Narrative review: blood and tumor biomarker testing in non-small cell lung cancer without an oncogenic driver

Background and Objective: For patients with metastatic non-small cell lung cancer (NSCLC) without an oncogenic driver, systemic therapy with immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have significantly improved the outcomes. However, the majority of patients do not have a durable response, and there is a need for additional predictive biomarkers. The objective of this narrative review is to describe potential biomarkers for immunotherapy.Methods: Narrative overview of the literature synthesizing the findings of literature reporting retrospective, prospective, and subset analyses of studies investigating potential predictive biomarkers for ICI.Key Content and Findings: Tumor expression of programmed death ligand-1 (PD-L1) is the only clinically available biomarker for patients receiving ICI-based therapy. However, PD-L1 has significant limitations and studies have investigated the predictive value of higher PD-L1 expression levels. There has been interest in tumor mutation burden (TMB) based on the premise that a higher TMB would be associated with a more neoantigens, which would increase the likelihood of an immune response. The studies to date have not revealed a consistent association with TMB level and survival benefit. Kelch-like ECH Associated Protein 1 (KEAP1) and serine/threonine kinase 11 (STK11) mutations have been associated with worse outcomes with ICI but these mutations appear to be associated with a worse prognosis, and not predictive for ICI. Tumor infiltrating lymphocytes (TIL's) are the mechanism of immune response, and there is interest in further investigating the presence, type and distribution of TIL's to predict immune benefit. Circulating tumor deoxyribonucleic acid (ctDNA) levels, at baseline and on treatment samples, are being investigated to assess response to therapy and long-term benefit of ICI.Conclusions: None of the current biomarkers in development are validated for use in routine clinical care. Given the complexity of NSCLC biology and immune response to ICI most likely a composite biomarker using multiple biomarkers will need to be develop.