Editor’s Note: Small cell lung cancer (SCLC), often known as the “king of lung cancer,” has long relied on the EP regimen (cisplatin plus etoposide) as the foundation of first-line therapy for nearly three decades. Although recent years have seen the introduction of immunotherapy combined with chemotherapy, which has brought incremental survival benefits, long-term outcomes for patients remain limited. At the 2025 ASCO Annual Meeting, Dr. Yan Huang from Sun Yat-sen University Cancer Center presented the results of a Phase I study (Abstract #3002) on BL-B01D1, a bispecific antibody-drug conjugate (ADC) targeting EGFR and HER3, in patients with SCLC who had failed standard treatments. The study showed that in patients who progressed after first-line chemo-immunotherapy, BL-B01D1 achieved a median overall survival (OS) of 15.1 months and a confirmed objective response rate (ORR) of 75%—breakthrough data that may offer a potential new treatment option for this hard-to-treat disease. Oncology Frontier invited Dr. Huang to provide an in-depth interpretation of the study’s clinical significance and application prospects.Study Overview
iza-bren (BL-B01D1) is a first-in-class bispecific antibody-drug conjugate (ADC) designed to treat patients with locally advanced or metastatic small cell lung cancer (SCLC). It incorporates a bispecific antibody targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), linked via a stable tetrapeptide-cleavable linker to a novel topoisomerase I inhibitor payload (Ed-04). Unlike conventional ADCs that broadly target tumor-associated antigens, iza-bren specifically targets the EGFR and HER3 pathways, which are closely associated with the aggressive biology of SCLC. The drug has already shown promising clinical activity and a manageable safety profile in patients with advanced or metastatic solid tumors. This Phase I study was designed to assess the safety and efficacy of iza-bren in SCLC.
Study Design and Methods
The study enrolled patients with locally advanced or metastatic SCLC who had progressed following prior systemic treatment. Patients received one of several dosing regimens: 2.0 mg/kg or 2.5 mg/kg on Days 1 and 8 of a 21-day cycle (D1D8 Q3W), or 4.5 mg/kg or 5.0 mg/kg on Day 1 of each 21-day cycle (D1 Q3W). Tumor imaging assessments were performed every six weeks. Efficacy was evaluated in the overall population and in specific subgroups, with particular attention to patients who had received only a limited number of prior therapies.
Study Results
As of December 5, 2024, a total of 58 patients with SCLC had been enrolled. All patients who received at least one dose of iza-bren were included in the analysis. The median follow-up duration was 16.4 months. In the overall population, the objective response rate (ORR) was 55.2%, with a confirmed ORR of 44.8%. The median progression-free survival (PFS) was 4.0 months, and the median overall survival (OS) was 12.0 months.
Among the 52 patients who received the 2.5 mg/kg dose, 20 had only received prior first-line treatment with PD-(L)1 inhibitors plus platinum-based chemotherapy (PBC). In this subgroup, the ORR was 80.0%, the confirmed ORR was 75.0%, the median duration of response (DoR) was 5.6 months, the median PFS was 6.9 months, and the median OS reached 15.1 months.
Safety The most common treatment-related adverse events (TRAEs) of any grade were anemia (84.5%), leukopenia (74.1%), thrombocytopenia (72.4%), and neutropenia (70.7%). Non-hematologic TRAEs included fatigue (41.4%), hypoalbuminemia (39.7%), stomatitis (34.5%), nausea (31.0%), and vomiting (31.0%). Grade ≥3 TRAEs were primarily hematologic and were manageable with standard supportive care, including dose adjustments. The incidence of TRAEs leading to treatment discontinuation was 12.1%. Two treatment-related deaths were reported: one due to respiratory failure and one due to gastrointestinal infection. No cases of interstitial lung disease (ILD) were observed, and no new safety signals were identified.
Conclusion
iza-bren demonstrated encouraging efficacy and a manageable safety profile in SCLC patients. Notably, the confirmed ORR of 75% observed in patients who had received only one prior line of treatment highlights its potential as a novel therapeutic option in a field where few advancements have been made in recent decades. A Phase III trial of iza-bren is currently ongoing in patients who progressed following first-line treatment with PD-(L)1 inhibitors plus PBC (NCT06500026).
Expert Insights
Oncology Frontier: First of all, congratulations to you and your team for being selected for an oral presentation at ASCO. The Phase I trial yielded promising results in SCLC. Could you briefly introduce the key findings of the study? Based on these results, what do you consider to be the most important priorities for future research, and what potential impact might this have on clinical practice?
