Over 50% ORR Achieved With Disitamab Vedotin in HER2+ and HER2-Low Bladder Cancer

The antibody-drug conjugate (ADC) disitamab vedotin demonstrated favorable antitumor responses, including complete responses (CRs) in previously treated patients with either HER2-positive or HER2-low locally advanced or metastatic urothelial carcinoma, according to results presented during the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium.¹

In cohort A of the phase 2 RC48G001 study (NCT04879329), which e patients with HER2-positive disease (n = 71; immunohistochemistry [IHC] 3+ or IHC 2+ and in situ hybridization [ISH] positive), the ADC elicited an objective response rate (ORR) of 54.9%, which included a CR rate of 16.9% and a partial response (PR) rate of 38.0%. Moreover, 32.4% of patients had stable disease (SD), and 7.0% experienced disease progression. The median follow-up time in this cohort was 11.3 months (range, 0-31), and the disease control rate (DCR) was 87.3% (95% CI, 77.3%-94.0%); the median duration of response (DOR) was 5.8 months (95% CI, 4.6-9.4).

In cohort B, which included patients with HER2-low disease (n = 76; IHC 2+ and ISH-negative/unevaluable or IHC 1+), disitamab vedotin induced an ORR of 52.6%, which comprised CR and PR rates of 18.4% and 34.2%, respectively; the SD and PD rates were 31.6% and 10.5%. The median follow-up time in this cohort was slightly longer, at 17.1 months (range, 1-40). In this group, the DCR achieved with the ADC was 84.2% (95% CI, 74.0%-91.6%) and the median DOR was 6.9 months (95% CI, 4.7-9.4).

The median progression-free survival (PFS) and overall survival (OS) were comparable between the cohorts and consistent across HER2 expression levels. In cohort A, the median PFS was 5.7 months (95% CI, 4.1-7.1) and the median OS was 20.0 months (95% CI, 12.8-not evaluable). The 12-month PFS and OS rates in this cohort were 19.1% and 65.8%, respectively. In cohort B, the median PFS was 5.7 months (95% CI, 4.6-6.9) and the median OS was 17.0 months (95% CI, 9.6-23.9). The PFS and OS rates at 12 months in this group were 21.8% and 57.7%, respectively.

“Overall, the global study results are aligned with clinical trials conducted in China^2,3 for disitamab vedotin in previously treated participants with HER2-expressing locally advanced/metastatic urothelial carcinoma,” Thomas Powles, MD, MBBS, MRCP, said in a late-breaking presentation of the data. “A phase 3 study [NCT05911295] evaluating disitamab vedotin combined with pembrolizumab [Keytruda] is ongoing⁴ in participants with HER2-expressing locally advanced/metastatic urothelial carcinoma.”

Powles is a professor of genitourinary oncology and director of Barts Cancer Centre at St Bartholomew’s Hospital, Queen Mary University of London in England.

Study Design of the RC48G001 Trial

The global, multicohort, single-arm, open-label, phase 2 study enrolled patients with locally advanced or metastatic urothelial carcinoma who had received 1 to 2 prior lines of systemic therapy, which included a platinum-containing regimen. Patients must have experienced PD during or following their most recent line of therapy. They were also required to have HER2 status of IHC 1+ or higher per central laboratory testing and an ECOG performance status no higher than 1. If they had previously received monomethyl auristatin E (MMAE)–based ADCs or HER2-directed therapy, they were excluded.

All patients received the ADC intravenously at a dose of 1.5 mg/kg every 2 weeks. Treatment continued until PD or unacceptable toxicity. Investigators conducted disease assessments every 6 weeks from day 1 of cycle 1 for 72 weeks, and then every 12 weeks until PD.

Moreover, the primary end point of the study is confirmed ORR by blinded independent central review (BICR) and RECIST 1.1 criteria, and select secondary end points include DOR, DCR, and PFS by BICR; OS; and safety.

A total of 293 patients underwent screening, and 151 were enrolled in the study. Of the 151 patients, 73 comprised cohort A and 78 comprised cohort B. In cohort A, all patients received at least 1 dose of treatment, and 12.3% were still on treatment at the data cutoff of September 12, 2025. The most common reason for going off treatment was PD (65.8%; n = 48/64), and the most common reason for going off study was death (46.6%; n = 34/34). In cohort B, all patients received at least 1 dose of treatment, and only 6.4% of patients remained on treatment at the cutoff. Again, the most common reasons for going off treatment and off study were PD (70.5%; n = 55/73) and death (64.1%; n = 50/50), respectively.

The median patient age across cohorts A and B was 69.5 years (range, 28-88), and most patients were male (71.2%; 70.5%). In cohort A, 54.8% of patients had an ECOG performance status of 0, and 43.8% had a status of 1; in cohort B, these rates were 39.7% and 60.3%, respectively. In terms of HER2 IHC score and ISH status, in cohort A, 30.1% of patients had a HER2 IHC score of 2+ with ISH positivity, and 69.9% had a HER2 IHC score of 3+. In cohort B, 28.2% of patients had a HER2 IHC score of 1+, and 71.8% had a HER2 IHC score of 2+ with ISH negativity or not evaluable. Across the cohorts, most patients had localized early-stage disease (65.8%; 75.6%).

