Real-world efficacy and safety of bispecific antibody ivonescimab-based regimens in EGFR-TKI–resistant advanced NSCLC.

8577 Background: Ivonescimab is a first-in-class bispecific monoclonal antibody targeting programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF)-A. In the phase III HARMONi-A trial, ivonescimab plus chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone in patients with epidermal growth factor receptor (EGFR)-mutant advanced non–small cell lung cancer (NSCLC) after resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, in real-world clinical practice, ivonescimab is administered across heterogeneous treatment lines after EGFR-TKI resistance, and evidence regarding its effectiveness in these settings remains limited. Methods: This real-world study included patients with advanced NSCLC who received ivonescimab plus chemotherapy following progression on EGFR-TKIs. The primary endpoints were median PFS (mPFS) and safety. Results: A total of 254 patients were included. At the data cutoff of November 30, 2025, the median follow-up was 8.9 months. The median age was 61 years; 54.3% were female, and 48.0% had brain metastases. The overall objective response rate (ORR) was 47.9%, with a mPFS of 6.9 months (95% CI, 6.2–7.5). A total of 124 patients were treated with ivonescimab plus chemotherapy immediately after EGFR-TKI resistance with HARMONi-A–like sequence and achieved an ORR of 52.9% with a mPFS of 7.0 months (95% CI, 4.5–9.4). The other 130 patients receiving ivonescimab plus chemotherapy after failure of prior immunotherapy-, anti-angiogenic therapy-, and/or chemotherapy-based regimens achieved an ORR of 43.1% with a mPFS of 6.7 months (95% CI, 6.0–7.4). No statistically significant difference in PFS was observed between the two groups ( p = 0.269). Grade 3–4 adverse events occurred in 14.6% of patients, including leukopenia (n = 9), neutropenia (n = 7), immune-related pneumonia (n = 6), and checkpoint inhibitor–related myocarditis (n = 5). Given the relatively short follow-up, overall survival data were not mature. Conclusions: In this real-world cohort, ivonescimab plus chemotherapy demonstrated clinically meaningful efficacy and a manageable safety profile when administered both immediately after EGFR-TKI resistance and following multiple prior lines of therapy, supporting its use across diverse treatment sequences in patients with EGFR-mutant advanced NSCLC.