Izalontamab brengitecan versus platinum-based chemotherapy in EGFR-mutated advanced non-squamous non-small-cell lung cancer after progression on third-generation EGFR tyrosine kinase inhibitors (PANKU

Izalontamab brengitecan (iza-bren) is a first-in-class bispecific antibody-drug conjugate targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) and has shown antitumour activity in EGFR-mutated non-small-cell lung cancer (NSCLC). We compared iza-bren with platinum-based chemotherapy in participants with EGFR-mutated advanced non-squamous NSCLC after progression on third-generation EGFR tyrosine kinase inhibitors (TKIs). In this multicentre, randomised, open-label, phase 3 trial (PANKU-Lung01) conducted at 73 sites in China, eligible participants had EGFR-mutated locally advanced or metastatic non-squamous NSCLC, disease progression after third-generation EGFR TKIs, and had received no previous chemotherapy for advanced disease. Participants were randomly assigned (1:1) to receive iza-bren (2·5 mg/kg intravenously on days 1 and 8 of each 3-week cycle) or pemetrexed plus carboplatin or cisplatin for four to six cycles, with pemetrexed maintenance permitted in participants without progression. The primary endpoint was progression-free survival assessed by blinded independent central review (BICR). The primary analysis included all randomly assigned participants who received at least one dose of study treatment (modified intention-to-treat population). We report the prespecified final progression-free survival and interim overall survival analyses. This trial is registered with ClinicalTrials.gov, NCT06382116. Between May 22, 2024, and Sept 1, 2025, we screened 654 participants. After 222 (34%) were excluded, 432 (66%) participants were randomly assigned to iza-bren (n=217 [50%]) or chemotherapy (n=215 [50%]); 422 (98%) received study treatment (216 [51%] in the iza-bren group and 206 [49%] in the chemotherapy group) and comprised the modified intention-to-treat population. At the data cutoff (July 15, 2026; median follow-up for progression-free survival 14·6 months [95% CI 12·9-16·7] in the iza-bren group vs 15·2 months [11·2-18·2] in the chemotherapy group), median BICR-assessed progression-free survival was 11·1 months (9·2-12·7) with iza-bren versus 5·7 months (5·5-5·9) with chemotherapy (hazard ratio [HR] 0·40 [95% CI 0·31-0·51]; one-sided p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 170 (79%) of 216 participants in the iza-bren group and 128 (62%) of 206 in the chemotherapy group (predominantly haematological); treatment-related adverse events led to permanent discontinuation of at least one study-treatment component in four (2%) participants in each group and treatment-related deaths occurred in one participant in each group. Treatment-related interstitial lung disease occurred in two (1%) participants in the iza-bren group and none in the chemotherapy group. In participants with EGFR-mutated advanced non-squamous NSCLC after progression on third-generation EGFR TKIs, iza-bren significantly prolonged progression-free survival, although treatment-related adverse events of grade 3 or worse were more frequent than with chemotherapy. To our knowledge, these findings provide the first phase 3 evidence for a bispecific antibody-drug conjugate and support iza-bren as a potential treatment option in this population. Baili-Bio (Chengdu) Pharmaceutical.