Endoscopic Thulium Laser Ablation with Disitamab Vedotin and Immunotherapy in High-risk Upper Tract Urothelial Carcinoma: A Prospective Pilot Study of a Novel Kidney-sparing Strategy.

Background and objective: Kidney-sparing treatment (KST) is an emerging alternative to radical nephroureterectomy for selected patients with upper tract urothelial carcinoma (UTUC), particularly those with imperative indications. Our aim was to evaluate the efficacy and safety of a novel KST approach combining endoscopic thulium laser ablation (TLA) with perioperative systemic therapy (disitamab vedotin [DV] and an immune checkpoint inhibitor [ICI]; toripalimab or tislelizumab) in a carefully selected cohort of patients with localized high-risk UTUC.

Methods: This single-center prospective pilot study conducted from June 2021 to February 2024 and enrolled patients with localized high-risk UTUC with HER2 expression. Patients underwent multimodal treatment comprising sequential induction therapy, endoscopic TLA, consolidation therapy, and maintenance therapy. Co-primary endpoints were local recurrence-free survival (LRFS) and conversion-free survival (CFS). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), intravesical recurrence-free survival (IVRFS), renal function benefits, and therapy-related adverse events (TRAEs).

Key findings and limitations: A total of 33 patients were enrolled. Median follow-up was 23 mo for those without death or salvage surgery. LRFS rates were 67% at 1 yr and 64% at 2 yr. HER2 positivity was identified as a candidate protective factor for local recurrence within the first year (odds ratio 0.12, 95% confidence interval 0.01-0.95; p = 0.042). The 2-yr survival rates were 94% for CFS, 88% for IVRFS,100% for MFS, 94% for OS, and 100% for CSS. A renal function benefit was observed within the first year after ablation. The 1-yr ureteral stricture rate was 12% and no grade >3 TRAEs were observed.

Conclusions and clinical implications: The combination of endoscopic TLA with perioperative systemic therapy demonstrated promising efficacy and manageable safety in selected patients with localized high-risk UTUC. Our results suggest that there is potential for a paradigm shift in the management of this challenging patient population.