Dr. Yan Huang: It was a pleasure to share our team’s selected work with the global community at ASCO. This study focused on the SCLC cohort from the Phase I trial of the bispecific ADC BL-B01D1, which targets both HER3 and EGFR and carries a topoisomerase I inhibitor payload known as Ed-04. Looking back, Professor Li Zhang first reported early-phase data on this agent in patients with locally advanced or metastatic solid tumors at the 2023 ASCO Annual Meeting. This time, our oral presentation centered on its potential application in SCLC. SCLC, often referred to as the “king of lung cancer,” has long been dominated by EP-based regimens (cisplatin + etoposide) as the first-line standard. While adding immunotherapy to EP has brought some progress, the overall survival benefit remains limited.
The most clinically meaningful data from our study came from the second-line treatment cohort. For patients who had progressed following chemo-immunotherapy, BL-B01D1 demonstrated notable efficacy. Median overall survival reached 15 months, which is a major improvement compared to historical data. The confirmed objective response rate (ORR) of 75% is also clearly superior to the 20–40% response rates typically seen with standard second-line chemotherapy. These encouraging outcomes were key to the study’s selection for oral presentation.
Oncology Frontier: Compared to traditional chemotherapy, what are the core mechanistic advantages of BL-B01D1 as a bispecific ADC targeting EGFR and HER3 in SCLC?
Dr. Yan Huang: SCLC treatment is relatively unique. Aside from a few rare targets such as DLL3, the disease remains largely chemotherapy-driven. This contrasts sharply with non-small cell lung cancer (NSCLC), where there are well-defined targeted therapy pathways for driver mutations such as EGFR, ALK, and MET. From the current data, BL-B01D1’s breakthrough potential lies in its dual capacity: whether in second-line or later-line settings following standard regimens, the drug delivers strong ORR, PFS, and OS outcomes. I believe these results stem from its distinct bispecific ADC design. On the one hand, EGFR and HER3 are commonly overexpressed in SCLC, giving the drug high tumor selectivity and targeting precision. On the other hand, its innovative linker and optimized payload design enable higher intracellular drug concentrations while minimizing systemic toxicity. This overcomes the traditional dilemma in chemotherapy of balancing potency with safety. For patients with chemo-sensitive SCLC, prolonged and well-tolerated treatment can ultimately translate into clinically meaningful survival benefits.
Oncology Frontier: BL-B01D1 has already shown promise in other solid tumors. Based on its results in SCLC, how would you assess its future potential in broader cancer treatment?
Dr. Yan Huang: The main advantage of BL-B01D1 as a bispecific ADC lies in its precision targeting. The EGFR/HER3 dual-target design could offer enhanced efficacy in tumors with high expression of these markers, such as urothelial carcinoma and breast cancer. ADCs themselves, by delivering cytotoxic payloads directly to tumor cells, break through the intensity limitations of traditional chemotherapy and provide patients with more durable responses.
That said, there are two critical areas where ADC development needs to advance. First, most current ADCs are based on a single cytotoxic payload, such as a topoisomerase inhibitor. However, standard treatments for many solid tumors—lung cancer included—often rely on combination regimens like platinum-based doublet chemotherapy. How to integrate classic agents like platinum into ADCs and move them from later-line to frontline treatment is a crucial direction to explore. Second, toxicity management must be further optimized. Although this study reported manageable safety, hematologic toxicities were still observed. Future ADCs should aim to reduce systemic toxicity through improved linker technologies or payload designs while preserving efficacy.
Beyond this, we need to investigate new molecular targets, develop more efficient payloads, and design post-ADC resistance treatment strategies. These will be key elements to focus on moving forward.
Reference:
Yan Huang, Li Zhang, Yuxiang Ma, 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 small cell lung cancer (SCLC). ASCO 2025; Abstract 3002.
About Dr. Yan Huang
· MD, PhD, Professor and Doctoral Supervisor
· Chief Physician, Department of Internal Medicine
· Sun Yat-sen University Cancer Center
Key Roles and Affiliations:
· Vice Chair, Cancer Rehabilitation and Palliative Care Committee, Chinese Anti-Cancer Association (CACA)
· Executive Member, Committee on Supportive and Rehabilitative Care, Chinese Society of Clinical Oncology (CSCO)
· Executive Member, CSCO Committee on Geriatric Oncology
· Chair, Committee on Cancer Rehabilitation and Palliative Care, Guangdong Anti-Cancer Association
· Vice Chair, Committee on Chemotherapy, Guangdong Anti-Cancer Association
· Vice Chair, Committee on Precision Medicine, Guangdong Clinical Medical Association
· Vice Chair, Committee on Lung Cancer Precision Therapy and Clinical Research, Guangdong Clinical Medical Association
