Disitamab Vedotin Shows Activity in HER2-Expressing Urothelial Carcinoma

Disitamab vedotin demonstrated consistent, clinically meaningful antitumor activity in previously treated patients with locally advanced or metastatic urothelial carcinoma across HER2 expression levels, according to findings from cohorts A and B of a global phase 2 study presented at the 2026 ASCO Genitourinary Cancers Symposium.

Cohort A included patients with HER2-positive disease (73 patients; immunohistochemistry 3+ or 2+ with in situ hybridization positive). In this group, disitamab vedotin, an antibody-drug conjugate, elicited an objective response rate of 54.9%, including a complete response rate of 16.9% and a partial response rate of 38.0%. Stable disease was observed in 32.4% of patients and disease progression occurred in 7.0%. Median follow-up in this cohort was 11.3 months, and the disease control rate was 87.3%. The median duration of response was 5.8 months.

Cohort B included patients with HER2-low disease (78 patients; immunohistochemistry 2+ and in situ hybridization negative or not evaluable, or immunohistochemistry 1+). Disitamab vedotin induced an objective response rate of 52.6%, with complete and partial response rates of 18.4% and 34.2%, respectively. Stable disease and disease progression were reported in 31.6% and 10.5% of patients, respectively. Median follow-up in this cohort was 17.1 months. The disease control rate was 84.2%, and the median duration of response was 6.9 months.

Median progression-free survival and overall survival were similar across cohorts and consistent across HER2 expression levels. In cohort A, median progression-free survival was 5.7 months and median overall survival was 20.0 months, with 12-month progression-free survival and overall survival rates of 19.1% and 65.8%, respectively. In cohort B, median progression-free survival was 5.7 months and median overall survival was 17.0 months, with 12-month progression-free survival and overall survival rates of 21.8% and 57.7%, respectively.

“Overall, these global study results are aligned with clinical trials conducted in China for disitamab vedotin in previously treated patients with HER2-expressing locally advanced or metastatic urothelial carcinoma,” said Thomas Powles in his late-breaking presentation. Powles is a professor of genitourinary oncology and director of Barts Cancer Centre at St Bartholomew’s Hospital, Queen Mary University of London. He noted that a phase 3 study evaluating disitamab vedotin combined with pembrolizumab is ongoing in participants with HER2-expressing advanced urothelial carcinoma.

The study was a global, multicohort, single-arm, open-label phase 2 trial enrolling patients with locally advanced or metastatic urothelial carcinoma who had received 1 or 2 prior systemic therapy regimens, including platinum-based chemotherapy. All patients had disease progression during or after their most recent therapy and HER2 expression of 1+ or higher. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and could not have previously received MMAE-based antibody-drug conjugates or HER2-targeted therapy.

All patients received disitamab vedotin intravenously at 1.5 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Disease assessments occurred every 6 weeks for 72 weeks and then every 12 weeks until progression. The primary end point was confirmed objective response rate by blinded independent central review, with secondary end points including duration of response, disease control rate, progression-free survival, overall survival, and safety.

Of 151 enrolled patients, 73 were assigned to cohort A and 78 to cohort B. In cohort A, 12.3% of patients remained on treatment at data cutoff, with progressive disease and death being the most common reasons for discontinuation. In cohort B, 6.4% remained on treatment, with similar reasons for going off therapy. Median patient age across cohorts was 69.5 years, and most were male. Cohort A included 54.8% with performance status 0 and 43.8% with performance status 1, while cohort B included 39.7% and 60.3%, respectively. Most patients had localized early-stage disease, and the majority had received prior systemic therapy in the metastatic setting.

Clinical activity was observed across HER2 expression levels, in patients with visceral metastases or lymph node–only disease, and in those with or without prior radical surgery. Subgroup analyses showed similar response rates between upper and lower tract tumors, 1 or 2 prior lines of therapy, and across HER2 expression levels.

Following disitamab vedotin, a proportion of patients received subsequent therapies, including PD-(L)1 inhibitors, chemotherapy, enfortumab vedotin (Padcev) monotherapy, TROP2-targeted antibody-drug conjugates, enfortumab vedotin plus pembrolizumab, and other HER2-directed therapies. Responses to these subsequent treatments were observed in both cohorts.

The median number of disitamab vedotin cycles was 9. Grade 1 or 2 side effects occurred in 50.3% of patients, and grade 3 or higher side effects occurred in 41.1%. The most common side effects included fatigue, peripheral sensory neuropathy, nausea, decreased appetite, alopecia, diarrhea, constipation, weight loss, pruritus, arthralgia, peripheral motor neuropathy, and vomiting. One patient experienced pneumonitis, and 1 patient had a fatal side effect of unknown cause. Adverse effects led to dose delays in 68.9%, dose reductions in 60.9%, and treatment discontinuation in 16.6%. Peripheral sensory neuropathy and fatigue were the most common reasons for dose reduction, while neuropathy, fatigue, and paresthesia were the most frequent causes of discontinuation.

Disitamab vedotin continues to demonstrate robust antitumor activity and manageable safety in patients with previously treated HER2-expressing advanced urothelial carcinoma, supporting ongoing investigations in combination regimens and larger trials.

References

1. "RC48G001: a phase 2 study of disitamab vedotin in HER2-expressing previously treated advanced UC," by Dr. Thomas Powles. Journal of Clinical Oncology
2. "Efficacy and safety of disitamab vedotin in patients with Human Epidermal Growth Factor Receptor 2–positive locally advanced or metastatic urothelial carcinoma: a combined analysis of two phase II clinical trials," by Dr. Xinan Sheng. Journal of Clinical Oncology.
3. "Efficacy and safety of DV in HER2-negative and HER2-low locally advanced or metastatic urothelial carcinoma: results of a phase 2 study," by Dr. Xieqiao Yan, et al. Med: A Cell Press Journal.
4. "SGNDV-001: disitamab vedotin with pembrolizumab in HER2-expressing locally advanced or metastatic urothelial carcinoma," by Dr. Thomas Powles. Future Oncology Journal.

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