Izalontamab Brengitecan in Locally Advanced or Metastatic Non–Small Cell Lung Cancer With Actionable Genomic Alterations Outside of Classical EGFR Mutations: A Phase Ib Study

PURPOSE To evaluate the safety and efficacy of izalontamab brengitecan (iza-bren) in patients with non–small cell lung cancer (NSCLC) harboring actionable genomic alterations (GAs) outside of classical epidermal growth factor receptor ( EGFR ) mutations. METHODS Eligible patients had locally advanced or metastatic NSCLC with prespecific actionable GAs, had progressed after standard treatment and received no more than one previous line of chemotherapy. iza-bren was administered at the dose of 2.5 mg/kg once per day on days 1 and 8 of each 3-week cycle. The primary end point was safety. The secondary end points included objective response rate (ORR), disease control rate (DCR), and duration of response. The exploratory end points included progression-free survival (PFS) and overall survival (OS). RESULTS A total of 83 patients with NSCLC were enrolled in four cohorts: EGFR exon20ins/nonclassical mutations (n = 14), human epidermal growth factor receptor 2 ( HER2 ) mutation (n = 19), KRAS / BRAF / MET mutation (n = 26), and ALK / ROS1 / RET / NTRK fusion (n = 24). The most common grade ≥3 treatment-related adverse events (TRAEs) were thrombocytopenia (51.8%), anemia (44.6%), and neutropenia (43.4%). The most frequent nonhematologic TRAEs of all grades were nausea (49.4%), asthenia (45.8%), stomatitis (44.6%), and diarrhea (38.6%). One case of grade 2 interstitial lung disease was observed. The confirmed ORR was 39.7%, and the DCR was 85.9%. The median PFS was 7.0 months (95% CIs, 5.4 to 10.5), while OS data were immature. Patients with EGFR exon20ins or other nonclassical mutations achieved an ORR of 69.2% with a median PFS of 10.5 months (95% CI, 6.9 to not reached); the HER2 -mutant cohort had an ORR of 52.9% and a median PFS of 7.5 months (95% CI, 5.4 to not reached). CONCLUSION iza-bren demonstrated encouraging antitumor activity and a manageable safety profile in pretreated NSCLC patients with diverse GAs outside of classical EGFR mutations, especially in EGFR exon20ins/nonclassical and HER2 mutations.