Is Treatment Possible Without Losing the Kidney? 70% Complete Response With Padeliporfin VTP in Low-Grade Upper Tract Urothelial Cancer in the ENLIGHTED Phase 3 Trial

KEY FINDINGS

• Trial: ENLIGHTED / UCM301 (NCT04620239) - a single-arm, non-randomized, open-label, pivotal phase 3 trial; 29 centres in the United States, Europe and Israel, with a target of 100 patients.
• Treatment: Intravenous padeliporfin (3.66 mg/kg) followed by 10 minutes of near-infrared laser illumination through an optical fibre positioned adjacent to the tumour under ureteroscopic guidance. A non-thermal, drug-activated ablation method.
• Data cut-off (20 April 2026): 82 patients started treatment; 72 completed the primary response evaluation (PRE) and were considered evaluable for efficacy.
• Complete response (primary endpoint): 70% (50/72).
• Overall response rate: 88% - with an additional 13 patients (18%) achieving a partial response.
• Durability: In 85.7% (18/21) of patients who completed the maintenance treatment phase (MTP), the complete response in the treated field was maintained for at least 12 months.
• Median duration of response: 23.9 months in the treated field; responses are ongoing.
• Safety: The majority of adverse events were mild to moderate and largely related to the ureteroscopic procedure. Two patients experienced a treatment-related grade 3 serious adverse event, both resolving within two days. No adverse event led to treatment discontinuation.
• Regulatory: The FDA granted Fast Track designation to padeliporfin ImPACT therapy in the indication of low-grade, unifocal UTUC. Topline data are expected at the end of 2026 and a regulatory submission in 2027.

Background: One of the Costliest Decisions in Uro-Oncology

Upper tract urothelial carcinoma (UTUC) accounts for approximately 5-10% of all urothelial tumours and is a relatively rare but disproportionately difficult disease to manage. The difficulty stems less from the biology of the disease than from its anatomy: the renal collecting system and ureter form a narrow, tortuous space far less amenable to instrumentation than the bladder.

The consequence is this: a low-grade, non-invasive tumour - a disease whose biological behaviour could be considered indolent - is in most cases treated with radical nephroureterectomy, that is, complete removal of the kidney, ureter and bladder cuff. While oncologically highly effective, this operation exacts a permanent cost from the patient: life with a single kidney, an average 25-35% loss in glomerular filtration rate, an increased risk of chronic kidney disease and the loss of cisplatin eligibility should systemic chemotherapy become necessary in future.

Endoscopic ablation (laser, electrocautery) offers a kidney-sparing alternative; however, high recurrence rates and the need for repeated ureteroscopy limit the acceptability of this approach. The approval of a mitomycin-containing reverse thermal gel (UGN-101) introduced the concept of pharmacological kidney-sparing treatment, but local toxicities such as ureteral stricture have drawn attention. The clinical need is clear: a local treatment that preserves the kidney, can be repeated, has low toxicity and provides a durable response.

Padeliporfin VTP: The Rationale of the Method

Padeliporfin (Tookad) is a water-soluble bacteriochlorophyll-derived photosensitizer that has been used in Europe since 2017 for focal therapy in low-risk prostate cancer. The ENLIGHTED trial carries the same platform into the upper urinary tract.

Administration consists of the following steps:

1. Intravenous administration. Padeliporfin is given intravenously and remains in the circulation; it does not enter cells to any meaningful extent.
2. Endoluminal illumination. Under retrograde ureteroscopy, an optical fibre with a 20-40 mm diffuser is positioned adjacent to the tumour and near-infrared laser light is applied for 10 minutes. The procedure is performed under anaesthesia and in low-light conditions.
3. Vascular-targeted ablation. Light activation triggers the formation of reactive oxygen species in the region where the drug is present; the microvascular bed feeding the tumour is selectively occluded and the tumour undergoes necrosis.

The distinguishing feature of the method is that it is non-thermal. Because no heat is generated, the risk of thermal injury to the ureteral wall leading to stricture is theoretically reduced - and indeed, no long-term ureteral stricture has been reported in early analyses. This is a design choice that directly targets the most critical technical constraint on kidney-sparing approaches in UTUC.

