Early identification of efficacy and toxicity-related markers in non-small cell lung cancer patients treated with immune checkpoint inhibitors

Background: Patients with advanced Non-Small Cell Lung Cancer (NSCLC) non-oncogene addicted could benefit from immunotherapy alone or in combination with chemotherapy. Predictive factors of response/resistance are not so defined. In this study we looked for biomarkers that could predict benefit and adverse events from immunotherapy. Methods: tissues and peripheral blood samples from 75 patients, were analyzed at baseline and blood also at the progression of disease. The TruSightTM Oncology 500 target panel (Illumina) was applied to analyse 523 cancer-related genes, TMB and MSI. Circulating levels of PD-L1, CTLA-4, TIM-3, and LAG-3 were determined by ELISA multiplex technique. Survival distributions were estimated using the Kaplan-Meier method and compared across groups with the log-rank test. The association of clinicopathological variables with survival outcomes was assessed using Cox proportional hazards models. Associations between circulating protein (PD-L1, CTLA-4, TIM-3, and LAG-3) levels and patients’ clinical outcomes were evaluated using Student’s t-test. Results: Among 75 patients progression free survival (PFS) was influenced by kind of therapy (p-value 0.035), number of metastatic sites (p-value 0,046) and the sites of metastases at the diagnosis (p-value 0,023). Overall survival (OS) was influenced by ECOG (p-value 0.028) and number of metastatic sites (p-value 0.025). Mutations in LRP1B gene are related to better PFS (p-value=0,022) and OS (p-value=0,006). Comparing at baseline and progression disease (PD) plasma samples, increase in TIM-3 levels was significantly associated with PD (p=0.005). Conclusion: PFS seem influenced by having at the diagnosis metastases in brain and/or liver or more than 3 metastatic sites. Mutations in LRPB1 gene are related to a better PFS as well as better OS. OS is also influenced by having metastases in brain and/or liver or 3 or more metastatic sites at the diagnosis and by a worse ECOG at the baseline. TIM-3 levels increased significantly in plasma samples collected at PD.