Izalontamab Brengitecan Data Reinforce the Value of ADCs in Advanced Urothelial Carcinoma

Izalontamab brengitecan (BL-B01D1) led to a confirmed objective response rate (ORR) of 44.1% (95% CI, 27.2%-62.1%) and a disease control rate (DCR) of 88.2% (95% CI, 72.5%-96.7%) in 34 patients with locally advanced or metastatic urothelial carcinoma, according to data from the single-arm, phase 2 BL-B01D1-201 trial (NCT05785039) published in the Journal of Clinical Oncology.1

Additionally, the best ORR (50%; 95% CI, 32.4%-67.6%) consisted of 17 (50%) partial responses (PRs), which included 2 unconfirmed PRs. The stable disease rate was 38.2% (n = 13); 4 patients were not evaluable.

“BL-B01D1 showed promising preliminary efficacy and a favorable safety profile at 2.2 mg/kg in patients with locally advanced or metastatic urothelial carcinoma who had progressed after systemic therapy,” lead study author Xiaojie Bian, MD, PhD, of the Department of Urology at Fudan University Shanghai Cancer Center in Shanghai, China, and coauthors wrote in the publication. “These results suggest that BL-B01D1 could be a promising new agent for patients with locally advanced or metastatic urothelial carcinoma with few treatment options.”

What Is the Need for a Bispecific Antibody-Drug Conjugate in Urothelial Carcinoma?

Despite the relatively short overall survival (OS) benefit afforded, platinum-based chemotherapy has remained the longstanding standard of care for patients with locally advanced or metastatic urothelial carcinoma. The introduction of checkpoint inhibitors to the maintenance setting have extended OS, but prognosis remains poor.

Antibody-drug conjugates (ADCs) have emerged holding renewed promise for improved outcomes in this population. EGFR- and HER3-directed ADCs may hold great promise in urothelial carcinoma given their high expression on epithelial cells.

Izalontamab brengitecan is a first-in-class EGFR-HER3-directed bispecific ADC designed to bind to these tumor antigens, releasing Ed-04, a camptothecin-derived topoisomerase I inhibitor within lysosomes, triggering tumor cell death.

What Should I Know About The BL-B01D1-201 Trial?

BL-B01D1-201 is a multicenter trial designed to evaluate the activity of izalontamab brengitecan in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed on standard therapy in China. Results from the trial were first shared at the 2024 ESMO Congress.2

To be eligible for enrollment, patients had to be between the ages of 18 and 75, experienced disease progression on the last line of therapy, and have adequate organ function, an ECOG performance status of 0 or 1, and life expectancy of at least 3 months.1 At least one measurable lesion per RECIST 1.1 criteria was also required.

Eligible patients received BL-B01D1 at doses of 2.2, 2.5, and 2.75 mg/kg of body weight without any compensation intravenously over approximately 60 minutes on days 1 and 8 of each 3-week cycle.

The primary end point was ORR. Secondary end points included progression-free survival (PFS), DCR, duration of response (DOR), and safety.

Dose modifications were permitted to manage hematologic and nonhematologic toxicity. Treatment continued until disease progression, intolerable toxicity, death, consent withdrawal, or investigator's discretion. Patients were followed for survival every 3 months after the last dose of study treatment.

A total of 57 patients underwent screening, 41 of whom were subsequently enrolled and received at least 1 dose of either 2.2 (n = 34), 2.5 (n = 4), or 2.75 (n = 3) mg/kg of izalontamab brengitecan. A total of 32 patients ultimately withdrew from the study, leaving 9 patients on treatment at data cutoff in the 2.2 (n = 7), 2.5 (n = 1), or 2.75 (n = 1) mg/kg arms.

Between May 2023 and June 2024, 41 patients were enrolled across 21 sites in China. As of the data cutoff, 23 patients (56.1%) were still being followed for progression or survival.

The median age in the overall population was 62 years (range, 42-74). Tumors originated in the bladder in 53.7% (n = 22) of patients and in the upper urinary tract in 46.3% (n = 19). Most tumors were urothelial only (85.4%; n = 35). All patients had metastatic disease, and liver metastases were present in 14.6% of cases. Most patients had received prior platinum-based chemotherapy (92.7%; n = 38) and checkpoint inhibitors (92.7%; n = 38). At baseline, 17 patients (41.5%) had received 1 line of chemotherapy.

What Additional Efficacy and Safety Data Were Shared From the Study?

At a median follow-up time for PFS of 10.2 months, the median PFS was 7.3 months (95% CI, 5.5-9.8). The median OS was 12.3 months (95% CI, 8.5-not reached [NR]). The median DOR was 11.3 months (95% CI, 4.3-NR). The 6-month DOR rate was 69.8% (95% CI, 31.8%-89.4%).

With respect to safety, 2.75 mg/kg had been chosen as the recommended phase 2 dose based on previous data from the phase 1 trial. However, all 3 patients who received this dose in the phase 1 portion experienced grade 3 or greater treatment-related adverse effects (TRAEs) after the first cycle. As a result, the dose was de-escalated to 2.2 mg/kg, and the protocol was amended to include an optimized intermediate actual dose of 2.5 mg/kg.

