Disitamab vedotin plus toripalimab shows early efficacy in HER2-positive MIBC

Disitamab vedotin is a novel humanized anti-HER2 antibody-drug conjugate that previously demonstrated encouraging anti-tumor activity in combination with toripalimab in patients with metastatic urothelial carcinoma.

Data from a phase 2 study (NCT05297552; RC48-C017) presented at the 2024 ASCO Annual Meeting showed tolerability and preliminary efficacy with neoadjuvant disitamab vedotin plus toripalimab in patients with operable HER2-positive muscle-invasive bladder cancer (MIBC).¹

Disitamab vedotin is a novel humanized anti-HER2 antibody-drug conjugate that previously demonstrated encouraging anti-tumor activity in combination with toripalimab in patients with metastatic urothelial carcinoma. The current phase 2 study sought to assess the combination in patients with HER2-positive MIBC.

Overall, 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%). At 12 months, the event-free survival (EFS) rate was 85% (95% CI, 64%-94%). The median follow-up for EFS was 5.4 months, but both EFS and overall survival (OS) data were not yet mature at the time of data report.

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%). TREAs were generally grade 1 or 2. In total, 14.9% of patients experienced a TRAE of grade 3 or 4. No deaths occurred during the neoadjuvant phase and no TRAEs led to the cancellation of surgery.

In total, 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. Further, 10.6%, 57.4%, and 31.9% of patients had HER2 expression of immunochemistry 1+, 2+, or 3+, respectively. The median age of participants in the study was 64 years.

Patients were eligible for the trial if they had previously untreated MIBC (cT2-T4a, N0-1, M0), were set to undergo radical cystectomy with pelvic lymph node dissection with curative intent, and had HER2 expression of immunochemistry 1+ or greater. Those included in the study received neoadjuvant treatment 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. Patients will then receive adjuvant treatment of 3 mg/kg of toripalimab dosed once every 2 weeks for 20 cycles.

The primary end point for the trial is the pathological complete response rate. The trial’s secondary end points are the rate of pathologic partial response, the 1-year disease-free survival rate, the objective response rate, and OS.²

As of the data cutoff in February 2024, 45 patients had completed neoadjuvant treatment and 29 patients (65.9%) in the study had received radical cystectomy with pelvic lymph node dissection. Overall, 78.7% of patients in the trial had completed all 6 treatment cycles, 6.4% had received 6 incompleted cycles, and 14.9% had received fewer than 6 cycles.

Final study completion is expected for February 2025.²

References

1. Sheng X, Yang K, Ji Y, et al. Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle invasive bladder cancer (MIBC) with HER2 expression. J Clin Oncol. 2024;42 (suppl 16). https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4568

2. A study of RC48-ADC combined with JS001 for perioperative treatment of muscle-invasive bladder cancer. ClinicalTrials.gov. Last updated February 20, 2024. Accessed June 13, 2024. https://clinicaltrials.gov/study/NCT05297552