In cohort A, 60.3% of patients had received 1 prior line of systemic therapy, and 39.7% had received 2 prior lines; in cohort B, these respective rates were 71.8% and 26.9%. The majority of patients across cohorts A and B had previously received systemic therapy in the metastatic setting (86.3%; 76.9%). Most patients had a primary tumor located in the bladder (82.2%; 78.2%) and visceral metastases (68.5%; 82.1%).

Additional Efficacy Data

“CR was observed in participants primarily with IHC 2+/3+ tumors, those with visceral metastases or lymph node–only disease, and those with or without prior radical surgery,” Powles noted. He added that a response to the ADC was achieved across HER2 expression levels.

Additionally, for both cohorts, a numerically higher ORR was observed in the subgroup with lymph node metastases. “ORR was similar in subgroups with upper vs lower tract primary tumors, 1 to 2 prior lines of therapy, and across HER2 expression levels,” he said.

Outcomes With Subsequent Therapy

In cohort A, half of patients (50.0%) received any subsequent therapy; this included a PD-L1 inhibitor (9.4%), chemotherapy (14.1%), enfortumab vedotin-ejfv (Padcev; EV) monotherapy (17.2%), TROP2-targeted ADC (10.9%), enfortumab vedotin plus pembrolizumab (P; 6.3%), HER2-directed ADC (6.3%), or other (9.4%). Moreover, 54.8% of those in cohort B received a subsequent therapy. In this group, the most common therapy received was a PD-L1 inhibitor (20.5%), followed by chemotherapy (15.1%), TROP2-directed ADC (13.7%), single-agent EV (11.0%), other (11.0%), EV+P (9.6%), and HER2-directed ADC (2.7%).

“Clinical activity was observed with subsequent EV-based therapy after discontinuation of DV,” Powles said. In cohort A, 17.2% of patients received EV monotherapy with best responses of PR (18.2%), SD (18.2%), and PD (27.3%). Moreover, 6.3% of patients in this cohort received EV+P with best response of SD (50.0%). Eleven percent of patients in cohort B received single-agent EV with best responses of PR in 12.5%, SD in 25.0%, and PD in 50.0%. Almost 10% (9.6%) received EV+P and experienced best responses of SD (28.6%) and PD (42.9%).

Safety and Tolerability

The ADC was administered for a median of 9 cycles in both cohorts. Grade 1 or 2 treatment-related adverse effects (TRAEs) were reported by 50.3% of patients across cohorts A and B, and grade 3 or higher TRAEs by 41.1% of patients. The most common TRAEs experienced across the cohorts were fatigue (grade 1/2, 39.1%; grade ≥ 3, 13.9%), peripheral sensory neuropathy (50.3%; 2.0%), nausea (31.2%; 1.3%), decreased appetite (29.2%; 1.3%), alopecia (27.8%; 0%), diarrhea (23.8%; 4.0%), constipation (16.5%; 0.7%), decreased weight (15.9%; 0.7%), pruritus (11.9%; 0%), arthralgia (8.6%; 2.0%), peripheral motor neuropathy (9.9%; 0.7%), and vomiting (8.0%; 2.6%).

Powles reported that 1 patient in cohort B experienced a grade 1 treatment-emergent toxicity of pneumonitis, and that 1 patient experienced a TRAE that proved fatal, although the cause of death was unknown.

Across the cohorts, AEs led to dose delays, reductions, or discontinuation for 68.9%, 60.9%, and 16.6% of patients, respectively. The most common AEs to lead to dose reductions of the ADC were peripheral sensory neuropathy (29.1%) and fatigue (11.3%). The AEs that led to discontinuation of disitamab vedotin were peripheral sensory neuropathy (6.0%), fatigue (1.3%), paresthesia (1.3%), and peripheral motor neuropathy (1.3%), which is “a known AE associated with MMAE payload–containing ADCs,” Powles noted.

Disclosures: Powles disclosed receipt of honoraria from Astellas Pharma, AstraZeneca, BMS GmbH & Co KG, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson/Janssen, MashupMD, Merck, Merck Serono, Novartis, Pfizer, Roche, and Seagen. He serves in a consulting or advisory role for Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, MashupMD, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seagen. Research funding was provided by Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seagen. Research funding was provided by Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seagen. Travel, accommodations, and expenses were covered by AstraZeneca, Ipsen, MSD, Pfizer, and Roche.

REFERENCES

1. Powles T, Koshkin VS, Rosenberg JE, et al. RC48G001: a phase 2 study of disitamab vedotin in HER2-expressing previously treated advanced UC. J Clin Oncol. 2026;44(suppl 7):LBA631. doi:10.1200/JCO.2026.44.7_suppl.LBA631

2. Sheng X, Wang L, He Z, et al. 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. J Clin Oncol. 2024;42(12):1391-1402. doi:10.1200/JCO.22.02912

3. Yan X, Li J, Xu H, et al. Efficacy and safety of DV in HER2-negative and HER2-low locally advanced or metastatic urothelial carcinoma: results of a phase 2 study. Med. 2025;6(7):100637. doi:10.1016/j.medj.2025.100637

4. Powles TB, Grande E, Alimohamed N, et al. SGNDV-001: disitamab vedotin with pembrolizumab in HER2-expressing locally advanced or metastatic urothelial carcinoma. Future Oncol. 2025;21(21):2705-2712. doi:10.1080/14796694.2025.2535280