Neoadjuvant tislelizumab combined with disitamab vedotin (RC48) for patients with Her-2 expressing upper tract urothelial carcinoma: A pilot study.

e16588 Background: Cisplatin-based chemotherapy is regarded as the standard treatment for the neoadjuvant therapy of upper urinary tract urothelial carcinoma (UTUC). However, its unsatisfactory efficacy and nephrotoxicity limit its further application. Several clinical trials have demonstrated the efficacy of the combination of Tislelizumab, a type of anti-PD-1 immune checkpoint inhibitors (ICIs), and Disitamab Vedotin (RC48), a kind of anti-HER-2 antibody-drug conjugate (ADC), in advanced urothelial carcinoma. However, evidence of this regimen in the set of neoadjuvant treatments for localized UTUC is still lacking. Herein, we report the results of a pilot study evaluating the efficacy and safety of neoadjuvant Tislelizumab combined with RC48 for patients (pts) with Her-2 expressing UTUC. Methods: In this study, pts with Her-2 expressing (Her-2 expression was 1+/2+/3+ at baseline pathological specimen) cT1-4N0-2M0 UTUC were enrolled and received 3 cycles of neoadjuvant RC48 2.0mg/kg and Tislelizumab 200mg intravenously on days 1, Q3W, followed by radical nephroureterectomy (RNU) , segmental ureterectomy (SU) or endoscopic laser ablation (ELA). Pts refusing or ineligible for RNU underwent SU or ELA, determined by patients' tolerance for surgery. The primary endpoint is clinical complete response (cCR, defined with negative CTU, negative urine cytology and no residual lesions found in the pathological specimen in evaluation surgery, including RNU, SU, and ureteroscopy before ELA). Secondary endpoints include overall survival (OS) and relapse-free survival (RFS). Treatment-related adverse events (TRAEs) are evaluated according to CTCAE v5.0. Results: 15 pts were enrolled, comprising males (80%), with a median age of 71 years (IQR 64-74). Baseline Her-2 expression was 1+ in 3 (20%) pts, 2+ in 9 (60%) pts, and 3+ in 2 (20%) pts. 12 in 15 pts have received 3 cycles of treatment, then completed evaluations and surgical interventions, while RNU, SU, and ELA were performed in 5 (42%), 5 (42%), and 2 (16%) pts, respectively. 3 pts withdrew from the study for personal request. 3 (25%) pts achieved cCR, distributed among different HER-2 expression groups: 1 (33%) in group HER-2 1+, 1 (17%) in group HER-2 2+, and 1 (33%) in group HER-2 3+. The median follow-up time was 117 days as of December 2024, with no death or recurrence reported. The TRAEs of any grade with the highest incidence were fatigue (33.3%), peripheral sensory neuropathy (20.0%) and alopecia (13.3%). Only 1 (10.5%) pts experienced grade 3 TRAEs, including fatigue and alanine aminotransferase increase. Conclusions: This pilot study indicated that neoadjuvant Tislelizumab combined with RC48 demonstrates promising efficacy and a manageable safety profile in pts with HER-2 expressing UTUC. The effect of HER-2 expression in UTUC on the efficacy of this regimen needs further exploration. Clinical trial information: NCT05837806 .