Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches

Abstract

Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents. In addition, mutations leading to resistance to first-line EGFR and ALK TKIs can now be successfully inhibited by soon to be approved third-generation EGFR TKIs (osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, alectinib). Notably, increasing feasibility, accessibility, and application of molecular profiling technologies has permitted dynamic growth in the identification of actionable driver oncogenes. Emerging genomic aberrations for which TKIs have shown impressive results in clinical trials and expansion of drug labels for approved agents are awaited include ROS1 rearrangements (1-2% of tumors, drug: crizotinib) and BRAF-V600E mutations (1-3% of tumors, drugs: vemurafenib, dafrafenib + trametinib). Evolving genomic events in which TKI responses have been reported in smaller series include MET exon 14 skipping mutations (2-4% of tumors, drug: crizotinib); high-level MET amplification (1-2% of tumors, drug: crizotinib); RET rearrangements (1% of tumors, drug: cabozantinib); and ERBB2 mutations (2-3% of tumors, drug: afatinib), among others. Unfortunately, the most common genomic event in NSCLC, KRAS mutations (25-30% of tumors), is not targetable with approved or in development small molecule inhibitors. Here, we review currently approved, emerging, and evolving systemic precision therapies matched with their driver oncogenes for the management of advanced NSCLC.

<b><i>V600E BRAF</i></b> versus Non-<b><i>V600E BRAF</i></b> Mutated Lung Adenocarcinomas: Cytomorphology, Histology, Coexistence of Other Driver Mutations and Patient Characteristics

“…Considerable interest in lung ACAs harboring BRAF mutations has emerged due to the availability of therapeutic agents that can directly target BRAF or its downstream signaling constituents [7,8]. Involved in the RAS-MEK-ERK signaling pathway, BRAF is a serine/threonine kinase that lies downstream of RAS [9].…”

Ceritinib: A primer for pharmacists

“…16 However, advances in our understanding of the molecular basis of disease have led to targeted approaches for certain patients in whom an actionable genetic alteration is discovered and have been associated with improved prognosis. 27 For patients with an activating EGFR mutation, EGFR tyrosine kinase inhibitors demonstrated a survival advantage over chemotherapy. 16,27 Similarly, in patients in whom an ALK rearrangement is discovered, targeted therapy with an ALK inhibitor can confer improved outcomes.…”

“…25,26,35 While crizotinib is effective initially, patients ultimately develop resistance. [25][26][27]31,[33][34][35] In addition, spread of disease into the central nervous system (CNS) has been observed in patients whose disease progressed after treatment with crizotinib. 3,34 Clinical characterization of ALK-positive NSCLC patients who were treated with crizotinib beyond disease progression revealed that the brain was the most common single organ site for new lesions.…”

Detection of EGFR and BRAF mutations by competitive allele-specific TaqMan polymerase chain reaction in lung adenocarcinoma

“…At present, driver mutations are continuing to be identified; there are a number of clinical trials regarding targeted therapies in progress (10,11). Serine/threonine-protein kinase B-raf (BRAF) is a member of the RAF kinase family, which serves an important function in the MAPK signaling pathway (12,13).…”