ES30.04 Monoclonal Antibodies Targeting the ErbB Receptors

Abstract

Blockade of a critical oncogenic target is envisioned as a promising strategy for treating cancer. The blockade of ErbB receptors with anti-ErbB monoclonal antibody represents one such strategy that has been successful in the treatment of HER2-overexpressing multiple solid tumors including NSCLC. Approximately 6% of EGFR mutated NSCLC have EGFR exon 20 insertion (E20Ins) mutations. EGFR E20Ins is the third most common type of EGFR mutation Multiple subtypes and structural differences may limit development of novel targeted therapies. Amivantamab is a fully human EGFR-MET bispecific antibody targeting activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab demonstrated clinical activity across diverse EGFR mutant NSCLC. In CHRYSALIS phase 1study, amivantamab showed robust efficacy with tolerable safety profile in post-platinum EGFR E20Ins NSCLC. HER 2 mutation occurs in about 2% of lung adenocarcinoma. HER2 mutation is more frequently found in never-smoker, women, Asian, and adenocarcinoma. Contrast to HER2 mutation, HER2 overexpression and amplification is not a definite biomarker to HER2 directed therapy. Anti-HER2 monoclonal antibody as monotherapy or in combination has shown conflicting results in HER2 overexpressed or amplified NSCLC. Compared to EGFR and HER2, HER3 has been somwhat ignored as a therapeutic target most likely due to lack of intrinsc kinase activity. However, upon ligand binding and subsequent dimerization with HER2, HER3 potently activates PI3K pathway and MAPK pathway. HER3 Monoclonal antibody as a monotherapu may not sufficient to fully inhibit tumor cells and combination with other ErbB therapy, chemotherapy may enhance therapeutic effects. Recently, monoclonal antibody targeting HER3 exhibited clinical activity in NRG1 fusion+ NSCLC. In conclusion, rapid pace of targeted drug development transforms lives of NSCLC patients with these rare actionable mutations. ErbB receptor, monoclonal antibody, rare mutation