Non-small Cell Lung Cancer with EGFR or HER2 Exon 20 Insertion Mutations: Diagnosis and Treatment Options

Abstract

Molecular testing is performed upon diagnosis of non-small cell lung cancer (NSCLC) because of the large success of targeted therapies for oncogenic mutations. Epidermal growth factor receptor (EGFR) mutations are the most commonly identified mutation in NSCLC, and EGFR exon 20 insertion mutations (exon20ins) are the third most common mutation in EGFR following EGFR exon 19 deletions and exon 21 L858R mutations. EGFR exon20ins have regularly demonstrated resistance to classical EGFR inhibition. Two treatments-mobocertinib and amivantamab-have recently been the first drugs to be approved by the US Food and Drug Administration (FDA) for treatment of lung cancers with these mutations following platinum-based therapy. Research surrounding these two drugs demonstrates strong efficacy, but with an intense array of side effects. Another targetable driver mutation is the human epidermal growth factor receptor 2 (HER2) exon20ins, representing approximately 2-3% of NSCLC patients. This mutation has been heavily studied in vitro as well as clinically, and trastuzumab deruxtecan was just recently granted accelerated FDA approval based on the high efficacy demonstrated in the Destiny-Lung01 study. However, similar to their EGFR counterparts, HER2 inhibitors also have evidence of toxicity in clinical studies. In this paper, we discuss the limited response of EGFR and HER2 exon20ins to a wide range of standard treatment regimens, such as platinum-based chemotherapy and classic EGFR tyrosine kinase inhibitors, as well as immunotherapy. We also review recently approved and upcoming targeted therapeutic options, considering what research is presently being done regarding efficacy and the reduction of side effects, as well as the agents' risks and benefits for incorporation into an approved treatment regimen.

Proximal Femoral Metastasis From Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma Mimicking Osteosarcoma on Magnetic Resonance Imaging

“…According to a retrospective study, the mean age of patients with lung cancer and bone metastases is 61.5 years, and most of the patients were presented between 50 and 59 or 60 and 69 years old [ 10 ]. Among the oncogenic mutations, EGFR mutations are the most commonly identified mutation in non-small cell lung cancer, including squamous cell carcinoma, lung adenocarcinoma, and large cell carcinoma; Of which, EGFR exon 21 L858R mutations are the most common mutation in EGFR followed by EGFR exon 19 deletions and EGFR exon 20 insertion mutations (exon20ins) [ 11 ]. The presence of EGFR mutation in lung cancer can induce the upregulation of the EGFR signaling pathway, consequently resulting in an increase in vascular endothelial growth factor (VEGF) expression to promote angiogenesis and facilitate tumor invasion and metastasis [ 12 , 13 ].…”

Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases

“…2 Most of these mutations occur within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. 3 HER2 exon 20 mutations comprise point mutations, such as L755S and G776C, or, more frequently, insertions. Among these mutations is the YVMA insertion−duplication variant (p.Y772dupYVMA or p.A775_G776insYVMA), accounting for 34 to 83% of HER2 variants in NSCLC.…”

“…In a report from the Cancer Genome Atlas, HER2 mutations were found in some non-small-cell lung cancer (NSCLC) patients . Most of these mutations occur within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways …”

A study of high dose furmonertinib in EGFR exon 20 insertion mutation-positive advanced non-small cell lung cancer

“…Before Mobosetinib and Amivantamab were approved for EGFR ex20ins NSCLC by FDA, the main treatment for patients with EGFR ex20ins mutation were traditional EGFR-TKIs, platinum-containing chemotherapy and immunotherapy. However, these treatment options have limited benefits (4)(5)(6). Hence, better treatment plans are needed for these patients.…”