Among 34 patients who received 2.2 mg/kg, 100% experienced at least 1 TRAE that was deemed possibly related to izalontamab brengitecan. No treatment-related death occurred in this cohort. Treatment discontinuation owing to TRAEs occurred in 2 patients (5.9%), and 10 patients (29.4%) required dose reductions. Grade 3 or greater TRAEs occurred in 61.8% of patients (n = 21) and 15 patients (44.1%) experienced serious TRAEs.

Within the 2.2-mg/kg cohort, the most common hematologic TRAEs included anemia (any grade, 88.2%; grade ≥3, 38.2%), leukopenia (any grade, 76.5%; grade ≥3, 38.2%), neutropenia (any grade, 64.7%; grade ≥3, 41.2%), thrombocytopenia (any grade, 64.7%; grade ≥3, 32.4%), and decreased lymphocyte count (any grade, 26.5%; grade ≥3, 11.8%).

The most common nonhematologic TRAEs included decreased appetite (any grade, 52.9%; grade ≥3, 2.9%), nausea (any grade, 52.9%; grade ≥3, 2.9%), hypoalbuminemia (any grade, 32.4%; grade ≥3, 2.9%), and vomiting (any grade, 32.4%; grade ≥3, 0%).

What Were the Authors Concluding Thoughts?

“To our knowledge, the BL-B01D1-201 study is the first phase 2 trial of an EGFR/HER3-targeting ADC in patients with locally advanced or metastatic urothelial carcinoma who have progressed on at least one previous line of systemic therapy. These findings are encouraging for patients with locally advanced or metastatic urothelial carcinoma with limited treatment options,” study authors concluded.

In a past exclusive interview with OncLive®, Dingwei Ye, MD, PhD, of Fudan University Prostate Cancer Institute and GU Cancer Committee of Chinese Anti-Cancer Association, discussed the safety and efficacy outcomes from the study that were shared at the 2024 ESMO Congress:3

Is Izalontamab Brengitecan Under Exploration in Other Cancers?

The phase 2 BL-B01D1-203 study (NCT05880706) is examining izalontamab brengitecan in combination with osimertinib (Tagrisso) in the first-line treatment of patients with EGFR-mutated, locally advanced or metastatic non–small cell lung cancer.4 Data from the International Association for the Study of Lung Cancer World Conference on Lung Cancer showed that the regimen induced responses in this population and proved tolerable. In August 2025, the FDA granted breakthrough therapy designation to the agent for use in patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations who progressed on or following treatment with an EGFR TKI and platinum-based chemotherapy.5 The decision was supported by findings from BL-B01D1-203, as well as the phase 1 BL-B01D1-101 (NCT05194982) and BL-B01D1-LUNG-101 (NCT05983432) studies.

Moreover, a phase 1 study (NCT05470348) is examining the use of izalontamab bregitecan in heavily pretreated patients with advanced or metastatic HER2-negative or -low breast cancer.6 Data shared at the 2025 ESMO Breast Congress indicated that the agent showed preliminary responses with a manageable toxicity profile in this population.

References

1. Bian X, Yang T, Yin H, et al. Efficacy and safety of BL-B01D1 in patients with locally advanced or metastatic urothelial carcinoma: a phase II clinical trial. J Clin Oncol. Published online October 8, 2025. doi:10.1200/JCO-25-00109
2. Ye D, Bian X, Yang T, et al. BL-B01D1, an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic urothelial carcinoma (UC). Ann Oncol. 2024;35(suppl 2):S1133. doi:10.1016/j.annonc.2024.08.2044
3. Ye D. Dr Ye on the safety and efficacy of BL-B01D1 in locally advanced/metastatic urothelial carcinoma. OncLive.com. September 17, 2024. Accessed October 15, 2025. https://www.onclive.com/view/dr-ye-on-the-safety-and-efficacy-of-bl-b01d1-in-locally-advanced-metastatic-urothelial-carcinoma
4. Zhou F, Wang Q, Wang H, et al. Phase II study of iza-bren (BL-B01D1) in combination with osimertinib in patients with EGFR-mutated locally advanced or metastatic non–small cell lung cancer. Presented at: IASLC 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Press Briefing. Abstract 2114.
5. Izalontamab brengitecan (EGFRxHER3 ADC) granted breakthrough therapy designation by U.S. FDA for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. Bristol Myers Squibb. August 18, 2025. Accessed October 15, 2025. https://news.bms.com/news/details/2025/Izalontamab-Brengitecan-EGFRxHER3-ADC-Granted-Breakthrough-Therapy-Designation-by-U-S--FDA-for-Patients-with-Previously-Treated-Advanced-EGFR-Mutated-Non-Small-Cell-Lung-Cancer/default.aspx
6. Du Y, Zhang J, Wu J, et al. Phase I study of iza-bren (BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic breast cancer (BC). Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract. 302MO.