Related Experiment Video
Updated: Jan 31, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Izalontamab brengitecan (Iza-bren; BL-B01D1), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, for
Background:
Therapeutic options after progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain limited for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Izalontamab brengitecan (Iza-bren; BL-B01D1) is a first-in-class bispecific antibody-drug conjugate targeting EGFR and human epidermal growth factor receptor 3 (HER3) with preclinical and early clinical activity.
Patients And Methods:
We pooled individual patient data from a phase Ia/Ib dose-escalation/expansion trial (BL-B01D1-101; NCT05194982) and a phase II multicohort trial (BL-B01D1-203; NCT05880706) in patients with advanced EGFR-mutated NSCLC who had disease progression on prior EGFR TKI therapy. Key endpoints were confirmed objective response rate (cORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The recommended phase II dose (RP2D) was 2.5 mg/kg on days 1 and 8 every 3 weeks.
Results:
A total of 171 patients were included (data cut-off 30 June 2025; median follow-up 20.5 months). In the pooled population, cORR was 47.4% [95% confidence interval (CI) 39.7% to 55.1%] and DCR was 81.3% (95% CI 74.6% to 86.8%); median DoR was 8.5 months (95% CI 6.9-11.2 months), median PFS was 6.9 months (95% CI 5.5-9.6 months), and median OS was 24.8 months (95% CI 18.5 months to not reached). Efficacy at the RP2D (n = 121) was consistent (cORR 48.8%; DCR 81.0%; median PFS 6.9 months; median OS 24.8 months). In chemotherapy-naive, post-TKI patients treated at the RP2D (n = 50), cORR was 56.0%, DCR was 90.0%, median DoR was 13.7 months, median PFS was 12.5 months, and median OS was not reached. Treatment-related adverse events occurred in 98.8% (grade ≥3: 70.2%), predominantly hematologic; interstitial lung disease was rare (0.6%, all grade 1). Discontinuation for treatment-related adverse events was 1.2%; no treatment-related deaths were reported.
Conclusions:
In this exploratory post hoc pooled analysis, Iza-bren demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated EGFR-mutated NSCLC. These findings are hypothesis-generating and are being further evaluated in ongoing randomized trials.
Insights
Izalontamab brengitecan (Iza-bren) shows promising results for EGFR-mutated non-small cell lung cancer (NSCLC) patients who progressed on TKIs. This bispecific antibody-drug conjugate demonstrated significant antitumor activity and a manageable safety profile in a pooled analysis.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Limited therapeutic options exist for patients with EGFR-mutated non-small cell lung cancer (NSCLC) following progression on EGFR tyrosine kinase inhibitors (TKIs).
- Izalontamab brengitecan (Iza-bren; BL-B01D1), a novel bispecific antibody-drug conjugate targeting both EGFR and HER3, has shown early promise in preclinical and clinical studies.
Purpose of the Study:
- To evaluate the efficacy and safety of Izalontamab brengitecan (Iza-bren) in patients with advanced EGFR-mutated NSCLC who have progressed on prior EGFR TKI therapy.
- To determine the recommended phase 2 dose (RP2D) for Iza-bren and assess its activity in specific patient subgroups.
Main Methods:
- A pooled analysis of individual patient data from a phase 1a/1b dose-escalation/expansion trial (BL-B01D1-101) and a phase 2 multicohort trial (BL-B01D1-203).
- Included 171 patients with advanced EGFR-mutated NSCLC who progressed on EGFR TKI therapy.
- Key endpoints included confirmed objective response rate (cORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The RP2D was established at 2.5 mg/kg every 3 weeks.
Main Results:
- In the pooled population (n=171), Iza-bren achieved a cORR of 47.4% and a DCR of 81.3%, with a median DoR of 8.5 months, median PFS of 6.9 months, and median OS of 24.8 months.
- Efficacy at the RP2D (n=121) was consistent with the pooled population.
- In chemotherapy-naïve, post-TKI patients at the RP2D (n=50), cORR was 56.0%, DCR was 90.0%, median DoR was 13.7 months, and median PFS was 12.5 months. The safety profile was manageable, with predominantly hematologic TRAEs and rare interstitial lung disease.
Conclusions:
- Izalontamab brengitecan (Iza-bren) demonstrates promising antitumor activity and a manageable safety profile in heavily pretreated patients with EGFR-mutated NSCLC.
- These findings are hypothesis-generating and support further evaluation in ongoing randomized trials to confirm the clinical benefit of Iza-bren.
Related Concept Videos
01:14Phase II Conjugation Reactions: Overview
01:19Phase II Reactions: Miscellaneous Conjugation Reactions
A key example involves the conjugation of cyanide ions, which impair cellular respiration and alter hemoglobin into non-oxygen-carrying cyanmethemoglobin. To neutralize this threat, a sulfur atom from thiosulphate is transferred to the cyanide ion, catalyzed by the enzyme rhodanese, resulting in an inactive compound called thiocyanate. The production of...
02:39Phase Diagrams
02:31Phase Transitions
01:17Drug Metabolism: Phase I Reactions
01:14Drug Metabolism: Phase II Reactions