ImPact Biotech’s Phase III ENLIGHTED trial (NCT04620239) is a single-arm, open-label study evaluating Padeliporfin vascular targeted photodynamic therapy (VTP) in up to 100 patients with low-grade, non-invasive Upper Tract Urothelial Carcinoma (UTUC). Padeliporfin VTP therapy, a minimally invasive drug-device combination for selective ablation of unresectable solid tumors. The novel VTP platform delivers non-thermal laser light via optical fibers to locally activate Padeliporfin in the tumor microenvironment. 

Conducted at 29 global sites, the study includes two phases: an Induction Treatment Phase (ITP)—up to three laser-activated VTP treatments at 4-week intervals until complete response—and a Maintenance Phase (MTP) with optional VTP at 3-month intervals for up to 12 months. Padeliporfin is given IV and activated locally via laser during endoscopy. Primary goal: response rate at end of ITP; secondary: safety, tolerability, and durability of response.

As of the November 2024 data cut-off, 43 patients had begun treatment in the Phase III ENLIGHTED study , with 37 completing ITP and evaluable for efficacy. Among them, 73% (27/37) achieved a complete response (CR) and 13.5% (5/37) had a partial response (PR) at the end of ITP, showing strong local tumor control. 

Padeliporfin VTP was well-tolerated, with most treatment-emergent adverse events (TEAEs) being mild to moderate and primarily related to the endoscopic procedure, resolving within days. The most common Grade 3 events—hematuria, dysuria, and flank pain—also resolved quickly. Importantly, no TEAEs of special interest or treatment discontinuations were reported. 

KOL insights

“Photodynamic therapy in this patient population seems to be effective, at least based on this interim analysis. The safety profile is excellent, and I think we may have another tool in our toolbox to allow these patients to maintain their kidney function and preserve their organs.” – Expert Opinion

“This treatment is efficacious, at least in this interim analysis. It does have an excellent safety profile. Recruitment will continue and hopefully will result in approval,”– Expert Opinion

Conclusion

Upper tract urothelial carcinoma accounts for only 5–10% of urothelial cancers. At present, Padeliporfin VTP is currently being evaluated in a pivotal Phase III study in low-grade UTUC with earlier stage studies ongoing or planned in high-grade UTUC, pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). In low-grade UTUC (phase III ENLIGHTED trial), after evaluating 50% of the study's target enrollment, interim analysis is conducted; enrollment completion is expected in the second-half of 2025 with year-end topline data. 

This study focuses on patients with low-grade UTUC, a population that often faces limited treatment options. Due to the lack of effective endoscopic tools, many patients ultimately undergo kidney removal. This is especially problematic, as these patients often already have compromised renal function and are at significant risk for kidney insufficiency and its downstream consequences. There is a clear unmet need for reliable and effective organ-preserving therapies.

Interim results from the phase III ENLIGHTED trial highlight Padeliporfin VTP as a promising organ-sparing therapy for low-grade UTUC, demonstrating an impressive 86.5% overall response rate and 73% complete response rate. 

Although the current responses seem to be long-lasting, more research is needed to confirm the longevity of the benefit. It is important to highlight that photodynamic treatment is considered an adjunct/complimentary  to the therapeutic toolbox rather than a stand-alone solution. If necessary, it might be utilized to debulk tumors and be followed by more technically complex therapies, providing a versatile and supplemental method of managing UTUC.