Baseline tumor burden predicts the efficacy of first-line chemoimmunotherapy in patients with advanced non-small cell lung cancer: results from 2 phase 3 randomized placebo-controlled trials

Baseline tumor burden (TB), measured radiographically, has emerged as a potential biomarker for stratifying survival outcomes with immune checkpoint inhibitors (ICI) across solid tumors. However, the predictive value for ICI plus chemotherapy (chemoimmunotherapy) in NSCLC has not been confirmed with large cohorts that include a chemotherapy-only control group. This post hoc analysis utilized data from ORIENT-11 trial, a phase III, randomized clinical trial of advanced NSCLC patients who were administered with either chemoimmunotherapy or chemotherapy alone. TB was measured as the sum of the diameters of target lesions at baseline following RECIST 1.1 criteria. The relationships between baseline TB and outcomes were assessed using the Cox proportional hazards model. Validation was conducted using data from ORIENT-12 trial. In chemoimmunotherapy arm, patients with low TB demonstrated longer progression-free survival (PFS: 11.60 vs. 7.20 months, hazard ratio [HR] = 0.625, p = 0.004) and overall survival (OS: 28.77 vs. 20.10 months, HR = 0.683, p = 0.020) compared to those with high TB. In the chemotherapy-only arm, no significant survival differences were observed based on TB levels. Multivariate analyses confirmed that regardless of tumoral PD-L1 expression, low TB as an independent marker of improved survival with chemoimmunotherapy. Patients with high TB and low PD-L1 expression had the shortest survival, deriving minimal benefit from chemoimmunotherapy over chemotherapy alone (PFS: 5.53 vs. 5.07 months; OS: 10.52 vs. 13.80 months). These findings were validated in ORIENT-12 cohort. Baseline TB is a predictive, rather than prognostic, clinical biomarker for survival outcomes in advanced NSCLC patients treated with chemoimmunotherapy. TB assessment, integrated with PD-L1 status evaluation, may improve patient stratification for first-line chemoimmunotherapy in clinical practice and provide valuable insight for the clinical trials designs.