Study Design

ENLIGHTED is a single-arm pivotal phase 3 trial conducted in patients with newly diagnosed or recurrent, low-grade, non-invasive UTUC. The trial comprises two phases:

• Induction Treatment Phase (ITP): VTP administered at four-week intervals until a complete response is achieved, up to a maximum of three times.
• Maintenance Treatment Phase (MTP): VTP every three months for up to 12 months, alongside standard of care.

The primary endpoint is the response rate at the end of the induction phase; complete response is defined as the absence of tumour in the ipsilateral kidney and ureter at the time of primary response evaluation. Secondary endpoints are safety, tolerability, duration of response, renal function and kidney loss/preservation.

Key Results

Distribution of Responses

Durability

The most meaningful contribution of this update is the maturation of data on the duration of response. In 18 of the 21 patients (85.7%) who completed the maintenance treatment phase, the complete response in the treated field was maintained for at least 12 months; patients still in the maintenance phase who have not yet completed the 12-month assessment period are excluded from this analysis. Based on the current follow-up, the median duration of response in the treated field has been calculated as 23.9 months, with ongoing responses observed.

This figure directly contradicts the expectation of "early and frequent recurrence" that has historically been the weak point of kidney-sparing approaches in low-grade UTUC, and is clinically noteworthy.

Safety

The great majority of treatment-emergent adverse events (TEAEs) were mild or moderate, related mainly to the ureteroscopic procedure itself, and resolved within a few days. In early-phase analyses the most frequently reported events were haematuria (14%), flank pain (10%), procedural pain (6.4%), dysuria (5.2%), urinary tract infection (5.2%), abdominal pain (4.7%), vomiting (4.7%), fatigue (4%) and nausea (3.5%).

At the current data cut-off, a grade 3 serious adverse event related to VTP treatment occurred in two patients, both resolving within two days (renal colic and flank pain). No adverse events of special interest were reported and no adverse event led to discontinuation of study treatment.

"Photodynamic therapy appears effective in this patient group. The safety profile was excellent and I believe we have another tool that allows patients to preserve their renal function and their organ."
- Vitaly Margulis, MD, Professor of Uro-Oncology, UT Southwestern Medical Center (ENLIGHTED presentation)

Implications for Clinical Practice

1. Extending the nephron-sparing paradigm to the upper urinary tract

The replacement of radical nephrectomy by partial nephrectomy in renal cell carcinoma was one of the most important gains in uro-oncology over the past three decades. In upper tract urothelial cancer, a comparable transformation has not yet taken place. The ENLIGHTED data show that this transformation may be technically possible in low-grade disease. A 70% complete response and a 23.9-month median duration of response mean that nephroureterectomy may be deferred, or avoided altogether, in selected patients.

2. Patient selection is decisive

The eligibility criteria of the trial were kept narrow: at most two lesions, limited size, biopsy-proven low grade and no high-grade cells on cytology. This makes clear that the method is not applicable to everyone. In high-grade or invasive disease, radical surgery remains the standard. Discussing this distinction clearly with the patient is a precondition for creating realistic expectations.

3. Particular value in patients with a solitary kidney or chronic kidney disease

In patients with a solitary kidney, bilateral disease or limited baseline renal function, nephroureterectomy may mean dialysis. In this subgroup, the availability of a kidney-sparing treatment option is a factor that changes the treatment decision entirely.

4. The urologist's skill set does not change, it expands

VTP is built on existing retrograde ureteroscopy infrastructure. It requires not separate surgical training but additional competence in fibre placement, illumination geometry and photosensitivity management. Its feasibility is high in centres with a substantial robotic and endoscopic surgical volume.

5. From the perspective of the patient's psychological burden

The sentence "we need to remove your kidney" fundamentally changes how a patient positions the disease within their own body. For a low-grade, slow-growing tumour, losing an organ is a cost that patients often find disproportionate and struggle to accept for a long time. Being able to put a kidney-sparing option on the table shifts the treatment process from an axis of "loss" to one of "control". At the same time, the physician's responsibility is to present this option not as a promise of hope but as a treatment with defined criteria and limits.

