Immune Checkpoint Inhibitors in Lung Cancer: Role of Biomarkers and Combination Therapies

Lung cancer is the leading cause of cancer-related death worldwide, with a poor prognosis. Despite aggressive treatment, progression-free survival (PFS) and overall survival are limited. Recently, various kinds of immune checkpoint inhibitors (ICIs) have emerged for several cancers, targeting PD1, PDL1, and CTLA-4. ICIs have made a significant breakthrough in cancer and revolutionized the management of cancer including lung cancer. However, there are a lot of controversies regarding which group of patients is most suitable to be treated with ICIs in terms of monotherapy, combination, and predictive biomarkers. We reviewed various kinds of studies, such as meta-analysis, randomized control trials, multi-center cohort studies, and case-control studies from PubMed written in English from the last five years. ICIs have significant benefits in the overall survival compared with traditional chemotherapy. Patients with a higher level of PDL1 expression and high tumor mutational burden (TMB) have a higher response rate, and those with EGFR-/ALK- were better than those with EGFR+/ALK+. The patient who responded to immunotherapy completely can still maintain the efficacy after two years of treatment. Neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer resulted in a 45% major pathology response (MPR) and 40% downstaging. Combined therapy (ICIs + chemotherapy) was better than chemotherapy alone, irrespective of PD-L1 expression. A combination of ICIs such as CTLA-4 and PD-1/PD-L1 improved PFS as well. Radiochemotherapy ahead of ICIs is promising as well. However, ICIs combined with EGFR/ALK-TKI (tyrosine kinase inhibitor) are not suggested for the time being. PDL1 expression, TMB, and EGFR/ALK mutations are promising predictive biomarkers. Gut microbiota, galectin-3, and intensity of CD8 cell infiltration are other potential predictive biomarkers. These are very important in the future management of lung cancers as they can prevent unnecessary toxicities and cost of treatment.