(UroToday.com) The 2025 AUA annual meeting featured an upper tract urothelial carcinoma session and a presentation by Dr. Vitaly Margulis discussing results of the phase 3 ENLIGHTED study assessing the efficacy and safety of padeliporfin vascular targeted photodynamic (VTP) therapy for treatment of low-grade upper tract urothelial cancer. Padeliporfin VTP is a combination product, whereby (i) the drug, padeliporfin (a photosensitizer), is intravenously administered, (ii) a device – a laser light delivery system, emits near-infrared light at 753 nm, and (iii) an optic fiber – delivers the light to the target lesion(s) in the upper tract urothelium:
Upon laser light activation, padeliporfin VTP triggers a cascade of events (non-thermal radical oxygen species generation, vascular occlusion, necrosis) that strongly impact tumor vasculature and induce an anti-tumor immune response, as illustrated below:
Padeliporfin VTP has demonstrated safety and efficacy for upper tract urothelial cancer treatment in a phase 1 study. At the 2025 AUA annual meeting, Dr. Margulis and colleagues reported the preliminary efficacy and safety outcomes of padeliporfin VTP for treatment of low-grade upper tract urothelial cancer in the ENLIGHTED phase 3 study.
This is an open-label phase 3 study from the USA, the European Union, and Israel, with 100 patients planned to be enrolled at 27 sites. Inclusion criteria are up to 2 biopsy-proven low-grade upper tract urothelial cancers with an index tumor ≤15mm in the kidney and ≤20mm in the ureter with an absence of high-grade cells on cytology. Key exclusion criteria include:
- Current high grade or muscle invasive (>pT1) urothelial carcinoma of the bladder
- CIS current or previously in the upper urinary tract
- History of invasive T2 or higher urothelial carcinoma in the past 2 years
- Prohibited medication that could not be adjusted or discontinued prior to study treatment
- Patients with photosensitive skin diseases or porphyria
VTP is performed via retrograde upper tract endoscopy under anesthetic and low light conditions, padeliporfin is injected IV, and a laser light diffuser fiber 20-40 mm is positioned in proximity to the tumor through the scope. After padeliporfin injection, the laser fiber is illuminated for 10 min. The fiber can be repositioned to provide up to 3 treatments within the upper tract. Patients are treated in two phases: induction and maintenance treatment phases. Induction consists of 1-3 VTPs provided at 4 week intervals until achieving complete response or treatment failure. Patients achieving complete response will proceed to maintenance and be followed with endoscopic evaluation every 3 months with VTP provided for recurrent tumors only up to 12 months. Patients with high-grade recurrences will be deemed treatment failures and removed from the study to standard of care treatment. Patients completing maintenance will be followed for an additional 48 months for long-term outcomes. The primary outcome is complete response on endoscopic evaluation and selective cytology at the time of primary response evaluation (28+/-3 days post last treatment) during padeliporfin VTP induction. The trial schema of ENLIGHTED is as follows:
As of November 4, 2024, 44 patients have been treated, including 33 patients completing induction with a complete response rate of 78.8% (26/33), partial response rate of 18.2% (6/33), and 1 (3%) patient having no response (stable disease). The most frequent adverse events were grade 1-2 hematuria 14%, flank pain 10%, procedural pain 6.4%, dysuria 5.2%, UTI 4.7%, abdominal pain 4.7%, vomiting 4.7%, fatigue 4%, and nausea 3.5% (resolving in a few days). There were 16 (9.2%) grade 3 serious adverse events reported, with those related to the VTP treatment including 2 patients with renal colic and flank pain, resolving in 2 days.
Dr. Margulis concluded his presentation discussing results of the phase 3 ENLIGHTED study with the following take home points:
- Padeliporfin VTP has shown evidence of safety and efficacy with preliminary data that is consistent with prior experience
- Recruitment for the ENLIGHTED trial is ongoing with results expected to provide basis for approval of a new therapy offering clinical benefits and an organ sparing alternative for patients
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 American Urological Association (AUA) annual meeting held in Las Vegas, NV, Saturday, April 26 - Tuesday, April 29, 2025