TPS4643 Background: Padeliporfin VTP is a drug-led combination therapy consisting of IV Padeliporfin activated by a low-power near-infrared (753 nm) laser–fiber system. A non-contact cylindrical fiber positioned near the tumor provides circumferential illumination, inducing vascular occlusion and coagulative tumor necrosis while preserving tissue structure. Safety and efficacy were shown in a Phase 1 UTUC study (NCT03617003). We report emerging efficacy, durability, and safety from the ENLIGHTED Phase 3 trial in LG UTUC (NCT04620239). Methods: ENLIGHTED is an open-label Phase 3 study conducted in the US, EU, and Israel, evaluating the efficacy, durability, and safety of padeliporfin VTP in LG UTUC. Eligible patients (pts) may have new or recurrent disease, be treatment-naïve or previously treated, and have up to two biopsy-confirmed LG lesions (5–15 mm kidney or 5–20 mm ureter) without high-grade cells on instrumented cytology. VTP is performed via retrograde upper tract endoscopy under anesthesia and low-light conditions. Padeliporfin is administered IV, and an optical fiber with a 20–40 mm diffuser is positioned near the tumor through the scope, followed by 10 minutes of laser illumination. Treatment consists of an Induction Treatment Phase (ITP) of 1–3 VTP sessions at 4-week intervals until complete response (CR) or treatment failure at Primary Response Evaluation (PRE). Pts achieving CR enter a 12-month Maintenance Treatment Phase (MTP) with quarterly endoscopic surveillance and retreatment for treatable recurrences, followed by long-term follow-up up to 48 months. The primary endpoint is CR at PRE (28 ± 3 days post last ITP treatment), defined by absence of visible tumor on endoscopy and negative instrumented cytology. A total of 100 pts are to be enrolled. As of January 19, 2026, 78 pts were enrolled and 63 completed ITP. Response rates were: CR 73.0%, PR 17.7%, DR 3.2%, PD 4.8%, and stable disease 1.6%. Among pts with CR at PRE, 39.5% had completed MTP by data cutoff, with 88.2% maintaining CR in the treated area (TA) for ≥12 mos. Median Duration of Response in the TA was not reached and is ≥23.9 mos. Most pts remains in MTP or follow-up. The most common treatment-emergent adverse events were hematuria (10.6%), flank pain (8.6%), nausea (5.5%), procedural pain (4.5%), abdominal pain (4.1%), dysuria (4.1%), vomiting (3.4%), and fatigue (3.1%), all Grade 1–2 with a median duration of 5 days. 23 serious adverse events (7.7%) were reported, mostly unrelated to treatment. One Grade 3 SAE (renal colic related to VTP) resolved within 2 days. Padeliporfin VTP demonstrates favorable preliminary efficacy, durable responses, and a safety profile consistent with prior experience. Enrollment is ongoing, and final outcomes are anticipated to support regulatory approval of an organ-preserving therapy for LG UTUC. Clinical trial information: NCT04620239 .
Margulis et al. (Thu,) studied this question.