A phase 3, global, open-label, randomized trial published in The New England Journal of Medicine on March 7, 2024 has found that first-line treatment with enfortumab vedotin plus pembrolizumab significantly improves progression-free and overall survival compared to platinum-based chemotherapy in patients with locally advanced or metastatic urothelial carcinoma. The study, known as EV-302, was funded by Astellas Pharma US, Merck Sharp and Dohme, and Seagen.
Urothelial carcinoma is the most common type of bladder cancer, and patients with advanced disease have historically had poor outcomes with standard platinum-based chemotherapy. While the addition of immunotherapy maintenance with avelumab after initial chemotherapy has shown some benefit, many patients progress before receiving maintenance therapy. This trial aimed to evaluate whether combining an antibody-drug conjugate (enfortumab vedotin) targeting nectin-4 with a PD-1 inhibitor (pembrolizumab) could improve outcomes compared to standard chemotherapy as initial treatment.
The study enrolled 886 patients at 185 sites across 25 countries between 2020-2023. Eligible patients had previously untreated, histologically confirmed locally advanced or metastatic urothelial carcinoma. Patients were randomized 1:1 to receive either enfortumab vedotin (1.25 mg/kg on days 1 and 8) plus pembrolizumab (200 mg on day 1) every 3 weeks, or chemotherapy with gemcitabine plus either cisplatin or carboplatin. Randomization was stratified by cisplatin eligibility, PD-L1 expression status, and presence of liver metastases.
The demographic and baseline characteristics were well-balanced between the two treatment arms. The median age was 69 years, 76.7% were male, and 67.5% were White. About 27% had upper tract disease as the primary site of origin. Approximately 55% were eligible for cisplatin-based chemotherapy. The study population was representative of the general advanced urothelial carcinoma patient population, though Black patients were underrepresented.
At a median follow-up of 17.2 months, the study met both of its primary endpoints, showing significant improvements in both progression-free survival (PFS) and overall survival (OS) with enfortumab vedotin plus pembrolizumab compared to chemotherapy. The median PFS was 12.5 months in the combination arm versus 6.3 months in the chemotherapy arm (HR 0.45, 95% CI 0.38-0.54, p<0.001). The median OS was 31.5 months versus 16.1 months, respectively (HR 0.47, 95% CI 0.38-0.58, p<0.001).
The overall response rate was also significantly higher with the combination therapy at 67.7% versus 44.4% with chemotherapy (p<0.001). Notably, 29.1% of patients achieved a complete response with enfortumab vedotin plus pembrolizumab compared to 12.5% with chemotherapy. The median duration of response was not reached in the combination arm versus 7.0 months in the chemotherapy arm.
The PFS and OS benefits were consistent across all pre-specified subgroups, including those based on cisplatin eligibility and PD-L1 expression status. This suggests the combination may be effective regardless of these factors that have traditionally influenced treatment selection.
Regarding safety, treatment-related adverse events of any grade occurred in 97.0% of patients receiving the combination therapy and 95.6% of those receiving chemotherapy. However, grade 3 or higher treatment-related adverse events were less frequent with the combination (55.9%) compared to chemotherapy (69.5%), despite a longer duration of treatment exposure.
The most common treatment-related adverse events with enfortumab vedotin plus pembrolizumab were peripheral sensory neuropathy (50.0%), pruritus (39.8%), and alopecia (33.2%). For chemotherapy, the most common were anemia (56.6%), neutropenia (41.6%), and nausea (38.8%). The most frequent grade 3 or higher adverse events in the combination arm were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%).
Adverse events of special interest associated with enfortumab vedotin included skin reactions, peripheral neuropathy, and hyperglycemia. Those associated with pembrolizumab included severe skin reactions, pneumonitis, and hepatitis. Most of these were manageable with dose modifications. Treatment-related adverse events led to discontinuation of any study drug in 35.0% of patients in the combination arm compared to 18.5% in the chemotherapy arm.
One limitation of the study is that the control arm did not mandate the use of maintenance avelumab after chemotherapy, which has become a standard approach. However, 32.2% of patients in the chemotherapy arm did receive subsequent PD-1/PD-L1 inhibitor therapy, including 30.4% who received avelumab maintenance. This is in line with real-world utilization rates of 20-40% for avelumab maintenance therapy.
Another potential limitation is that the study was open-label, which could introduce some bias in adverse event reporting or decisions about treatment discontinuation. However, the primary endpoints of PFS and OS were assessed by blinded independent review, mitigating potential bias for these key outcomes.
The authors conclude that enfortumab vedotin plus pembrolizumab represents a new standard of care for first-line treatment of advanced urothelial carcinoma, regardless of cisplatin eligibility or PD-L1 status. The combination demonstrated a clinically meaningful and statistically significant improvement in survival outcomes compared to platinum-based chemotherapy, with a manageable safety profile.
The potential clinical impact of these findings is substantial. If approved by regulatory agencies, this combination could become the new first-line standard of care for patients with locally advanced or metastatic urothelial carcinoma. The impressive complete response rate of nearly 30% is particularly noteworthy and could translate to improved long-term outcomes for a significant proportion of patients.
The study results also challenge the current treatment paradigm that bases initial therapy selection on cisplatin eligibility and PD-L1 status. The consistent benefit seen across subgroups suggests this combination could be effective for a broad patient population. This could potentially simplify treatment decision-making and reduce the need for biomarker testing to guide first-line therapy selection.
Additionally, the combination's efficacy in preventing early disease progression may allow more patients to benefit from systemic therapy. In the current treatment landscape, a significant proportion of patients progress during or shortly after initial chemotherapy and never receive subsequent lines of therapy or maintenance treatment. The improved progression-free survival with enfortumab vedotin plus pembrolizumab could translate to more patients being able to receive and benefit from multiple lines of treatment.
However, several questions remain that will need to be addressed in future research and real-world use. The optimal duration of therapy is unclear, as patients could continue treatment until progression or unacceptable toxicity. Long-term follow-up will be important to assess the durability of responses and survival benefit, as well as to identify any late toxicities that may emerge with prolonged treatment.
The role of this combination in earlier disease settings, such as muscle-invasive bladder cancer, is also an area for future investigation. Given the high complete response rate, studies evaluating this regimen in the neoadjuvant setting could be of particular interest.
Cost considerations will also be important, as both enfortumab vedotin and pembrolizumab are expensive therapies. Pharmacoeconomic analyses will be needed to assess the cost-effectiveness of this combination compared to current standard approaches.
In conclusion, the EV-302 trial represents a significant advancement in the treatment of advanced urothelial carcinoma. The combination of enfortumab vedotin and pembrolizumab demonstrated superior efficacy to platinum-based chemotherapy, with a tolerable safety profile. If approved, this regimen has the potential to become the new standard first-line treatment for patients with locally advanced or metastatic urothelial carcinoma, regardless of cisplatin eligibility or PD-L1 status. The results of this study may lead to a paradigm shift in how we approach initial therapy for this challenging disease.
References
Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
