EGFR Exon 20 insertions in NSCLC: from biology to amivantamab, optimal treatment strategy and emerging therapeutics

EGFR exon 20 insertion (Ex20ins) mutations are the third most frequent EGFR mutations, which accounts for around 4-12% of EGFR mutations in advanced NSCLC. It is well known that conventional EGFR-TKI monotherapy is less effective for patients with EGFR Ex20ins. Amivantamab is the first in class drug for established standard therapy of advanced stage NSCLC harboring Ex20ins mutations. Amivantamab has the following four unique mechanisms of action for Ex20ins mutated NSCLC; 1) dual-blocking receptor and inhibition of signaling pathway of EGFR and cMET, 2) antibody-dependent cellular cytotoxicity (ADCC) by NK cells, 3) antibody-dependent cellular trogocytosis (ADCT) by macrophages, 4) lysosomal receptor internalization and subsequent degradation. Amivantamab, in combination with carboplatin plus permetexed, was established in the PAPILLON study. However, it is unclear regarding the efficacy and CNS penetration of amivantamab for patients with Ex20ins mutations involving CNS/brain metastases. For patients with A763_Y764insFQEA mutation involving serious brain metastases, conventional EGFR-TKI might be an important treatment option. There are four phase III studies ongoing investigating new EGFR-TKI monotherapies or combination therapy with cytotoxic chemotherapy for EGFR Ex20ins mutations in the first-line setting. This review comprehensively summarized the biology and clinical characteristics of Ex20ins mutations and provide cutting-edge information and future perspectives.