Combination treatment with disitamab vedotin (DV) plus the anti-PD-1 inhibitor toripalimab has demonstrated promising efficacy and acceptable safety in patients with muscle-invasive bladder cancer (MIBC) with HER2 expression. These findings come from the updated results of the phase 2 RC48-C017 trial (NCT05297552), presented at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium. The study evaluated neoadjuvant DV plus perioperative toripalimab in patients with MIBC with HER2 expression.
Trial Design and Patient Population
The single-arm phase 2 RC48-C017 trial enrolled patients with histologically confirmed urothelial carcinoma, MIBC at stage cT2-T4a, N0-1, and M0, eligibility for radical cystectomy plus pelvic lymph node dissection, and HER2 expression. Patients received DV 2 mg/kg plus toripalimab 3 mg/kg once every 2 weeks followed by radical cystectomy and adjuvant toripalimab 3 mg/kg once every 2 weeks for 20 cycles. The primary endpoint was pathologic complete response (pCR) rate, defined as ypT0N0. Secondary endpoints included pathological response rate (ypT1N0M0 or lower), event-free survival (EFS), overall survival (OS), and adverse events (AEs).
Efficacy Outcomes
Of the 63 patients screened, 47 were enrolled and received neoadjuvant treatment. Thirty-three patients underwent radical cystectomy, while 14 did not. Sixteen patients received adjuvant treatment, and 17 did not. The median age was 64.0 years (range, 30-82 years), with most patients being male (72.3%). HER2 expression was IHC 1+ in 10.6% of patients, 2+ in 57.4%, and 3+ in 31.9%. PD-L1 expression was negative in 53.2% of patients, positive in 27.7%, and not available in 19.1%.
The median time from the end of neoadjuvant treatment to radical cystectomy was 5.0 weeks (range, 2.6-13.1 weeks). In the 33 patients who underwent radical cystectomy, pCR was observed in 21 (63.6%) patients (95% CI, 45.1-79.6), and pathological response was seen in 25 (75.8%) patients (95% CI, 57.7-88.9).
Notably, the pCR rate varied based on baseline cTN stage: 85.7% in patients with T2N0 disease, 36.4% in T3N0, 66.7% in T4N0, and 60.0% in TanyN1. The pCR rate in patients with pure urothelial carcinoma was 66.7% compared to 55.6% in those with urothelial carcinoma with other differentiations or variants.
Survival Analysis
With a median follow-up of 14.1 months, the median EFS was not reached. The 12-month EFS rate was 92.5% (95% CI, 72.8-98.1), and the 18-month EFS rate was 85.9% (95% CI, 60.5-95.5). In the intent-to-treat (ITT) population, median EFS was not reached at a median follow-up of 15.6 months. The 12-month EFS rate was 90.5% (95% CI, 76.6-96.4), and the 18-month EFS rate was 82.7% (95% CI, 64.4-92.1).
Median OS in the ITT population was not reached at a median follow-up of 17.9 months. The 12-month OS rate was 95.5% (95% CI, 83.3-98.9).
Safety Profile
All 47 patients in the ITT population experienced treatment-emergent AEs (TEAEs), with grade 3 or higher TEAEs occurring in 27.7% of patients. Serious TEAEs were reported in 23.4% of patients. Treatment-related AEs (TRAEs) occurred in 97.9% of patients, with grade 3 or higher TRAEs in 21.3%. Serious TRAEs occurred in 12.8% of patients. The most common TEAEs included alopecia, increased aspartate aminotransferase, and increased alanine aminotransferase.
Postoperative complications (Clavien Dindo I, II, IIIa, and IIIb) were observed in 24.2%, 15.2%, 3.0%, and 3.0% of patients undergoing radical cystectomy, respectively. Other complications included postoperative pain, stoma site infection, clotting disorder, pyrexia, pneumonia, intestinal obstruction, urinary tract infection, hydronephrosis, and septic shock.
Expert Commentary
According to Dr. Xinan Sheng, of the Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, China, "Neoadjuvant DV combined with toripalimab did not delay radical surgery. The safety profile was manageable, with no new safety signals. The results [indicate] that neoadjuvant DV combined with toripalimab had promising efficacy and acceptable safety in patients with HER2-expressing MIBC."
