Disitamab Vedotin/BCG Could Provide a New Bladder Sparing Therapy in HER2-Expressing High-Risk NMIBC

Disitamab Vedotin/BCG in NMIBC | Image Credit:

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Disitamab vedotin (RC48), an antibody-drug conjugate (ADC), plus BCG demonstrated promising complete responses (CR) and event-free survival (EFS) rates with manageable toxicity in patients with HER2-expressing, high-risk non–muscle-invasive bladder cancer (HR-NMIBC), according to data from a small study presented at the 2025 American Urological Association Annual Meeting.1

Among patients who were unable to undergo complete tumor resection or had carcinoma in situ (CIS), the clinical complete response (cCR) rates were both 100% for 11 patients evaluable at 3 months and 5 patients evaluable at 6 months. Further, in the 3 evaluable patients who underwent complete tumor resection, the event-free survival (EFS) rate at 6 months was 100%.

Regarding safety, 65% of patients (n = 13/20) experienced any-grade treatment-related adverse events (TRAEs). These included elevated aspartate aminotransferase/alanine aminotransferase (40%; n = 8), alopecia (45%; n = 9), peripheral sensory neuropathy (35%; n = 7), anorexia (10%; n = 2), and rash (5%; n = 1). BCG-related AEs were experienced by 60% of patients (n = 12) and included bladder irritation, fever, arthralgia, conjunctivitis, and hematuria. Only 2 patients (10%) experienced grade 3 TRAEs: 1 patient had grade 3 peripheral sensory neuropathy related to disitamab vedotin, and 1 patient had grade 3 hematuria related to BCG.

“Disitamab vedotin plus BCG may potentially provide a new bladder-sparing therapy for very high-risk NMIBC patients with HER2 expression who refused radical cystectomy or did not meet the requirements for radical cystectomy,” Yijun Shen, MD, of the Department of Urology at Fudan University Shanghai Cancer Center in Shanghai, China, said during a presentation of the data.

Study Background and Patient Characteristics

Explaining the rationale for the study, Shen said, “Forty percent to 60% of patients with HR-NMIBC will relapse after BCG treatment. Moreover, there is a high incidence of postoperative complications and a negative impact on health-related quality of life after radical cystectomy.”

Accordingly, Shen et al launched their prospective, open-label, single-center study to explore the HER2-targeting ADC disitamab vedotin in this setting. To enroll in the study, patients had to have histologically confirmed NMIBC of stage Tis, Ta, or T1, and a HER2 expression level as determined by immunohistochemistry (IHC) of 1+, 2+, or 3+. Patient ECOG performance status had to be 0 or 1 and be categorized as high-risk by the European Association of Urology guidelines. Further, patients had to be ineligible for or unwilling to receive radical cystectomy.

Overall, the study included 20 patients with HER2-expressing, high-risk NMIBC. Patients were stratified into 2 cohorts: cohort A consisted of 15 patients with residual tumor or CIS following transurethral resection of bladder tumor (TURBT) and cohort B comprised 5 patients without residual tumor following TURBT.

In cohort A, the patient age range was 55 to 83 years. There were 13 men and 2 women, and NMIBC was the primary tumor for 12 of the 15 patients. One patient had a tumor stage of Ta and all other patients had a tumor stage of T1. All patients had multiple lesions and 12 patients had CIS. HER2 expression scores per IHC comprised 3 patients who were 1+, 8 who were 2+, and 4 who were 3+. Twelve patients had residual tumors at second transurethral resection (TUR).

Patients in cohort B had an age range of 62 to 78 years. There were 3 males and 2 females and NMIBC was the primary tumor for all 5 patients. Across all patients, NMIBC was the primary tumor and the tumor stage was T1. Four patients had multiple lesions and none of the patients had concurrent CIS or residual tumors at second TUR. HER2 expression by IHC was 2+ for 3 patients and 3+ for 2 patients.

All patients were treated with disitamab vedotin at 2.0 mg/kg every 3 weeks for up to 8 cycles. This was followed by 1-year of BCG bladder instillation.

The primary end points were 3-month CR rate for cohort A and 6-month EFS rate for cohort B. Secondary end points for both cohorts were 6- and 12-month CR rates, duration of CR, 1- and 2-year EFS rates, 1- and 2-year cancer-specific survival rates, overall survival, and safety.

The cutoff date for the data presented at the AUA meeting was September 12, 2024.

Reference

Shen Y, Peng L, Lu X, et al. Preliminary efficacy and safety of disitamab vedotin (dv) combined with Bacillus Calmette-Guérin (BCG) in the treatment of high-risk non-muscle invasive bladder cancer with HER2 expression: a prospective, open label, single-center study. J Urol. Published online April 26, 2025. doi:10.1097/01.JU.0001109848.08748.9e.09