Background
Phase 3, multicentre, open-label, randomized trial at 73 sites in China. N=432. EGFR-mutated advanced non-squamous NSCLC after progression on a third-generation EGFR TKI, no prior chemotherapy for advanced disease. Izalontamab brengitecan (iza-bren) is a first-in-class EGFR x HER3 bispecific ADC.
Results
Interventions and follow up: Arm A: iza-bren 2.5 mg/kg IV days 1 and 8 q3w (n=217)
Arm B: pemetrexed + carboplatin or cisplatin x4-6 cycles, pemetrexed maintenance allowed (n=215)
Primary endpoint: PFS (BICR)
mFollow up: 14.6 mo (iza-bren) vs 15.2 mo (chemotherapy)
Results: PFS: median 11.1 mo (9.2-12.7) vs 5.7 mo (5.5-5.9); HR 0.40 (0.31-0.51); one-sided P<.0001
OS: interim analysis, NR in abstract
Arm B: pemetrexed + carboplatin or cisplatin x4-6 cycles, pemetrexed maintenance allowed (n=215)
Primary endpoint: PFS (BICR)
mFollow up: 14.6 mo (iza-bren) vs 15.2 mo (chemotherapy)
Results: PFS: median 11.1 mo (9.2-12.7) vs 5.7 mo (5.5-5.9); HR 0.40 (0.31-0.51); one-sided P<.0001
OS: interim analysis, NR in abstract
Adverse events
Grade ≥3 TRAEs: 79% vs 62% (predominantly hematologic)
Discontinuation (≥1 component): 2% vs 2%
Treatment-related deaths: 1 vs 1
Treatment-related ILD: 2 (1%) vs 0
Discontinuation (≥1 component): 2% vs 2%
Treatment-related deaths: 1 vs 1
Treatment-related ILD: 2 (1%) vs 0
Conclusions
Iza-bren significantly prolonged PFS versus platinum chemotherapy after progression on third-generation EGFR TKIs, with more grade ≥3 toxicity. This is the first phase 3 evidence for a bispecific ADC.
Key Limitations
Open-label; China-only population. OS is interim and immature. Primary analysis in the modified ITT population (treated patients). Comparator is platinum-pemetrexed, not the contemporary post-osimertinib comparator of amivantamab-based or other ADC regimens (e.g., HER3-DXd, sac-TMT), and no crossover data are given. Higher grade ≥3 AE rate (79% vs 62%).
Clinical Context
After osimertinib, platinum-pemetrexed chemotherapy (with or without amivantamab or other agents, per local availability) remains the usual next step; TROP2 and HER3 ADCs are emerging. PANKU-Lung01 supports iza-bren as a candidate option, but OS data, global validation, and regulatory review are pending. No approval is cited here.
