antiEGFR

Anti-EGFR refers to therapies that inhibit the epidermal growth factor receptor (EGFR, also known as ERBB1 or HER1), a cell-surface receptor involved in promoting cell proliferation and survival. Anti-EGFR agents include monoclonal antibodies that bind the receptor’s extracellular domain (for example, cetuximab and panitumumab) and small-molecule tyrosine kinase inhibitors that block the intracellular kinase activity (such as erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib). These agents aim to disrupt EGFR signaling and can affect tumor growth directly and, for some antibodies, engage immune effector mechanisms.

Mechanism and resistance: Monoclonal antibodies prevent ligand binding and receptor activation, potentially promoting receptor downregulation and antibody-dependent cellular cytotoxicity. Tyrosine kinase inhibitors compete with ATP at the kinase domain to shut down downstream pathways like RAS-RAF-MAPK and PI3K-AKT. Resistance commonly arises through mutations in downstream effectors (e.g., KRAS/NRAS mutations in colorectal cancer), EGFR alterations that prevent drug binding, or amplification of alternative signaling drivers (e.g., MET). In NSCLC, first-generation TKIs may be limited by the EGFR T790M resistance mutation, with third-generation inhibitors such as osimertinib designed to overcome it.

Clinical use: Anti-EGFR monoclonal antibodies are used in metastatic colorectal cancer with wild-type RAS and, in some settings, specific tumor profiles; in head and neck squamous cell carcinoma as part of combination therapy; and EGFR tyrosine kinase inhibitors are used in non-small cell lung cancer harboring activating EGFR mutations. Side effects commonly include an acneiform rash, diarrhea, hypomagnesemia, mucositis, and infusion-related reactions for antibodies, with potential rare interstitial lung disease for some TKIs.