To analyze the clinical significance of potential genomic characteristic factors in predicting the response to immune checkpoint inhibitors (ICIs) combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).

A total of 52 patients with advanced NSCLC without baseline EGFR/ALK/ROS1 mutations, who received at least two cycles of ICIs and chemotherapy were enrolled in our hospital from January 2021 to February 2023. Pre-treatment plasma samples were collected for DNA extraction and circulating tumor DNA (ctDNA)-based targeted sequencing. After the first anti-PD-L1 antibody treatment, the responders 26 cases were divided into an observation group and non responders 26 cases in a control group. Patient objective response rate (ORR) and progression-free survival (PFS) were recorded during follow-up.

The ORR for ICIs combined with chemotherapy was 50.0%, 26 cases of partial response (PR), 15 cases of stable disease (SD), 11 cases of disease progression (PD). The median PFS for all 52 patients was 6.27 months (IQR: 3.05~9.40). During the follow-up period, 33 cases survived (63.46%)and 19 cases died(36.54%). The cause of death was PD. Age (P=0.021), smoking history (P=0.013), and first-line treatment (P=0.020) were associated with treatment response. Multi-organ metastasis (HR=2.73, 95%CI: 1.30~5.76, P=0.002) and later-line ICIs treatment (HR=0.32, 95%CI=0.15~0.67, P=0.002) were factors affecting PFS. Baseline ctDNA status, tumor mutational burden (TMB), and maximum somatic allele frequency showed no correlation (P>0.05). However, univariate and multivariate analyses revealed that RB1 mutation (OR=7.15, P=0.031) was associated with a poor response to ICIs combined with chemotherapy. RB1 mutation (vs. wild-type: log-rank=4.131, P=0.042) was associated with shorter PFS. Multivariate COX analysis showed that RB1 mutation was associated with worse PFS (HR=1.95, P=0.011), independent of PD-L1 expression status, TMB, tumor size, and C-reactive protein levels. TCGA prognostic data confirmed that NSCLC patients with RB1 mutations had a worse prognosis compared to those receiving PD-L1 combination therapy (P=0.012).

ctDNA-RB1 mutation is associated with poor PFS in advanced NSCLC patients treated with ICIs combined with chemotherapy. The ctDNA-RB1 mutation status may serve as a biomarker for predicting PFS.