What is the evidence for the use of concurrent radiotherapy with enfortumab vedotin (Antibody-Drug Conjugate)?

Concurrent Radiotherapy with Enfortumab Vedotin in Advanced Urothelial Cancer

Concurrent administration of radiotherapy with enfortumab vedotin appears to be safe and effective for symptom palliation in patients with metastatic urothelial carcinoma, with manageable toxicity profiles. 1

Evidence Base for Concurrent Therapy

The evidence regarding concurrent radiotherapy with enfortumab vedotin is emerging but limited. The most recent and highest quality evidence comes from a 2024 retrospective study that specifically examined this combination:

• A single-institution study evaluated 9 patients with locally advanced or metastatic urothelial carcinoma who received enfortumab vedotin and radiation therapy within 30 days of each other 1
• Patients experienced only grade 1-2 acute treatment-related adverse events (fatigue, nausea, dermatitis)
• Chronic toxicity was minimal (grade 1 neck pain, grade 2 fatigue in 2 patients)
• All patients demonstrated symptom relief at the irradiated sites, with 4 experiencing complete resolution of cancer-related symptoms

Current Standard of Care for Advanced Urothelial Cancer

Enfortumab vedotin plus pembrolizumab has recently become the standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma:

• The EV-302/KEYNOTE-A39 trial demonstrated superior overall survival (31.5 vs 16.1 months), progression-free survival (12.5 vs 6.3 months), and response rates (67.7% vs 44.4%) compared to platinum-based chemotherapy 2, 3
• The NCCN panel has assigned this combination a Category 1 designation (highest level of evidence and consensus) for both cisplatin-eligible and cisplatin-ineligible patients 2
• ESMO guidelines also recognize this combination as a preferred first-line regimen 2

Radiotherapy in Advanced Urothelial Cancer

While systemic therapy is the mainstay of treatment for metastatic urothelial bladder cancer, palliative radiotherapy remains an important option for symptom management:

• NCCN guidelines acknowledge that "palliative radiotherapy may be an option for some patients" with metastatic urothelial bladder cancer 2
• Radiotherapy is primarily used for local symptom control rather than as a definitive treatment in the metastatic setting

Safety Considerations for Concurrent Therapy

When administering enfortumab vedotin with radiotherapy, clinicians should be aware of potential overlapping toxicities:

• Skin reactions are common with enfortumab vedotin (48% of any grade) 4, 5
• Peripheral neuropathy occurs in approximately 50-56% of patients receiving enfortumab vedotin 6, 7
• Radiation dermatitis may compound skin toxicity when fields overlap with radiation treatment areas
• Close monitoring for enhanced toxicity at the radiation site is recommended

Practical Recommendations for Concurrent Therapy

Based on the available evidence, the following approach is recommended when considering concurrent radiotherapy with enfortumab vedotin:

1. Patient selection: Consider concurrent therapy for patients with symptomatic metastases requiring palliative radiation
2. Radiation dosing: Median radiation dose in the safety study was 30 Gy 1
3. Monitoring: Closely monitor for skin reactions, fatigue, and other overlapping toxicities
4. Supportive care: Implement early intervention for skin toxicity with topical steroids when needed 5
5. Dose modifications: Be prepared to modify enfortumab vedotin dosing if significant overlapping toxicities occur

Limitations and Future Directions

The current evidence has important limitations:

• Small sample size (9 patients) in the only dedicated study of concurrent therapy 1
• Retrospective design limits definitive conclusions
• Lack of randomized controlled trials comparing concurrent versus sequential approaches

Larger prospective studies are needed to further establish the safety profile and optimal timing of concurrent radiotherapy with enfortumab vedotin-based regimens.

Conclusion

While the evidence is limited, concurrent administration of radiotherapy with enfortumab vedotin appears to be a reasonable approach for symptom palliation in advanced urothelial carcinoma, with manageable toxicity. Close monitoring and early intervention for side effects are essential to optimize outcomes.