In recent years, lung cancer has moved to the forefront of the 2 most important trends in medical oncology - namely, targeted therapy and immunotherapy. The treatment landscape for non-small cell lung cancer (NSCLC) continues to evolve with the addition of newer generations of drugs for existing targets, as well as new and emerging targets. Current testing guidelines recommend broad next-generation sequencing (NGS)-based biomarker testing and PD-L1 expression by immunohistochemistry for all patients with newly diagnosed advanced NSCLC. Patients who receive targeted therapy have significantly better overall survival compared with patients who do not receive targeted therapy. Waiting for NGS-based biomarker test results is strongly recommended before initiating treatment with an immune checkpoint inhibitor (ICI)-based therapy to make the optimal first-line treatment choice and to avoid unnecessary and heightened toxicities associated with switching from upfront chemoimmunotherapy to an EGFR tyrosine kinase inhibitor, for example. Well-established genetic alterations and corresponding targeted treatments in the first-line treatment of advanced NSCLC include EGFR mutations (gefitinib, erlotinib, afatinib, dacomitinib, osimertinib), ALK rearrangements (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib), ROS1 fusions (crizotinib, entrectinib), and BRAF V600E mutations (dabrafenib plus trametinib). More recently, new targeted therapies are approved for patients with advanced NSCLC harbouring NTRK fusions (entrectinib and larotrectinib), MET exon 14 skipping mutations (capmatinib and tepotinib), RET fusion (selpercatinib and pralsetinib), KRAS G12C mutation (sotorasib and adagrasib after platinum-based chemotherapy), and EGFR exon 20 insertion mutations (amivantamab and mobocertinib after platinum-based chemotherapy).
Patients with advanced NSCLC and high PD-L1 expression (≥50%) whose disease does not harbour any actionable alteration should be considered for a single-agent ICI (pembrolizumab, atezolizumab, or cemiplimab), an ICI in combination with chemotherapy, or dual ICI therapy. Patients with low or no PD-L1 expression (<1% to 49%) should receive chemotherapy in combination with either an ICI or dual ICI therapy.