Enfortumab vedotin (EV), an antibody-drug conjugate (ADC), has shown promise in treating unresectable or metastatic urothelial carcinoma (UC) after chemotherapy and immune checkpoint inhibitors (ICIs). A recent study published in Frontiers in Oncology investigated the differential efficacy and durability of EV treatment between primary and metastatic sites in 39 patients with advanced UC.
The study retrospectively evaluated patients treated with EV at Iwate Medical University Hospital between January 2017 and March 2024. EV was administered at 1.25 mg/kg intravenously on days 1, 8, and 15 of a 28-day cycle. Tumor response was assessed every 8 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Key Findings on Tumor Shrinkage
Measurable metastatic organs included the lung (17 cases), lymph node (22 cases), liver (6 cases), and bone (5 cases). The mean tumor shrinkage rates at best response were 22% for the primary tumor, 21% for lung metastases, 13% for lymph node metastases, -8.5% for liver metastases, and -64% for bone metastases. Significant differences in tumor shrinkage rates were noted between the primary tumor and bone metastasis (p = 0.0373), between lung metastasis and bone metastasis (p = 0.0153), and between lymph node metastasis and bone metastasis (p = 0.0244).
Durability of Response
The duration of shrinkage maintenance was longest for lymph node metastases at 8.3 months, followed by lung metastases at 5.9 months. In contrast, the primary lesion showed a shorter duration of 1.8 months, and bone metastases only 0.7 months. The period of regrowth was shortest for the primary lesion at 2.5 months, while lung metastases showed the longest regrowth period at 7.3 months.
Clinical Outcomes and Comparisons
The study reported a median progression-free survival (PFS) of 7.7 months (95% CI, 4.8–17.1) and a median overall survival (OS) of 12.6 months (95% CI, 8.0–unavailable). The objective response rate (ORR) was 44%, and the disease control rate (DCR) was 85%. These results are comparable with other Japanese cohorts, as noted by Fukuokaya et al. (PFS: 6.0 months, OS: 14.5 months, ORR: 50.5%, DCR: 73.8%).
Nectin-4 Expression and Tumor Heterogeneity
The researchers suggest that the differential tumor shrinkage rates between primary and metastatic organs may be attributed to variations in Nectin-4 expression, the target of EV. Nectin-4 expression may change during EV administration due to prior chemotherapy and ICI treatment, with no correlation between primary tumors and matched lymph node metastases. Heterogeneous tumor clonality between primary and metastatic sites may also contribute to these mixed responses.
Implications for Treatment Strategies
The findings suggest that while EV monotherapy is effective for tumor shrinkage, strategies to overcome EV resistance are crucial. Combining EV with local treatments, such as radiotherapy, may enhance the durability of tumor response, especially in primary sites. This approach is supported by previous reports of successful durable responses to radiotherapy in combination with EV for metastatic UC.
Limitations
The study acknowledges limitations, including a small sample size and retrospective design. The number of liver and bone metastasis cases was relatively small, and Nectin-4 expression was not evaluated. Further prospective studies with larger cohorts are needed to validate these findings.
Expert Commentary
Janaki Neela Sharma, MD, from the University of Miami Health Systems, noted that the combination of enfortumab vedotin and pembrolizumab has reshaped the treatment landscape for advanced urothelial cancer. Data from the EV-302 trial led to the full FDA approval of this combination, demonstrating a significant overall survival benefit and high objective response rates, irrespective of cisplatin eligibility.
Conclusion
This real-world study highlights the varied efficacy of enfortumab vedotin across different tumor sites in metastatic urothelial carcinoma. While EV demonstrates significant tumor shrinkage in both primary and metastatic lesions, the durability of response differs, suggesting the need for tailored treatment strategies combining systemic and local therapies to improve long-term outcomes.
