Lung cancer remains one of the leading causes of cancer-related deaths in the United States. Approximately 60% of lung adenocarcinomas are associated with driver oncogenes. Among these oncogenes, epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and ROS1 proto-ongene (ROS1) rearrangements are found in 15% to 20%, 5% to 7%, and 1% of lung adenocarcinomas, respectively.

Other oncogenes found in lung cancer include Kirsten Rat Sarcoma Vial Oncogene Homolog (KRAS) mutations, V-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, Mesenchymal epithelial transition (MET) exon 14 insertions and/or amplifications, Rearranged During Transfecion (RET) rearrangements, Human Epidermal Growth Factor Receptor 2 (HERS) mutations, and Neurotrophic tyrosine receptor kinase (NTRK) fusions. The use of comprehensive molecular analysis of the tumor can facilitate targeted therapy.

A recent paper focused on the biologic role of KRAS, BRAF, MET, HERS, and NTRK as emerging targets in lung adenocarcinoma. KRAS is one of the most commonly mutated genes and is typically found in smokers, although it can also be found in never-smokers. KRAS encodes a membrane-bound guanosine triphosphate (GTP) binding protein, which possesses intrinsic GTPase activity. KRAS mutation may be associated with a poorer prognosis. Among the agents being studied in non-small cell lung cancer (NSCLC) are AMG510, a first-in-class KRAS inhibitor that binds to cysteine 12 inactivating the mutated KRAS protein, and MRTX849, an oral KRAS inhibitor. Downstream signaling of KRAS is also being targeted.

BRAF promotes cell proliferation and survival, with the most common mutation being BRAFV600E, which accounts for half of all BRAF mutations. This mutation is found in approximately 2% to 4% of patients with NSCLC. BRAF mutations are stratified into three distinct functional classes, with one class involving the V600 mutation and two classes involving nonV600 dimers or heterodimers. BRAF mutations are more common in females and smokers. A BRAF inhibitor used in NSCLC is dabrafenib, which targets the V600 mutation. It has been used in combination with trametinib, a MEK (mitogen-activated protein kinase) inhibitor; this combination was approved by the FDA in 2017 for metastatic NSCLC in patients harboring the BRAFV600E mutation.

Other BRAF/MEK inhibitor combinations being studied include encorafenib and binimetinib. Attempts are being made to counter resistance to BRAF inhibitors with the use of third-generation RAF inhibitors. Therapeutic strategies for NSCLC patients with non-V600E mutations are less defined.

MET is a proto-oncogene that binds to hepatocyte growth factor (HGF), triggering transphosphorylation of tyrosine residues and activation of downstream signaling pathways that are responsible for cell proliferation, survival, and invasion and forming c-MET. c-MET deregulation occurs in 3% to 4% of lung adenocarcinomas and 8% to 30% of pulmonary sarcomatoid carcinomas. However, MET can also be transactivated without binding to HGF. Agents that are under investigation that target MET include onartuzumab, a monoclonal antibody against c-MET, crizotinib, a multityrosine kinase inhibitor (TKI) with activity against MET.

Selective MET inhibitors being studied include capmatinib, tepotinib, and savolitinib. Strategies that are being considered to counter resistance to MET include switching between MET inhibitors or combining treatments involved in signaling pathways.

RET proto-oncogene encodes a transmembrane tyrosine kinase receptor of the glial cell-line–derived neurotrophic factor (GDNF) family. RET rearrangements are found in 1% to 2% of NSCLC patients. This type of mutation is more often found in younger patients or in those with a light/never smoking history. If an RET-fusion mutation is present, other NSCLC driver mutations will not be, as they are mutually exclusive. This mutation is associated with a high prevalence of pleural dissemination and brain metastases. These types of tumors are highly sensitive to pemetrexed-based regimens.

RET inhibitors under investigation include cabozantinib, vandetanib, sunitinib, lenvatinib, nintedanib, and selective agents such as agerafenib, pralsetinib, and selpercatinib. However, success with multitarget inhibitors in RET-rearranged NSCLC is limited as the development of resistance is a major concern.

HER2, which is encoded by the ERBB2 gene, is well-known for its association with breast cancer. However, mutations of HER2 are found in 1.7% of lung adenocarcinoma and up to 6% of lung cancers that lack mutations in EGFR, KRAS, and ALK, as these are mutually exclusive. Trastuzumab, a gold standard treatment of HER2+ breast cancer, has not been found to be effective in NSCLC. However, ado-trastuzumab emtansine has shown some benefit and is considered a therapeutic option for HER2-mutant, but not HER2-overexpressing, NSCLC.

Other HER2 inhibitory drugs that are currently under investigation for lung cancer include trastuzumab deruxtecan, poziotinib, pyrotinib, TAK-788, tarloxotinib and ZW49. However, drug resistance remains a problem.

NTRK1, NTRK2, and NTRK3 genes are primarily expressed in the central nervous system, but they can also be found in the lung and contribute to disease in about 0.1% to 3% of NSCLC patients. NTRK fusions are mutually exclusive with other NSCLC oncogenic drivers. There are issues with sensitivity of the testing modalities used to detect NTRK fusions. Larotrectinib and entrectinib, two first-generation tropomyosin receptor kinase (TRK) inhibitors that received FDA accelerated-approval status for solid tumors harboring NTRK fusions, are being studied in NSCLC. Novel strategies are being employed to overcome resistance such as combining TRK inhibitors with inhibitors of activated by-pass pathways, such as MEK and MET inhibitors.

As the field of specialty pharmacy continues to evolve, pharmacists are being called upon to manage oncology patients with complex, and at times, toxic drug regimens. Specialty pharmacists must have an understanding of how these medications work in order to best assist their patients with lung cancer and other malignancies.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.