EGFR

EGFR belongs to the ErbB family of epidermal growth factor receptors, which also includes ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). It is a kind of tyrosin kinase that locates on the cell surface and specifically binds with epidermal growth factors. The binding could induce dimerization and autophosphorylation, thereby activating a variety of downstream signaling pathways related with cell proliferation, such as RAs/Raf/MAPK and PI3K/AKT/mTOR. Activating mutation or overexpression of EGFR may lead to constant activation of the signaling pathways thus leading to abnormal cell proliferation, differentiation, and inhibited apoptosis, and is associated with development of multiple solid tumors, such as lung, head and neck, gliomas, and colorectal (PMID: 15118073, PMID: 25394504, PMID: 17373877). Activating mutatoins occur commonly in the tyrosine kinase domain adjacent to ATP-binding domain and increase the EGFR kinase activity. The most common mutations include L858R on exon 21 and Exon 19 deletion, and the most frequent drug-resistant mutation is T790M on exon 20.

Major therapies targeting EGFR include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. TKIs have evolved several generations due to the acquired resistant mutations in EGFR. Up to now, FDA has approved three generations of TKIs for treatment of patients with non-small cell lung cancer (NSCLC) who carry exon 21 L858R mutation and exon 19 deletion mutation, including the first-generation gefitinib and erlotinib, the second-generation afatinib and dacomitinib to overcome drug resistance mediated by T790M, and the third-generation osimertinib to overcome resistance mediated by T790M, D761Y, L747S, and T854A. In 2020, osimertinib was also approved by FDA for adjuvant therapy after tumor resectoin in patients with NSCLC who carry exon 19 deletion and exon 21 L858R mutation based on the clinical trial NCT02511106. Currently, the fourth-generation anti-EGFR TKIs are under investigation to overcome the newly emergent resistant mutation C797S in addition to T790M against osimertinib. In addition to TKIs, a few antibodies targeting EGFR were also approved by FDA (PMID: 31706618). Necitumumab was approved in 2015 in combination with gemcitabine and cisplatin for the first-line treatment of metastatic squamous NSCLC, but the benefits were modest in SQUIRE's Phase Ⅲ trial, with only a 1.6 month improvement in overall survival (PMID: 27668058). Cetuximab is the most extensively studied anti-EGFR antibody and was approved for use in multiple cancers. It was approved in 2012 in combination with FOLEIRI for the first-line treatment of metastatic colorectal cancer in patients with wild-type KRAS and EGFR-positive expression, approved in 2006 in combination with radiotherapy for treatment of locally or regionally advanced squamous head and neck carcinoma (SHNC) or as a single agent for recurrent or metastatic SHNC where prior platinum-based chemotherapy has failed. In 2021, cetuximab was approved a new dosage regimen (500 mg/m2 of 120-minute intravenous infusion every two week) for patients with wild-type KRAS, EGFR-expression positive colorectal cancer or SHNC. The NCCN recommends that the combination of cetuximab and afatinib benefit patients who have deteriorated in other EGFR-targeted therapies. Panitumumab was approved in 2006 for treatment of patients with EGFR-expression positive metastatic colorectal cancer with disease progression on or following chemotherapy (PMID: 17522246). Currently, there are several clinical trials of single drug or combination drug targeting exon 19 deletion mutation in NSCLC, such as NCT01928576 (P2)/(entinostat , azacytidine , and nivolumab); NCT03242915 (P2)/(carboplatin, pembrolizumab, pemetrexed); NCT03292133(P2)/(gefitinib and EGF816); NCT03410043 (P2)/Osimertinib.