Amivantamab: A Potent Novel EGFR/c-MET Bispecific Antibody Therapy for EGFR-mutated Non-small Cell Lung Cancer

While the majority of epidermal growth factor receptor (EGFR) driver mutations in non-small cell lung cancer (NSCLC) are sensitive to treatment with targeted tyrosine kinase inhibitors (TKIs), anti-EGFR TKIs are susceptible to resistance mechanisms through secondary mutations and also lack efficacy against tumours with non-classical EGFR mutations like exon 20 insertions. EGFR exon 20 insertions represent a challenging molecular subtype of NSCLC with no approved targeted therapy options and poor overall prognosis. Similarly, for NSCLC with EGFR mutations that are sensitive to TKIs, there are no approved targeted therapies following progression on a third-generation TKI without an alternative actionable mutation. Amivantamab is a novel, fully human bispecific anti-EGFR/c-MET antibody with clinical efficacy and favourable toxicity against both pre-treated EGFR exon 20 insertion NSCLC and classical EGFR mutations following development of TKI resistance. Preliminary findings from the phase I CHRYSALIS study report a 40% objective response rate with a median duration of response of 11.1 months for patients with pre-treated EGFR exon 20 insertion mutated tumours after platinum-based chemotherapy. Based on these results, the US Food and Drug Administration granted amivantamab accelerated approval in 2021 for treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. This review outlines the rational design and novel mechanism of action of the dual-targeted antibody, and describes preclinical and clinical data characterizing amivantamab in the treatment of NSCLC. Furthermore, we outline the practical clinical administration of this novel agent, including dosing and management of toxicities, and compare its mechanism, efficacy and safety profile to those of other EGFR exon 20 insertion targeted therapies currently available and under investigation.