Cadonilimab plus chemotherapy as first-line treatment in PD-L1-negative advanced non-small cell lung cancer: a phase II clinical trial.

Although immunotherapy is approved for patients with high PD-L1 expression, optimal therapeutic strategies for PD-L1-negative populations remain undefined. This study (ChiCTR2300071681) assessed the efficacy and safety of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus chemotherapy in patients with PD-L1-negative advanced non-small-cell lung cancer (NSCLC). The primary endpoint, 12-month progression-free survival (PFS) rate, is 42.1% (95% CI, 29.6%-60.0%), which has reached the prespecified threshold. Secondary endpoints include a median overall survival of not reached, a median PFS of 9.7 months, an objective response rate of 66.0%, a disease control rate of 100.0%, and a median duration of response of 9.5 months. Grade ≥3 treatment-related adverse events occur in 26 (52.0%) patients. cfDNA methylation-based molecular response predicts the actual clinical response approximately 5 cycles earlier than conventional radiographic evaluation. Baseline differentially methylated fragments scores show a significant correlation with PFS, with low-risk patients demonstrating a longer median PFS compared to high-risk patients (11.4 months versus 6.9 months). Overall, first-line cadonilimab plus chemotherapy shows an encouraging efficacy with a manageable safety profile for challenging-to-treat PD-L1-negative advanced NSCLC, warranting further evaluation in controlled studies.