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 bispecific antibody targeting EGFR–MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing first-in-human 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 IFNγ secretion in various models. Importantly, in vivo efficacy 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 pre-clinical work. These findings 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.
Original language | English |
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Pages (from-to) | 1194-1209 |
Number of pages | 16 |
Journal | Cancer Discovery |
Volume | 10 |
Issue number | 8 |
DOIs | |
Publication status | Published - 2020 |
Bibliographical note
Funding Information:This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1A2B3016282 and 2018R1C1B6008916), Republic of South Korea.
Publisher Copyright:
© 2020 American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Oncology