Iza-Bren Yields Encouraging Activity in Extensive-Stage SCLC

Izalontamab brengitecan (iza-bren; BL-B01D1), a first-in-class EGFR/HER3 bispecific antibody-drug conjugate (ADC), demonstrated encouraging antitumor activity in patients with previously treated extensive-stage small cell lung cancer (ES-SCLC), according to results from a phase 1b study (NCT05194982) published in the Journal of Clinical Oncology.¹

How effective was iza-bren in ES-SCLC?

Among the 52 patients enrolled, the objective response rate (ORR) was 48.1% (95% CI, 34.0%-62.4%), the median progression-free survival (PFS) was 4.1 months (95% CI, 3.0-5.5), and the median overall survival (OS) was 12.2 months (95% CI, 9.1-13.2); and the median duration of response (DOR) was 4.9 months (95% CI, 4.2-6.7). Among patients who received iza-bren as second-line treatment (n = 22), the ORR was 72.7% (95% CI, 49.8%-89.3%), the disease control rate (DCR) was 90.9% (95% CI, 70.8%-98.9%), the median PFS was 6.2 months (95% CI, 3.7-8.2), and the median OS was 15.0 months (95% CI, 8.7-not reached).

How safe was iza-bren in ES-SCLC?

Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 75% of patients, leading to dose reductions in 46% and treatment discontinuation in 13%. The most common TRAEs were hematologic toxicities, which included neutropenia, thrombocytopenia, anemia, and leukopenia, along with gastrointestinal events such as stomatitis.

No treatment-related interstitial lung disease was observed. Two patients (3.8%) experienced grade 5 TRAEs leading to death, including 1 case of respiratory failure and 1 gastrointestinal event.

The randomized controlled phase 3 PANKU-Lung03(NCT06500026) trial comparing iza-bren with topotecan is ongoing and, according to the authors, will provide more definitive data.²

"In summary, iza-bren demonstrated encouraging antitumor activity and a manageable safety profile in relapsed ES-SCLC," corresponding author Yan Huang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, wrote in the publication with study coinvestigators.¹ “The ongoing phase 3 trial will provide more definitive evidence.”

How was the phase 1b study designed?

The open-label, multicenter, dose-expansion phase 1b study enrolled patients with ES-SCLC who had progressed on prior systemic therapies. As of the data cutoff of December 5, 2024, 52 patients had been enrolled, all of whom had received prior platinum-based chemotherapy. Patients received iza-bren at 2.5 mg/kg once daily on days 1 and 8 of each 3-week cycle. Iza-bren cotargets EGFR and HER3, the latter of which contributes to cell survival through heterodimerization with other ErbB receptors and has been implicated in lineage plasticity and treatment resistance.

The primary end points of the study were ORR and safety/tolerability. Secondary end points included DCR, DOR, PFS, and OS; an exploratory end point assessed potential associations between EGFR/HER3 expression and clinical outcomes.

Patients 18 years and older with a life expectancy of at least 3 months, an ECOG performance status of 0 or 1, adequate organ function, and histologically or cytologically confirmed SCLC that progressed after at least 1 line of platinum-based chemotherapy were eligible for enrollment. Having at least 1 measurable lesion per RECIST v1.1 criteria was another requirement for study entry.

An exploratory biomarker analysis suggested that positive HER3 expression may be associated with better treatment response. In vitro analyses across a panel of SCLC cell lines showed that iza-bren internalization tended to be greater in cell lines with higher EGFR expression.

According to the investigators, study limitations included the single-arm design and limited sample size, particularly for subgroup analysis, which constrained definitive conclusions. Additionally, the translational findings were regarded as exploratory and hypothesis-generating. The authors noted that predictive biomarkers for ADCs in SCLC remain elusive and complex, and that larger prospective cohorts and more extensive evaluation are warranted.

References

1. Zhao Y, Zhao H, Wang Q, et al. Izalontamab brengitecan (iza-bren), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate in extensive-stage small cell lung cancer: results from a phase Ib study. J Clin Oncol. Published online July 24, 2026. doi:10.1200/JCO-26-00243
2. A study comparing BL-B01D1 with topotecan in patients with recurrent small cell lung cancer(PANKU-Lung03). ClinicalTrials.gov. Updated April 17, 2026. Accessed August 12, 2026. https://tinyurl.com/57u2rbds