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Izalontamab Brengitecan (Iza-Bren), a First-in-Class EGFR-HER3 Bispecific Antibody-Drug Conjugate in Extensive-Stage
Yuanyuan Zhao1, Hongyun Zhao2, Qiming Wang3
1Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Purpose:
Small cell lung cancer (SCLC) remains one of the most aggressive malignancies, with limited treatment options beyond frontline chemo-immunotherapy. Izalontamab brengitecan (iza-bren, BL-B01D1) is a first-in-class bispecific antibody-drug conjugate cotargeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). We expanded the SCLC cohort to further evaluate the efficacy and safety of iza-bren in patients with extensive-stage SCLC (ES-SCLC).
Methods:
This open-label, multicenter, dose-expansion phase Ib study (ClinicalTrials.gov identifier: NCT05194982) enrolled patients with ES-SCLC who had progressed on prior systemic therapies. Patients received iza-bren 2.5 mg/kg once daily on days 1 and 8 of each 3-week cycle. The primary end points were objective response rate (ORR) and safety/tolerability. Secondary end points included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory end point included the assessment of potential associations between EGFR/HER3 expression and clinical outcomes.
Results:
As of December 5, 2024, 52 patients were enrolled. The ORR was 48.1% (95% CI, 34.0 to 62.4), with a median PFS of 4.1 months (95% CI, 3.0 to 5.5) and a median OS of 12.2 months (95% CI, 9.1 to 13.2). In patients who received iza-bren as second-line treatment (n = 22), the ORR was 72.7% (95% CI, 49.8 to 89.3), median PFS 6.2 months (95% CI, 3.7 to 8.2), and median OS 15.0 months (95% CI, 8.7 to not reached). The most common treatment-related adverse events were hematologic toxicities (neutropenia, thrombocytopenia, anemia, and leukopenia). Exploratory biomarker analysis suggested that positive HER3 expression may be associated with better treatment response.
Conclusion:
Iza-bren showed encouraging antitumor activity in relapsed ES-SCLC, particularly in the second-line setting. A phase III randomized controlled trial of iza-bren compared with topotecan (ClinicalTrials.gov identifier: NCT06500026) is ongoing.
Insights
Izalontamab brengitecan (iza-bren) shows promise in treating extensive-stage small cell lung cancer (SCLC) that has relapsed. This bispecific antibody-drug conjugate demonstrated encouraging antitumor activity, especially in patients receiving second-line treatment.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options.
- Frontline chemo-immunotherapy is standard, but outcomes for relapsed disease are poor.
- Izalontamab brengitecan (iza-bren) is a novel bispecific antibody-drug conjugate targeting EGFR and HER3.
Purpose of the Study:
- To evaluate the efficacy and safety of iza-bren in patients with extensive-stage SCLC (ES-SCLC).
- To expand the SCLC cohort in a phase Ib study to further assess iza-bren's potential.
- To investigate the association between EGFR/HER3 expression and clinical outcomes.
Main Methods:
- Open-label, multicenter, dose-expansion phase Ib study (NCT05194982).
- Enrollment of patients with ES-SCLC who progressed on prior therapies.
- Treatment with iza-bren at 2.5 mg/kg once daily on days 1 and 8 of 3-week cycles.
- Primary endpoints: objective response rate (ORR) and safety. Secondary endpoints: DCR, DOR, PFS, OS.
Main Results:
- 52 patients enrolled; ORR was 48.1% (95% CI, 34.0-62.4).
- Median PFS was 4.1 months (95% CI, 3.0-5.5); median OS was 12.2 months (95% CI, 9.1-13.2).
- In second-line patients (n=22), ORR was 72.7%, median PFS 6.2 months, median OS 15.0 months.
- Common toxicities included hematologic events; positive HER3 expression may correlate with better response.
Conclusions:
- Iza-bren demonstrates encouraging antitumor activity in relapsed ES-SCLC.
- The drug shows particular promise in the second-line treatment setting.
- A Phase III trial comparing iza-bren with topotecan (NCT06500026) is currently ongoing.
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