Disitamab Vedotin Combo Shows Efficacy in Unresectable ERBB2-Positive NMIBC

Disitamab vedotin (Aidixi) plus tislelizumab (Tevimbra) produced a high complete response (CR) rate and durable disease control in patients with very high-risk (VHR) non–muscle-invasive bladder cancer (NMIBC), according to results from the phase 2 TRUCE-04 trial (NCT05495724), published in JAMA Oncology.¹ The trial enrolled patients with transurethrally unresectable, ERBB2 (formerly HER2)–positive disease who were ineligible for or declined radical cystectomy.

Among 26 efficacy-evaluable patients, the CR rate of high-risk disease was 73.1% (95% CI, 54.8%-91.3%), meeting the prespecified 70% alternative-rate goal. In a conservative analysis of all 28 treated patients, which counted 2 preassessment withdrawals as nonresponders, the CR rate was 67.9% (95% CI, 49.4%-86.3%). The 19 responses exceeded the 17-response exact binomial threshold, so the primary end point was met in both analyses.

By ERBB2 status, CR rates of high-risk disease were 78.6% (95% CI, 54.0%-100.0%) in patients with immunohistochemistry (IHC) 2+ tumors and 66.7% (95% CI, 35.4%-98.0%) in those with IHC 3+ tumors. The CR rate of any disease was 65.4% (95% CI, 45.8%-85.0%).

The median duration of response (DOR) of high-risk disease was not reached (NR). The 12-month sustained response rate was 89.5% (95% CI, 76.7%-100.0%), and the 24-month rate was 83.5% (95% CI, 68.0%-100.0%). Median progression-free survival (PFS) was NR, with a 24-month PFS rate of 95.5% (95% CI, 87.1%-100.0%). The median overall survival (OS) was also NR, with a 24-month OS rate of 96.2% (95% CI, 89.0%-100.0%). No patient progressed to muscle-invasive or metastatic disease, and the single death was due to stroke, unrelated to treatment or disease.

Any-grade treatment-related adverse events (TRAEs) occurred in 89.3% of patients, and grade 3/4 TRAEs occurred in 14.3%. No grade 5 events were reported. The most common TRAEs were paresthesia (42.9%), alopecia (39.3%), pruritus (35.7%), and rash (25.0%). The most common grade 3/4 TRAEs included fatigue (7.1%), rash (3.6%), hypopituitarism (3.6%), and hyperglycemia (3.6%). Immune-related adverse events (AEs) occurred in 60.7% of patients. Two patients (7.1%) discontinued treatment because of TRAEs, and no dose adjustments were required.

“In this single-arm, phase 2, pilot trial, systemic ERBB2-targeted ADC therapy combined with PD-1 blockade showed preliminary antitumor activity in patients with ERBB2-positive, unresectable, high-risk tumors,” wrote Hailong Hu, MD, of the department of Urology at Tianjin Institute of Urology of The Second Hospital of Tianjin Medical University, in the publication with study coinvestigators.¹ “These findings support further evaluation of this strategy in larger studies.”

TRUCE-04 was an open-label, single-arm, phase 2 trial with a Simon 2-stage design, conducted at a single academic hospital in China from August 2022 to May 2024. Of 137 patients screened, 28 were enrolled. The median age was 72 years (IQR, 67-74), and 89% were male.

Eligible patients had urothelial carcinoma meeting the 2019 European Association of Urology VHR criteria and tumors scored as ERBB2 IHC 2+ or 3+. Tumors were defined as transurethrally unresectable based on visually incomplete resection or high-volume disease, verified by at least 2 senior urologists. Most patients had T1 high-grade disease alone (64%), and 7% were BCG-unresponsive.

Patients received intravenous disitamab vedotin at 120 mg on day 1 and tislelizumab was given intravenously at 200 mg on day 2 every 3 weeks for 3 cycles. Responders could continue for up to 8 cycles of disitamab vedotin and 17 cycles of tislelizumab. The median follow-up was 29.4 months.

The primary end point of the study was the CR rate of high-risk disease, defined as no high-grade tumor, T1 disease, carcinoma in situ, or progression at approximately 3 months. Secondary end points included safety, CR rate of any disease, DOR, PFS, OS, and subsequent treatment outcomes.

Among the 7 nonresponders, 4 (57.1%) underwent radical cystectomy, with no pathologic upstaging. Repeat testing of residual disease showed decreased ERBB2 expression in 5 of these 7 patients (71.4%). This included 4 conversions from IHC 2+ or 3+ to IHC 0 or 1+.

The investigators noted that the single-arm design and small sample size limit conclusions, particularly because the study included both BCG-naive and BCG-exposed patients. They also noted that CR of high-risk disease has not been validated as a surrogate for survival.

TRUCE-04 built on the phase 2 TRUCE-02 trial (NCT04730232), in which tislelizumab plus low-dose nab-paclitaxel achieved a 62.7% CR rate of high-risk disease in a similar population.² The trial's 41% null hypothesis was based on prior checkpoint inhibitor monotherapy data, including the phase 2 KEYNOTE-057 (NCT02625961) and SWOG S1605 (NCT02844816) trials, in BCG-unresponsive disease.^3,4

Reference

1. Qie Y, Jia K, Huang S, et al. Disitamab vedotin plus tislelizumab in transurethrally unresectable, ERBB2-positive, non–muscle-invasive bladder cancer: a nonrandomized clinical trial. JAMA Oncol. Published online October 8, 2026. doi:10.1001/jamaoncol.2026.3909
2. Qie Y, Huang S, Shen C, et al. Phase 2 pilot trial of tislelizumab plus low-dose nab-paclitaxel for extensive very high-risk non–muscle-invasive bladder cancer. Clin Cancer Res. 2025;31(5):839-847. doi:10.1158/1078-0432.CCR-24-3321
3. Necchi A, Roumiguié M, Esen AA, et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. J Clin Oncol. 2023;41(suppl 60):LBA442. doi:10.1200/JCO.2023.41.6_suppl.LBA442
4. Black PC, Tangen C, Singh P, et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J Clin Oncol. 2021;39(suppl 15):4541. doi:10.1200/JCO.2021.39.15_suppl.4541