The landscape of metastatic urothelial cancer treatment may be shifting with promising results from the first-in-human phase 1 FORAGER-1 trial of LY3866288 (LOXO-435), presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco.
Advancing Targeted Therapy in Urothelial Cancer
FGFR3 genetic alterations, present in up to 20% of metastatic urothelial cancer cases, have emerged as a crucial therapeutic target. While erdafitinib, the current FDA-approved treatment, targets multiple FGFR isoforms (1, 2, 3, and 4), LOXO-435 represents a new generation of highly selective FGFR3 inhibitors designed to minimize off-target effects.
Impressive Safety Profile
The dose escalation study, ranging from 6 mg daily to 400 mg twice daily, demonstrated remarkable tolerability with no dose-limiting toxicities. Dr. Gopa Iyer, genitourinary medical oncologist and section head of bladder cancer at Memorial Sloan Kettering Cancer Center, highlighted that the most common side effect was low-grade, manageable diarrhea.
"What was most important was that many of the side effects that we see that are the high-grade toxicities with erdafitinib, specifically skin toxicities and ocular toxicities, were notably quite low or even absent with LOXO-435," noted Dr. Iyer.
Compelling Efficacy Data
The trial's efficacy results are particularly encouraging:
- 41% objective response rate among 39 patients with metastatic urothelial cancer
- 50% response rate (6 out of 12 patients) in those previously treated with FGFR inhibitors
- Comparable efficacy to erdafitinib with a superior safety profile
Future Directions
The research team is currently optimizing dosing regimens and planning expansion cohorts. A particularly noteworthy development is the planned investigation of a triplet therapy combining LOXO-435 with enfortumab vedotin and pembrolizumab, the current first-line combination treatment for metastatic urothelial cancer.
This innovative approach could potentially reshape the treatment paradigm for patients with FGFR3-altered metastatic urothelial cancer, offering a more targeted and better-tolerated therapeutic option.
