Efficacy and safety of disitamab vedotin (RC48) combined with toripalimab as adjuvant therapy after radical surgery for patients with HER2-overexpression upper tract urothelial cancer (UTUC): A single-arm, prospective, phase 2 clinical trial.

4590 Background: UTUC is rare and highly aggressive. The prognosis is poor, especially for high-risk patients, even after radical surgery. Adjuvant chemotherapy is the standard therapy, but with limited efficacy, indicating a need for more effective regimens. RC48, an anti-HER2 antibody-drug conjugate, combined with toripalimab, an anti-PD-1 monoclonal antibody, has shown promising results in locally advanced or metastatic urothelial carcinoma (C014 trial). We evaluate the efficacy and safety of RC48 combined with toripalimab as adjuvant therapy for patients with HER2 IHC 2+/3+ UTUC after radical surgery. Methods: This is a single-arm, prospective, phase 2 clinical trial (NCT05917158). Eligible criteria were patients with histologically confirmed HER2 IHC 2+/3+ UTUC after radical surgery and were staged as T2-4NanyM0 or TanyN1-2M0, with no prior neoadjuvant therapy. The intervention was intravenous RC48 (2 mg/kg) combined with toripalimab (3 mg/kg) triweekly for 6 cycles, followed by toripalimab (3 mg/kg) triweekly for up to 1 year. The primary endpoint was DFS, and the secondary endpoints were OS, safety, and MRD analysis. Results: 45 patients (35 males [77.8%], median age 68 years [IQR 58-71]) were enrolled. The patients were staged as: 43 (95.6%) in II, 1 (2.2%) in III, and 1 (2.2%) in IV. All patients were HER2-overexpression (80% in IHC 2+, 20% in IHC 3+). 25 patients (55.6%) met cisplatin-ineligibility. By the data cutoff date on January 14, 2025, the median follow-up time was 12.2 months (IQR 6.7-17.6). 4 relapses occurred: 2 in lymph nodes, 1 in the prostate, and 1 in lymph nodes and the bladder. The 1-year DFS rate was 90.0%, and the median DFS has not been reached. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were hypoesthesia (51.1%), increased blood glucose (48.9%), anemia (46.7%), increased creatinine (46.7%), and hypertriglyceridemia (46.7%). TRAEs of grade ≥3 occurred in 20% of patients. 8.9% of patients experienced immune-related adverse events, including rash and hypothyroidism. Among the patients, 16 (35.6%) completed treatment, 19 (42.2%) were still undergoing intervention, 4 (8.9%) discontinued therapy due to TRAEs: 1 with hypoesthesia, 1 with lymphocytopenia and hypoesthesia, 1 with nausea, vomiting, and decreased appetite, and 1 with pruritus and diarrhea, and 2 withdrew after completing 4 cycles of combined regimen due to personal reasons. No deaths occurred during the follow-up period. Conclusions: This is the first prospective clinical trial evaluating the efficacy and safety of the new adjuvant regimen for patients with HER2-IHC 2+/3+ UTUC. It showed promising DFS outcomes and a manageable safety profile, highlighting its potential as a new adjuvant therapy in patients with HER2-IHC 2+/3+ UTUC. Clinical trial information: NCT05917158 .