The study enrolled patients representative of the cisplatin-ineligible population with la/mUC. Key characteristics included that 84% of patients had visceral disease, 17.8% had an ECOG-PS of 2, and approximately one-third of tumors were located in the upper tract. Patients received a median of 7 cycles of EV plus pembrolizumab, with a median treatment duration of 7 months.
Efficacy Outcomes
The confirmed overall response rate (ORR) for EV plus pembrolizumab was 73.3%, comprising a 15.6% complete response rate and a 57.8% partial response rate. The disease control rate (DCR) was 84.4%. The median duration of response (DOR) was 22.1 months, with the probability of responders remaining without progressive disease or death plateauing at 47% after 1.8 years.
The median progression-free survival (PFS) was 12.7 months, and the median overall survival (OS) was 26.1 months. Notably, 41.5% of patients treated with EV plus pembrolizumab were alive at 5 years.
Safety Profile
The most common treatment-related adverse events (TRAEs) associated with EV were skin reactions (67%) and peripheral neuropathy (62%). Grade ≥3 TRAEs included skin reactions (22.2%) and hyperglycemia (8.9%). Most EV-related TRAEs improved or resolved after therapy discontinuation. Specifically, 89.4% of patients with skin reactions experienced complete resolution, and among those with peripheral neuropathy, 25.6% had complete resolution, while 44% saw improvement.
Expert Commentary
Dr. Jonathan E. Rosenberg, a Genitourinary Oncologist at Memorial Sloan Kettering Cancer Center, highlighted that the five-year follow-up data supports the use of EV plus pembrolizumab as a first-line standard of care for patients with la/mUC, regardless of cisplatin eligibility. The survival outcomes surpass historical data, reinforcing the clinical benefit of this combination therapy.
Implications for Clinical Practice
The results from the EV-103 study, combined with data from the EV-302 trial, solidify the role of enfortumab vedotin plus pembrolizumab as a preferred first-line treatment for cisplatin-ineligible patients with advanced urothelial carcinoma. The durable responses and manageable safety profile make this combination a significant advancement in the treatment landscape for this challenging patient population.
