Disitamab Vedotin and Toripalimab for HER2-positive Muscle-invasive Bladder Cancer

In treating HER2-positive muscle-invasive bladder cancer, the combination of disitamab vedotin and perioperative toripalimab represents an important advance. A phase 2 study presented at the 2025 ASCO Genitourinary Cancers Symposium highlighted its effectiveness.

HER2 Positivity in Bladder Cancer

On January 27, 2025, Biol Proced Online published an article reporting that among patients with muscle-invasive bladder cancer (MIBC), HER2 positivity was 57.6% (IHC 2+ or 3+). Of 217 patients, 125 were HER2-positive.

HER2 positivity indicates abundant HER2 receptors on bladder cancer cells, helping them grow and spread. HER2 (Human Epidermal Growth Factor Receptor 2) normally regulates cell growth and division, but overexpression in cancer cells can drive uncontrolled growth and progression.

How Does Disitamab Vedotin Work?

Disitamab vedotin is a HER2-targeted antibody-drug conjugate (ADC). It contains an antibody specific to HER2 overexpressed on cancer cells. After binding the cell-surface HER2 receptor, it is internalized and releases its conjugated cytotoxic agent, or chemotherapy. The payload targets the microtubule network, blocking cell division and causing cell death.

How Does Toripalimab Work?

Toripalimab is an immune checkpoint inhibitor , a monoclonal antibody binding PD-1 (Programmed Death-1). PD-1 suppresses the immune system's ability, particularly that of T cells, to respond to abnormal cells such as cancer. By binding PD-1, toripalimab blocks this inhibition and allows T cells to attack cancer cells. 

Updated RC48-C017 Study Details

The Chinese study included patients with HER2-positive (IHC 2+ and 3+) MIBC considered suitable for radical cystectomy and pelvic lymph node dissection.

Before surgery, patients received 6 cycles of disitamab vedotin 2 mg/kg and toripalimab 3 mg/kg every two weeks. After surgery, toripalimab 3 mg/kg was given for up to 20 cycles.

The 47 participants had a median age of 64, range 30-82, and 72.3% were male. Most had pure urothelial carcinoma (76.6%), while 27.7% had PD-L1-positive disease.

Of the 33 patients undergoing surgery, 16 received adjuvant treatment. Postoperative complications occurred in 45.5%, most commonly stoma-site infections (15.2%) and postoperative pain (12.1%).

Pathological complete response was 63.6%, while the pathological response rate was 75.8%.

Among surgical patients, median event-free survival was not reached; 12-month event-free survival was 92.5% and the 18-month rate was 85.9%. Their 12-month overall survival was 95.5%.

Neoadjuvant treatment-related adverse events were recorded in all patients, and 27.7% experienced grade 3 or higher adverse events. The treatment-related adverse-event rate was 97.9%, with grade 3 or higher treatment-related events in 21.3%. Common events included alopecia (42.6%), elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), asthenia, hypertriglyceridemia, and weight loss.

These results suggest neoadjuvant disitamab vedotin plus perioperative toripalimab provides promising activity and an acceptable safety profile in HER2-positive MIBC. The findings offer a potentially effective approach to muscle-invasive bladder cancer and represent an important step in addressing this difficult disease.