BL-B01D1, an EGFR–HER3 Bispecific ADC, Shows Promising Activity in Advanced Urothelial Carcinoma: Phase II Results

Highlight

– BL-B01D1, an EGFR–HER3 bispecific antibody-drug conjugate (ADC), produced a confirmed objective response rate (ORR) of 44.1% at the 2.2 mg/kg dose in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) refractory to prior therapy (n=34).

– Median progression-free survival (PFS) was 7.3 months and median duration of response (DOR) was 11.3 months with a median follow-up of 10.2 months.

– The predominant toxicities were hematologic (anemia, leukopenia, neutropenia, thrombocytopenia), generally manageable but frequent; nonhematologic events were mostly low grade.

Background: disease burden and unmet needs

Advanced urothelial carcinoma remains a therapeutic challenge. Although platinum-based chemotherapy, immune checkpoint inhibitors, FGFR inhibitors for selected patients, and antibody–drug conjugates (ADCs) such as enfortumab vedotin have expanded options, many patients progress and have limited subsequent choices. ADCs harness the specificity of antibodies to deliver cytotoxic payloads selectively to tumor cells, and bispecific ADCs that engage two surface receptors may increase tumor targeting, internalization, and therapeutic index. BL-B01D1 is described as a first-in-class EGFR–human EGFR 3 (HER3) bispecific ADC conjugated to a payload designated Ed-04, developed to treat la/mUC after prior systemic therapy. The phase II BL-B01D1-201 study evaluated efficacy and safety in a refractory population with high unmet need.

Study design and methods

The BL-B01D1-201 trial was a multicenter, single-arm, phase II study enrolling patients with locally advanced or metastatic urothelial carcinoma who had progressed on prior systemic therapy. BL-B01D1 was administered intravenously on a day 1 and day 8 schedule every 3 weeks, at doses of 2.2 mg/kg (n=34), 2.5 mg/kg (n=4), and 2.75 mg/kg (n=3). The primary endpoint was objective response rate (ORR) by investigator assessment (confirmed responses). Key secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and safety. The reported results focus mainly on the 2.2 mg/kg expansion cohort, which was selected for further evaluation based on activity and tolerability.

Key findings

This section summarizes the principal efficacy and safety outcomes reported for the 2.2 mg/kg dose cohort (n=34) and provides interpretive context.

Efficacy

– Confirmed ORR: 44.1% (95% CI, 27.2 to 62.1) in the 2.2 mg/kg cohort. Responses were investigator-assessed and confirmed per protocol.

– Disease Control Rate (DCR): 88.2% (95% CI, 72.5 to 96.7), reflecting the proportion of patients achieving objective response or stable disease.

– Subgroup of patients who had received only one prior line of chemotherapy or ADC (n=15): confirmed ORR was 80.0% (95% CI, 51.9 to 95.7), suggesting heightened activity earlier in the treatment course.

– Median progression-free survival (PFS): 7.3 months (95% CI, 5.5 to 9.8) with median follow-up of 10.2 months.

– Median duration of response (DOR): 11.3 months (95% CI, 4.3 to not reached), indicating that responses were often durable within the observed follow-up.

Safety and tolerability

Hematologic toxicities were the most common treatment-related adverse events (TRAEs). In the 2.2 mg/kg group the most frequent TRAEs (all grade / ≥ grade 3) included:

Anemia: 88.2% / 38.2%
Leukopenia: 76.5% / 38.2%
Neutropenia: 64.7% / 41.2%
Thrombocytopenia: 64.7% / 32.4%
Appetite decrease: 52.9% / 2.9%
Nausea: 52.9% / 2.9%

Nonhematologic grade ≥3 events were uncommon. The hematologic profile suggests a myelosuppressive payload effect; rates of high-grade neutropenia and thrombocytopenia are noteworthy and require active management strategies including growth factor support, transfusions, dose interruption or reduction, and careful monitoring.

