(UroToday.com) The 2025 ASCO annual meeting featured an upper tract urothelial cancer rapid oral abstract session and a presentation by Dr. Vitaly Margulis discussing interim results of efficacy and safety of padeliporfin vascular targeted photodynamic (VTP) therapy in the treatment of low-grade upper tract urothelial cancer from the ENLIGHTED phase 3 study. Upper tract urothelial carcinoma accounts for 5-10% of urothelial cancer, with an annual incidence in the USA of ~2 cases per 100,000 people. Up to 60% of patients have pyelocaliceal tumors, with ~40% of tumors present in the ureter. Risk factors for upper tract urothelial carcinoma include smoking, aristolochic acid, Lynch and Lynch-like syndromes. The management of upper tract urothelial carcinoma is complicated by the fact that chronic kidney disease is a concern in this population. Tumor ablation is the preferred initial option for low risk favorable upper tract urothelial carcinoma, but may also be offered to patients with low risk unfavorable or select high risk favorable cases with low volume tumors or those with radical nephroureterectomy contraindications. Endoscopic surveillance is necessary, and effective organ-sparing options remain an unmet need.
The ENLIGHTED global pivotal phase III trial is a single arm, open label study at 22 sites across the USA, France, Spain, Germany, Austria, and Israel. The planned enrollment for ENLIGHTED is 100 patients, with the current analysis including 79 evaluable patients. Padeliporfin VTP is a combination product: padeliporfin (photosensitizer drug) is administered IV, a laser light delivery system, which is made up of a laser (source of light) that emits near-infrared light at 753 nm, and an optic fiber that delivers the light to the target lesion(s) in the upper tract urothelium:
Upon light activation, padeliporfin triggers a cascade of pathophysiological events that have a strong impact on tumor vasculature, and consists of the following consecutive steps:
The primary efficacy outcome of ENLIGHTED is the absence of upper tract urothelial tumors in the ipsilateral kidney and ureter during the primary response evaluation (28 +/- 3 days after up to 3 treatments in the padeliporfin VTP induction phase). Complete response is defined as absence of disease based on:
- Absence of visual tumor on endoscopy
- No evidence of tumor on biopsy (if feasible)
- Negative urinary cytology by instrumental collection
Key inclusion criteria include:
- New or recurrent low-grade, non-invasive upper tract urothelial carcinoma
- Up to 2 biopsy-proven tumor lesions of low-grade
- 5-15 mm in the kidney or 5-20 mm in the ureter (as measured by endoscopy) of the ipsilateral side
- Absence of high-grade cells on instrumental cytology
Key exclusion criteria include:
- Current high-grade or muscle invasive (>pT1) urothelial carcinoma of the bladder
- CIS current or previous in the upper urinary tract
- History of invasive T2 or higher urothelial cancer in past 2 years
- Patients with photosensitive skin diseases or porphyria
The ENLIGHTED trial schema (induction and maintenance phases) is as follows:
The interim analysis is defined in the study protocol and was conducted mid-way (50% of evaluable patients, n = 37) into the study with the cut-off date of November 5, 2024. These results included:
- Overall response: 86.5%
- Complete response: 73%
- Partial response: 13.5%
- Disease recurrence: 10.8%
- Progression of disease: 2.7%
From a safety standpoint, the most frequent adverse events (Grade 1-2) resolved within a few days and included: hematuria (14%), flank pain (10%), procedural pain (6.4%), dysuria (5.2%), UTI (5.2%), abdominal pain (4.7%), vomiting (4.7%), fatigue (4%), and nausea (3.5%). There were 16 (9.2%) grade 3 serious adverse events reported, and grade 3 events related to the VTP treatment were renal colic and flank pain, which resolved within 2 days.
Dr. Margulis concluded his presentation discussing interim results of efficacy and safety from the ENLIGHTED phase 3 study with the following take home points:
- Padeliporfin VTP treatment has demonstrated evidence of efficacy:
- Overall response: 86.5%
- Complete response: 73%
- Partial response: 13.5%
- Padeliporfin VTP treatment has demonstrated an acceptable safety profile
- Recruitment in the ENLIGHTED trial continues, with long term results expected to provide the basis for approval
Presented by: Vitaly Margulis, MD, UT Southwestern Medical Center, Dallas, TX
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.