PD-1/ PD-L1 bispecific antibody IBI318 combined with lenvatinib in advanced non-small cell lung cancer with acquired resistance to immune checkpoint inhibitors: a phase II trial.

Immune checkpoint inhibitors (ICIs) have improved survival in advanced non-small cell lung cancer (NSCLC), yet resistance remains a major challenge. Here, we report the results from cohort A of a multi-cohort, phase II, open-label trial [NCT04777084], evaluating the efficacy and safety of IBI318 (a bispecific anti-PD-1/PD-L1 antibody, 300 mg intravenous every 2 weeks) plus lenvatinib (a receptor tyrosine kinase inhibitor, 8 mg orally daily). Forty patients with advanced NSCLC and acquired resistance to first-line ICIs were enrolled and received at least 1 cycle of the study regimen. The primary endpoint of 12-week objective response rate was 40.0% (95% CI: 24.9-56.7), satisfying prespecified efficacy threshold. Secondary endpoints included other efficacy endpoints and safety. Median progression-free and overall survival were 6.9 months (95% CI: 4.8-9.5) and 18.2 months (95% CI: 10.7-29.1), respectively. The most common treatment-related adverse event was increased thyroid-stimulating hormone (n = 11). Grade ≥3 adverse events occurred in 12.5% (5/40) of patients. Further, we performed a post-hoc exploratory analysis and developed an XGBoost model (scPro-X) using scRNA-seq data from pre-treatment tumor samples to predict 12-week ORR identified CD4_Tfh_CXCL13 and CD8_Tex_CTLA4 as potential biomarkers predictive of response. These findings demonstrate that IBI318 plus lenvatinib exhibit promising clinical activity and a manageable safety profile in patients with advanced NSCLC.