A practical note. Padeliporfin is a photosensitizing agent. Light exposure precautions after administration, performing the procedure under low-light conditions and informing patients in detail on this subject are integral parts of the treatment protocol. Patients with a history of photosensitive skin disease or porphyria were excluded from the trial.

Limitations

ENLIGHTED is a single-arm, non-randomized trial; in the absence of a concurrent control group, the results cannot be directly compared with endoscopic laser ablation, UGN-101 or radical nephroureterectomy. The number of patients is limited (82 treated and 72 evaluable as of 20 April 2026) and the trial is still ongoing.

The durability data are not yet mature: the 12-month maintained response rate was calculated on only the 21 patients who completed the maintenance phase. This is a favourable rate but rests on a narrow base. Furthermore, the most critical secondary endpoint - the kidney preservation rate, that is, how many patients avoid nephroureterectomy in the long term - has not yet been fully reported; the real clinical decision will be shaped by those data.

From a regulatory standpoint the treatment is also not yet approved. The FDA has granted Fast Track designation; topline data are planned for release at the end of 2026 and a regulatory submission in 2027.

Conclusion

Low-grade upper tract urothelial cancer is the clearest example in uro-oncology of a mismatch between treatment intensity and disease aggressiveness: an organ is asked of the patient for a tumour with a favourable biological course. The current data from the ENLIGHTED trial - a 70% complete response, 88% overall response, a 23.9-month median duration of response and a largely procedure-related mild toxicity profile - provide evidence that deserves serious consideration that this mismatch can be closed.

With the interpretative limitations of a single-arm design and a limited patient number duly noted, non-thermal vascular-targeted photodynamic therapy is one of the first methods to address at the design level the most fundamental technical obstacle to kidney-sparing approaches in the upper urinary tract: thermal ureteral injury. The release of topline data and kidney preservation rates will determine the place of this approach in the clinical algorithm.

Important warning. This article is for scientific information purposes and does not replace personal medical advice. Padeliporfin VTP is still investigational in upper tract urothelial cancer and is not an approved treatment in routine clinical use. In upper tract tumours, treatment decisions must be individualised according to tumour grade, stage, size, number of foci, the status of the contralateral kidney and the patient's general health. Always consult your physician regarding treatment decisions.

References

• ImPact Biotech. ImPact Biotech Presents Updated Data from Phase 3 ENLIGHTED Trial of Padeliporfin VTP in LG-UTUC at AUA 2026. GlobeNewswire, 16 May 2026. - globenewswire.com
• BioSpace. ImPact Biotech Presents Updated Data from Phase 3 ENLIGHTED Trial of Padeliporfin VTP in LG-UTUC at AUA 2026. 17 May 2026. - biospace.com
• Margulis V, Kaufman RP, Marcq G, et al. ENLIGHTED phase 3 study: interim results of efficacy and safety of padeliporfin vascular targeted photodynamic therapy (VTP) in the treatment of low-grade upper tract urothelial cancer (LG UTUC). J Clin Oncol. 2025;43(suppl 17):LBA4513. - ascopubs.org
• Margulis V, et al. IP30-04: The ENLIGHTED Phase 3 Trial: Advancing Treatment of Low-Grade Upper Tract Urothelial Carcinoma (LG UTUC) with Padeliporfin Vascular-Targeted Photodynamic Therapy (VTP). Journal of Urology (AUA 2026 Abstracts). - auajournals.org
• UroToday. AUA 2026: ENLIGHTED Phase 3 Trial of Non-Thermal, Drug-Activated Padeliporfin Vascular-Targeted Photodynamic Therapy (VTP) for Low-Grade Upper Tract Urothelial Carcinoma. - urotoday.com
• OncLive. Padeliporfin Vascular Targeted Photodynamic Therapy Safely Produces High Response Rates in Low-Grade Upper Tract Urothelial Cancer. - onclive.com
• OncLive. FDA Grants Fast Track Status to Padeliporfin ImPACT for Upper-Tract Urothelial Cancer. - onclive.com
• ClinicalTrials.gov. ENdoluminal LIGHT ActivatED Treatment of Upper Tract Urothelial Cancer (ENLIGHTED) Study - UCM301, NCT04620239. - clinicaltrials.gov