A phase 2 study presented at the 2024 ASCO Annual Meeting (NCT05297552) reveals promising early efficacy and tolerability of neoadjuvant disitamab vedotin combined with toripalimab in patients with operable HER2-positive muscle-invasive bladder cancer (MIBC). The study, known as RC48-C017, suggests a potential new treatment approach for this aggressive cancer.
Disitamab vedotin is a novel humanized anti-HER2 antibody-drug conjugate that has previously shown encouraging anti-tumor activity in combination with toripalimab in metastatic urothelial carcinoma. This phase 2 study aimed to evaluate the efficacy and safety of this combination in the neoadjuvant setting for HER2-positive MIBC.
Efficacy Outcomes
The study reported a pathological complete response rate of 61.3% (19/31; 95% CI, 42.2%-78.2%) and a pathologic partial response rate of 74.2% (23/31; 95% CI, 55.4%-88.1%). The event-free survival (EFS) rate at 12 months was 85% (95% CI, 64%-94%). The median follow-up for EFS was 5.4 months, and overall survival (OS) data were not yet mature at the time of the report.
Safety Profile
Regarding safety, the most common treatment-related adverse events (TRAEs) were alopecia (38.3%), an increase in alanine aminotransferase (29.8%), an increase in aspartate aminotransferase (29.8%), rash (21.3%), and peripheral sensory neuropathy (21.3%). TRAEs were generally grade 1 or 2. In total, 14.9% of patients experienced a TRAE of grade 3 or 4. Notably, no deaths occurred during the neoadjuvant phase, and no TRAEs led to the cancellation of surgery.
Study Design and Patient Characteristics
The prospective, open-label, single-arm, multicenter study enrolled 47 patients with HER2-positive MIBC across clinical trial sites in China. Among all patients, 40.4% presented with cT2N0 disease, 29.8% had cT3N0 disease, 12.8% had cT4aN0 disease, and 17.0% had cT2-4aN1 disease. HER2 expression levels varied, with 10.6%, 57.4%, and 31.9% of patients having immunochemistry scores of 1+, 2+, or 3+, respectively. The median age of participants was 64 years.
Patients were eligible for the trial if they had previously untreated MIBC (cT2-T4a, N0-1, M0), were scheduled for radical cystectomy with pelvic lymph node dissection with curative intent, and had HER2 expression of immunochemistry 1+ or greater. Participants received neoadjuvant treatment consisting of 2 mg/kg disitamab vedotin plus 3 mg/kg toripalimab every 2 weeks for 6 cycles, followed by radical cystectomy with pelvic lymph node dissection within 4 weeks. Adjuvant treatment consisted of 3 mg/kg of toripalimab dosed once every 2 weeks for 20 cycles.
The primary endpoint of the trial is the pathological complete response rate. Secondary endpoints include the rate of pathologic partial response, the 1-year disease-free survival rate, the objective response rate, and overall survival.
As of the data cutoff in February 2024, 45 patients had completed neoadjuvant treatment, and 29 patients (65.9%) had undergone radical cystectomy with pelvic lymph node dissection. Overall, 78.7% of patients in the trial completed all 6 treatment cycles, 6.4% received 6 incomplete cycles, and 14.9% received fewer than 6 cycles.
Final study completion is expected in February 2025, with further data anticipated to provide a more comprehensive understanding of the long-term benefits of this treatment regimen.
