After the concept of immune checkpoint inhibition was introduced, research efforts in non–small-cell lung cancer (NSCLC) changed dramatically. Today, 2 anti–PD-1 antibodies, nivolumab and pembrolizumab, and 1 anti–PD-L1 antibody, atezolizumab, are approved for the treatment of patients with NSCLC based on reproducible effects of tumor response and survival benefits. In second-line NSCLC, these antibodies significantly improved survival compared with standard care of cytotoxic chemotherapy. In the first-line setting, recent data demonstrate that nivolumab did not extend progression-free survival (PFS) compared with chemotherapy, while pembrolizumab was superior to chemotherapy. Both trials selected patients on the basis of PD-L1 expression in lung cancer cells.
Despite a tendency for correlation between PD-L1 expression and objective response and survival, responses to these antibodies can be observed in PD-L1–negative patients. Key questions relate to identification of responsive patients and elimination of checkpoint inhibitor exposure for patients who are less likely to respond.
The development of molecularly targeted drugs in NSCLC directly reflects the critical value of translational work. EGFR-targeted tyrosine kinase inhibitors were the first to change the lung cancer treatment paradigm. Today, EGFR and other driver mutations classify NSCLC into genomic subtypes. Rare mutations, including ROS, RET, and ALK fusions; ERB2 mutation or amplification; BRAF mutation; MET amplification; and PIK3 mutations, can be targeted with novel agents in clinical trials. The future of NSCLC management will continue to be marked by further refinement in patient selection and use of precision medicine.
