(UroToday.com) The American Urological Association's 2026 Annual Meeting, in Washington D.C., was host to the Clinical Trials in Progress: Bladder Cancer Session. Dr. Jonathan Coleman presented the trial in progress ENLIGHTED Phase 3 Trial of Non-Thermal, Drug-Activated Padeliporfin Vascular-Targeted Photodynamic Therapy (VTP) for Low-Grade Upper Tract Urothelial Carcinoma (LG UTUC).
Dr. Coleman began by highlighting that upper tract urothelial carcinoma (UTUC) remains a rare but challenging disease, with approximately 7,000–8,000 new cases diagnosed annually in the United States. He noted that established risk factors include smoking, environmental toxin exposure, and hereditary cancer syndromes such as Lynch and Lynch-like syndromes. Importantly, many patients also present with significant comorbidities, particularly chronic kidney disease, which often complicates treatment selection.
He explained that current guidelines favor conservative kidney-preserving approaches whenever possible. Endoscopic management generally consists of tumor ablation with or without adjuvant topical endoluminal therapy. However, existing treatment approaches remain invasive, can be associated with significant toxicity, and have shown only modest efficacy, underscoring the need for better therapeutic options in UTUC.
The Endoluminal LIGHT ActivatED (ENLIGHTED) trial is a global pivotal phase III trial, a single-arm, open-label study conducted at 22 sites across the USA, France, Spain, Germany, Austria, and Israel. The planned enrollment is 100 patients, with the current analysis including 79 evaluable participants. Padeliporfin VTP is an IV-administered, photosensitizer-based combination therapy paired with a laser light delivery system that emits near-infrared light at 753 nm through an optic fiber to precisely target lesions in the upper tract urothelium.
Dr Coleman highlighted that 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 endpoint of ENLIGHTED is the absence of upper tract urothelial tumors in the ipsilateral kidney and ureter during the primary response evaluation 30 days after up to three treatments in the padeliporfin VTP induction phase. A complete response is defined by all of the following:
- Absence of visual tumor on endoscopy
- No evidence of tumor on biopsy, when feasible
- Negative urinary cytology obtained via instrumental collection
Progression of disease was defined as:
- New High-Grade biopsy or cytology
- More than 2 sites of Low-Grade recurrence (By protocol amended definition)
Key inclusion criteria are summarized below:
- New or recurrent low-grade, non-invasive upper tract urothelial carcinoma
- Up to two biopsy-confirmed low-grade tumor lesions
- Lesion size 5–15 mm in the kidney or 5–20 mm in the ureter (endoscopically measured) on the ipsilateral side
- No high-grade cells detected on instrumental cytology
Key exclusion criteria:
- Current high-grade or muscle-invasive (>pT1) urothelial carcinoma of the bladder
- Current or prior CIS in the upper urinary tract
- History of invasive T2 or higher urothelial cancer within the past 2 years
- Photosensitive skin disorders or porphyria
The ENLIGHTED induction and maintenance treatment schema is shown in the figures below.
The interim analysis, predefined in the protocol, was performed mid-way, with 50% of evaluable patients (n=37). As of the November 5, 2024, cutoff, the key findings were:
- Complete response: 73%
- Partial response: 13.5%
- Disease recurrence: 10.8%
- Disease progression: 2.7%
As of the April 20, 2026, data cut-off, 82 patients had been treated, and 72 had completed primary response evaluation. Dr. Coleman reported an overall response rate of 88%, including a complete response rate of 70% and a partial response rate of 18%. Disease recurrence was observed in 8% of patients, while progression of disease occurred in 4%.
Notably, from a safety standpoint, most treatment-emergent adverse events were grade 1–2 and transient, with a median duration of 5 days. The most commonly reported adverse events included hematuria (10.7%), flank pain (6.6%), nausea (5%), dysuria (3.5%), fatigue (2.8%), procedural pain (2.8%), vomiting (2.8%), abdominal pain (2.5%), and urinary tract infection (2.2%).
A total of 29 serious adverse events were reported in 19 patients, the majority of which were considered unrelated to treatment. Importantly, only two grade 3 treatment-related serious adverse events were observed, consisting of one case of renal colic and one case of flank pain, both of which resolved within 2 days.
Dr. Coleman concluded his presentation with the following key takeaways:
- Padeliporfin vascular-targeted photodynamic (VTP) therapy demonstrated preliminary evidence of efficacy for regional tumor ablation within the upper urinary tract, with encouraging durability at treated sites
- The treatment was associated with an acceptable safety profile, with most adverse events being low grade and transient
- Enrollment in the ENLIGHTED trial is nearing completion, with long-term follow-up expected to further define durability and support potential future regulatory approval
Presented by: Jonathan Coleman, MD, Professor, Department of Surgery and Urology, Memorial Sloan Kettering Cancer Center, New York, NY
Written by: Julian Chavarriaga, MD, Clinical Assistant Professor, Urologic Oncologist, Department of Urology at Penn State Health @chavarriagaj on Twitter during the American Urological Association (AUA) 2026 Annual Meeting, Washington, DC, Fri, May 15 – Mon, May 18, 2026.