Phase 1b study of izalontamab brengitecan for LA/M NSCLC with genomic alterations outside of classical EGFR mutations

A multicenter phase 1b study in China evaluated izalontamab brengitecan (iza-bren) in patients with locally advanced or metastatic non-small cell lung cancer (LA/M NSCLC) harboring actionable genetic alterations outside of the classical EGFR mutations, with progression after one previous line of chemotherapy. Patients received iza-bren at a dose of 2.5 mg/kg at days 1 and 8 of 3-week cycles. Among 83 patients, 14 had EGFR exon20ins/nonclassical mutations, 19 had HER2 mutation, 26 had KRAS/BRAF/MET mutation, and 24 had ALK/ROS1/RET/NTRK fusion. The primary endpoint was safety. The most common grade ≥ 3 treatment-related adverse events were thrombocytopenia (51.8%), anemia (44.6%), and neutropenia (43.5%), whereas the most frequent nonhematologic TRAEs of all grades were nausea (49.4%), asthenia (45.8%), stomatitis (44.6%), and diarrhea (38.6%). The confirmed objective response rate was 39.7% and the disease control rate was 85.9%; median progression-free survival was 7.0 months (95% CI 5.4-10.5), while overall survival data were immature. Patients with EGFR exon29ins or other nonclassical mutations achieved an ORR of 69.5% with a median PFS of 10.5 months (95% CI 6.9-NR); the HER2-mutant cohort had an ORR of 52.9% and a median PFS of 7.5 months (5.4-NR). The authors conclude that iza-bren demonstrated encouraging antitumor activity and a manageable safety profile in pretreated LA/M NSCLC with diverse genetic alterations.