Choosing the best first-line therapy: NSCLC with no actionable oncogenic driver

Combination platinum-based therapy has been the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC). Immunotherapy has emerged and demonstrated to show benefit in the treatment of patients with advanced NSCLC. In this review, we discuss the pivotal trials that led to the US FDA approval of specific immunotherapy regimens in particular patient populations. We discuss the optimal use of immunotherapy as monotherapy based on the KEYNOTE-024, KEYNOTE-042 and IMpower110 trials, chemo-immunotherapy based on KEYNOTE-189, KEYNOTE-407, IMpower150 and IMpower130 trials, and as doublet immunotherapy based on CheckMate-227. We also discuss the role and limitations of PD-L1 expression and tumor mutational burden as predictive biomarkers in response to single-agent immunotherapy and combination chemoimmunotherapy. Furthermore, we discuss emerging resistance markers such as STK11 and KEAP1 mutations in immunotherapy response and briefly discuss the role of immunotherapy in elderly patients and in patients with actionable mutations.