Interpretation of efficacy relative to available therapies

The confirmed ORR of 44.1% and median PFS of 7.3 months in a pretreated la/mUC population compare favorably with historical data for later-line therapies in urothelial carcinoma, where ORRs for single-agent ADCs and chemotherapy usually range more modestly and PFS is often shorter. The notably higher ORR (80%) in patients who had only one prior line of therapy supports the hypothesis that ADCs such as BL-B01D1 may be more effective in earlier salvage settings before cumulative tumor resistance and patient frailty increase. However, cross-trial comparisons must be cautious because of differences in patient selection, prior therapies, and trial design.

Mechanistic and translational considerations

BL-B01D1’s bispecificity for EGFR and HER3 may confer several theoretical advantages: enhanced tumor cell binding in tumors expressing either or both receptors, improved internalization and payload delivery, and potential engagement of heterogeneous tumor subclones. EGFR and HER3 are expressed variably in urothelial carcinoma, and co-targeting both receptors could increase the fraction of targetable cells. The payload Ed-04 (as described in the original report) appears to have potent cytotoxic activity with expected systemic myelotoxicity when released. Future translational work should further define receptor expression thresholds predictive of response, mechanisms of resistance, and the ADC’s tumor pharmacodynamics.

Expert commentary and limitations

Strengths of the study include encouraging single-agent activity in a refractory population, a high disease control rate, and a median DOR exceeding 11 months in responders. The 2.2 mg/kg dosing schedule (days 1 and 8 every 3 weeks) yielded a tolerable efficacy/toxicity balance sufficient to justify further development.

Key limitations include the single-arm design, relatively small sample size (particularly at higher dose levels), and short median follow-up (10.2 months) at the time of reporting. The study population heterogeneity (variable prior therapies including ADCs) complicates interpretation of comparative effectiveness. The high rates of hematologic toxicity raise pragmatic concerns: can the regimen be delivered safely in community settings, how frequently are dose modifications required, and what supportive-care resources are needed? Additional data are required to characterize long-term safety, overall survival benefit, and activity in molecularly defined subgroups (for example, EGFR/HER3 expression or other biomarkers).

Clinical implications and next steps

BL-B01D1 represents a promising candidate among novel ADC approaches for la/mUC. Next steps should include randomized trials comparing BL-B01D1 with standard-of-care regimens in appropriate lines of therapy to establish comparative efficacy and safety, and prospective biomarker programs to identify patients most likely to benefit. Important practical questions include optimal sequencing with existing agents (immune checkpoint inhibitors, enfortumab vedotin, FGFR inhibitors), management algorithms for hematologic toxicity, and combination strategies (for example, with immunotherapy) that could enhance efficacy without intolerable overlapping toxicities.

Conclusion

In this phase II single-arm study, BL-B01D1 demonstrated promising antitumor activity in la/mUC patients who progressed on systemic therapy, with a confirmed ORR of 44.1% at the 2.2 mg/kg dose, durable responses, and a manageable but notable hematologic toxicity profile. These data support further clinical development, ideally in randomized trials and with integrated biomarker analyses to define the role of this EGFR–HER3 bispecific ADC in the evolving urothelial carcinoma treatment landscape.

Funding, trial registration, and disclosures

The primary report provides funding and conflict-of-interest statements; readers should consult the original J Clin Oncol manuscript for full disclosures. The trial is designated BL-B01D1-201 in the publication; a specific ClinicalTrials.gov identifier was not reported in the summary text provided here. Investigators and sponsors should ensure public registration and full transparency in subsequent reports.

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. 2025 Nov 10;43(32):3505-3515. doi: 10.1200/JCO-25-00109. Epub 2025 Oct 8. PMID: 41061200.

2. Powles T, et al. Enfortumab vedotin and other ADCs in advanced urothelial carcinoma: pivotal data and clinical context. (See original literature for pivotal comparator trials and guidelines.)

AI-friendly thumbnail prompt

A clinical oncology scene: a multidisciplinary tumor board reviewing imaging and molecular maps; a vial labeled ‘BL-B01D1’ sits on the table next to an illustrated antibody binding both EGFR and HER3 receptors linked to a cytotoxic payload; subdued clinical colors, high realism, medical illustration style.