Personalized therapy for lung cancer: striking a moving target

Abstract

Molecular targeted therapy heralded a new era for the treatment of patients with oncogene-driven advanced-stage non-small-cell lung cancer (NSCLC). Molecular testing at the time of diagnosis guides therapy selection, and targeted therapies in patients with activating mutations in EGFR, BRAF, and rearrangements in anaplastic lymphoma kinase (ALK) and ROS1 have become part of routine care. These therapies have extended the median survival from a mere few months to greater than 3 years for patients with stage 4 disease. However, despite the initial success, these treatments are eventually met with molecular resistance. Selective pressure leads to cellular adaption to maintain cancer growth, making resistance complex and the treatment challenging. This review focuses on recent advances in targeted therapy, mechanisms of resistance, and therapeutic strategies to overcome resistance in patients with lung cancer.

Figure 1. Treatment algorithm for stage 4 non–small-cell lung cancer.

Molecular testing is used to identify patients that are candidates for targeted therapies based on mutations. Applicable therapies for EGFR mutation include osimertinib, erlotinib, gefitinib, and afatinib; for anaplastic lymphoma kinase gene (ALK) mutation include alectinib, crizotinib, and ceritinib; second-line brigatinib; for c-ros oncogene 1 (ROS1) mutation include crizotinib and ceritinib; for v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E include dabrafenib plus trametinib. Targeted therapy with activity against other genetic alterations have been identified for rearranged during transfection (RET) mutation (cabozantinib, vandetanib), for mesenchymal-to-epithelial transition (MET), amplification or exon 14 mutation (crizotinib) or human epidermal growth factor receptor 2 (HER2) mutation (ado-trastuzumab emtansine). Patients without actionable mutations will be tested for PDL1 expression, and treatment is determined by the overall level of expression and tumor mutational burden (TMB).

Figure 2. Genomic classification of lung adenocarcinoma.

The incidence of specific genetic mutations in NSCLC is reported, with mutations in KRAS, EGFR, and ALK having the highest prevalence.