Introduction
NSCLC, EGFR-addicted non-small-cell lung cancer
NSCLC
As the third most common activating mutations in epidermal growth factor receptor (EGFR), exon 20 insertions (20ins) comprise 10-12% cases in EGFR-addicted non-small-cell lung cancer (NSCLC)EGFR 20ins represent a heterogenous group of variants characterized by in-frame insertions of 1 to 7 amino acids in the αC-helix or αC-β4 loop of the EGFR tyrosine kinase domain (TKD)Currently, there are a number of 20ins-directed therapies in developmentIn this work, we report the antitumor activity, tolerability, potential mechanisms of response and resistance for dual targeting EGFR 20ins with JMT101 plus afatinib or osimertinib from preclinical models and a phase 1b clinical trial (NCT04448379). Our results demonstrate that JMT101 plus osimertinib has the potential to become a new treatment option for EGFR 20ins-positive NSCLC. Acquired resistance to the combination was predominantly driven by EGFR-independent mechanisms that partly overlapped with those observed in classic EGFR mutations.