EGFR mutation + MET amplification

Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.

HS-10241 in combination with almonertinib was well tolerated, and showed encouraging antitumor activity in treatment of advanced NSCLC with EGFR mutation and MET amplification following prior EGFR-TKI, whether MET GCN ≥10 or MET GCN ≥5 but < 10. Clinical trial information: NCT05430386.

Here, we described a case of a 64-year-old male with lung adenocarcinoma presented primary resistance on osimertinib combined with bevacizumab and platinum-based chemotherapy, next-generation sequencing revealed EGFR exon 21 L858R mutation and MET gene amplification. Our case highlights that EGFR-TKIs may be not the optimal choice for lung adenocarcinoma with primary EGFR-sensitive mutation with MET amplification simultaneously, whereas MET inhibitor alone may be an effective treatment option. In clinical practice, we should fully consider the possibility of primary resistance in EGFR-TKIs administration.

Osimertinib combined with MET inhibition synergistically induces apoptosis in the MET-amplified EGFR mutant NSCLC cells accompanied with augmented DR4 reduction both in vitro and in vivo. Furthermore, MET inhibition combined with TRAIL enhanced killing of MET-amplified EGFR mutant HCC827/AR cells, but not HCC827 parental cells. These data collectively suggest that DR4 may possess an unrecognized anti-apoptotic function, contributing to apoptosis resistance under given conditions.