Targeted therapy for lung cancer: Beyond EGFR and ALK

Abstract

Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with nonsmall cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy.Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR-driven and ALK-driven diseases. K E Y W O R D Sdriver mutations, genomic aberrations, nonsmall cell lung cancer (NSCLC), targeted therapy, tyrosine kinase inhibitors (TKI) 18.9 months with osimertinib versus 10.2 months with firstgeneration EGFR inhibitors (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.37-0.57) 6 in patients with EGFR-mutant NSCLC and 37.8 months with alectinib versus 23.0 months with crizotinib, respectively (HR, 0.43; 95% CI, 0.32-0.58), 7 in those with ALK-driven NSCLC. This has guided a consecutive generation of TKIs to regulatory approval and has established them as the standard of care for patients with EGFR-mutant and ALK-rearranged tumors in the first-line context for advanced NSCLC.

Role of Epiregulin in Lung Tumorigenesis and Therapeutic Resistance

“…Several druggable molecular targets for NSCLC have been identified over the last two decades [5]. KRAS mutations are common driver mutations in NSCLC and are identified in 25-30% of patients with NSCLC [5].…”

“…Several druggable molecular targets for NSCLC have been identified over the last two decades [5]. KRAS mutations are common driver mutations in NSCLC and are identified in 25-30% of patients with NSCLC [5]. Among the KRAS mutation subtypes, KRAS G12C mutations (approximately 40% of all KRAS mutations in NSCLC) are currently druggable drivers in NSCLC [76].…”

“…Lung cancer has the highest mortality rate worldwide [1,2] and is histologically classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); the latter includes lung adenocarcinoma (LUAD), which accounts for 50-60% of all lung cancers [3,4]. Several druggable genetic alterations, including mutations in the kinase domain of the epidermal growth factor receptor (EGFR), KRAS G12C mutations, BRAF V600E mutations, MET exon14-skipping mutations, HER2/ErbB2 exon 20 mutations, and fusions of ALK, ROS1, RET, and NTRK, have been identified in NSCLC (mainly in LUAD) [5,6]. Furthermore, immune checkpoint inhibitors, including antibodies to cytotoxic T lymphocyteassociated antigen 4 (CTLA-4), programed cell death-1 (PD-1), and programed cell death ligand 1 (PD-L1), have been reported to be clinically effective for patients with NSCLC [7,8].…”

Complete Response on Larotrectinib in NTRK2 Fusion-Positive Non-Small Cell Lung Cancer

“…The introduction of targeted therapy and immunotherapy has significantly improved outcomes of patients with metastatic non-small cell lung cancer (NSCLC) [ 1 – 4 ]. With a better understanding of the tumor biology and identification of various genetic alterations, the field of targeted therapies has evolved rapidly with several new therapeutic options for patients with oncogene-driven NSCLC [ 5 , 6 ]. In this context, NTRK mutations represent a rare oncogenic driver with a strong therapeutic potential [ 2 , 5 , 6 ].…”

“…With a better understanding of the tumor biology and identification of various genetic alterations, the field of targeted therapies has evolved rapidly with several new therapeutic options for patients with oncogene-driven NSCLC [ 5 , 6 ]. In this context, NTRK mutations represent a rare oncogenic driver with a strong therapeutic potential [ 2 , 5 , 6 ]. The NTRK family consists of NTRK1, NTRK2, and NTRK3 and encodes for 3 transmembrane proteins TRKA, TRKB, and TRKC [ 7 ].…”