Padeliporfin VTP Therapy Yields Complete Responses With Manageable Safety in Low-Grade, Upper Tract Urothelial Cancer

Upper Tract Urothelial Cancer
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Treatment with padeliporfin vascular targeted photodynamic (VTP) therapy showcased a safety profile that was consistent with prior findings and elicited complete responses (CRs) in patients with low-grade, upper tract urothelial cancer, according to data from the ongoing phase 3 ENLIGHTED trial (NCT04620239) presented at the 2025 American Urological Association Annual Meeting.1

Findings showed that among evaluable patients who underwent response evaluation at their second visit (n = 33), only one patient (3%) did not achieve a response; this patient had stable disease. Among responders (n = 32), the CR rate was 78.8%, and the partial response (PR) rate was 18.2%.

Regarding safety (n = 44), the most common grade 1/2 adverse effects (AEs) included hematuria (14%), flank pain (10%), procedural pain (6.4%), dysuria (5.2%), urinary tract infection (4.7%), abdominal pain (4.7%), vomiting (4.7%), fatigue (4%), and nausea (3.5%).

Grade 3 or higher serious AEs were reported in 9.2% of patients (n = 16). Grade 3 renal colic and flank pain were each reported in 1 patient and considered serious treatment-related AEs. All AEs were resolved within 2 to 7 days.

“To date, padeliporfin VTP has demonstrated efficacy and safety aligned with previous findings. Recruitment in [the] ENLIGHTED trial is ongoing, with results anticipated to support the approval of a new therapy offering clinical benefits and organ-sparing alternative for patients,” lead study author Vitaly Margulis, MD, and colleagues, wrote in a poster presentation of the data.

Margulis is a professor of urology and the Paul C. Peters, MD, Chair in Urology at the Harold C. Simmons Comprehensive Cancer Center of the University of Texas Southwestern Medical Center in Dallas.

An ENLIGHTED Trial Overview

The ongoing phase 3 study is evaluating padeliporfin TVP therapy, which comprises the intravenous administration of padeliporfin before a laser system delivers near-infrared light at 753 nm via an optic fiber directly to the target lesion or lesions.

In the open-label, single-arm study, investigators are enrolling patients at least 18 years of age with newly diagnosed or recurrent low-grade, non-invasive upper tract urothelial cancer.1,2 Patients are allowed to have up to 2 biopsy-proven tumor lesions of low-grade involvement, with the largest index tumor 5 mm to 15 mm in diameter and located in the calyces, renal pelvis, or the ureter of the ipsilateral kidney.1 High-grade cells must be absent on cytology. Other key inclusion criteria comprise a Karnofsky performance score of at least 50% and adequate organ function.2

Key exclusion criteria include current high-grade or muscle-invasive urothelial carcinoma of the bladder; current carcinoma in situ (CIS) or previous CIS in the upper urinary tract; and a history of invasive T2 or higher urothelial cancer within 2 years of enrollment.1 Notably, patients receiving other medications that cannot be adjusted or discontinued prior to study treatment are also excluded, along with those with photosensitive skin diseases or porphyria.

Patients are receiving the first administration of padeliporfin TVP therapy at their first visit within a maximum of 4 weeks of screening. Patients are then undergoing tumor assessment; those with no tumor or non-treatable tumors proceed to the maintenance phase, and those with visible and treatable tumors are undergoing a second course of padeliporfin TVP therapy. Patients without visible or treatable tumors after the second padeliporfin TVP therapy administration are also proceeding to the maintenance phase, and those with visible and treatable tumors remaining are receiving a third course of treatment. During induction, the second and third doses of padeliporfin TVP therapy are being administered 28 days (±3 days) apart.2

In the maintenance phase, patients are undergoing tumor evaluation (primary response evaluation), and those without a CR are proceeding to standard-of-care (SOC) therapy.1 Patients who achieve a CR are returning for visits every 3 months, and padeliporfin TVP therapy is allowed to be given up to 3 additional times for lesions arising outside the treated area and 1 additional course for lesions within the treated area. Patients who experience disease recurrence or progression are proceeding to SOC therapy.

Long-term follow-up includes visits at months 18, 24, 36, 48, and 60.

The primary end point of the study is the efficacy and durability of padeliporfin VTP therapy, defined as the absence of upper tract urothelial cancer in the entire ipsilateral calyces, renal pelvis, and ureter on endoscopic evaluation during the primary response evaluation.1,2 Safety/tolerability is a key secondary end point.1 Other secondary end points include duration of response, overall renal function, pathologic response rate, and the proportion of patients experiencing a ureteral obstruction and/or requiring a ureteral stent.2

Investigators plan to enroll 100 patients at 27 sites in the United States, European Union, and Israel.1

References

1. Margulis V, Kaufman R, Marcq G, et al. ENLIGHTED phase 3 study: efficacy and safety of padeliporfin vascular targeted photodynamic therapy (VTP) for treatment of low-grade upper tract urothelial cancer (LG UTUC). Presented at: 2025 American Urological Association Annual Meeting; April 26-29, 2025; Las Vegas, NV. Abstract IP12-14.
2. Endoluminal light activated treatment of upper tract urothelial cancer (ENLIGHTED) study (UCM301). ClinicalTrials.gov. Updated February 7, 2025. Accessed April 29, 2025. https://www.clinicaltrials.gov/study/NCT04620239