Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC

Abstract

EGFR exon 20 insertion driver mutations (Exon20ins) in non-small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecifi c antibody targeting EGFR-MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing fi rst-inhuman study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described. Ba/F3 cells and patient-derived cells/organoids/xenograft models harboring diverse Exon20ins were used to characterize the antitumor mechanism of amivantamab. Amivantamab inhibited proliferation by effectively downmodulating EGFR-MET levels and inducing immune-directed antitumor activity with increased IFN γ secretion in various models. Importantly, in vivo effi cacy of amivantamab was superior to cetuximab or poziotinib, an experimental Exon20ins-targeted TKI. Amivantamab produced robust tumor responses in two Exon20ins patients, highlighting the important translational nature of this preclinical work. These fi ndings provide mechanistic insight into the activity of amivantamab and support its continued clinical development in Exon20ins patients, an area of high unmet medical need. SIGNIFICANCE: Currently, there are no approved targeted therapies for EGFR Exon20ins-driven NSCLC. Preclinical data shown here, together with promising clinical activity in an ongoing phase I study, strongly support further clinical investigation of amivantamab in EGFR Exon20ins-driven NSCLC.

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

“…The preferred BsAb should enable novel biological function and therapeutic MOA which cannot be achieved using mAbs alone or in combination. Basic science supported a key role of c-MET in NSCLC patients developing resistance to EGFR TKIs, supporting design of JNJ-61186372 (EGFR × c-MET BsAb) and patient selection criteria leading to demonstrated anti-tumor activity in NSCLC patients with resistance to EGFR TKIs (Park et al 2020 ; Yun et al 2020 ). Interestingly, duligotuzumab (MEHD7945A), a BsAb targeting EGFR and HER3, showed no clinical benefit in comparison to cetuximab (anti-EGFR mAb) in phase 2 trials in patients with metastatic colorectal cancer or head and neck squamous cell carcinoma.…”

Mobocertinib (TAK-788): A Targeted Inhibitor ofEGFRExon 20 Insertion Mutants in Non–Small Cell Lung Cancer

“…3A). Mobocertinib inhibited viability of CUTO14 cells (IC 50 3C). Potent inhibition of EGFR and downstream signaling by mobocertinib was confirmed in all three cell lines by western-blot analysis ( Fig.…”

“…Taken together with the above mass spectrometry results, this is consistent with its mechanism of covalent binding. Mutants inhibited more potently than WT EGFR included all four variants containing common activating mutations with or without the T790M resistance DT, and LT: IC50 : 2.7-21.3 nM), and all five variants containing uncommon activating mutations (G719A, G719S, S768I, L861Q, and L861R; IC 50 s 3.5-20.2 nM). Most importantly, mobocertinib inhibited all five variants containing…”

Antibodies to watch in 2021

“…Amivantamab has been shown to function through multiple mechanisms of action in preclinical models of NSCLC with EGFR exon 20 insertion driver mutations, which cause tumor cells to be insensitive to EGFR tyrosine kinase inhibitors. 98 FDA granted Breakthrough Therapy designation to amivantamab for the treatment of patients with metastatic NSCLC with (EGFR) Exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy. A BLA or MAA for amivantamab for NSCLC is included in Janssen’s new molecular entity filings planned during 2020.…”