MET amplification (amp) as a resistance mechanism to osimertinib

Background: Osimertinib (osi) is an EGFR T790M inhibitor. Mechanisms (mech) of acquired resistance (AR) are under study. We report a cohort of osi-AR pts with extensive pre/post-osi tissue and plasma. Methods: We analyzed 23 pts with AR to osi. Tumor biopsies (bx) underwent NGS (SNaPshot, MGH) and FISH for EGFR, MET amp (target:CEP7 > 2.2.) Plasma underwent ctDNA NGS (Guardant360). Results: Of the 23 osi-treated EGFR-mutants (13 with EGFR del19, 10 L858R), 2 had de novo T790M, 21 acquired T790M. 13 had prior 3rd gen EGFR TKIs before osi - rociletinib(11), ASP8273(1), EGF816(1). Median time on osi was 12 mo (range 2-25), med total time on 3 rd -gen EGFR TKIs was 18 mo. Bx types were tissue (16), plasma (18), and both (11, med interval 31d). All pts retained their founder EGFR mutation, but 15/23 (65%) lost T790M post-osi, suggesting AR arose from a T790wt subclone (Table). Common AR mech were MET amp (7/23; 30%) and EGFR C797S (5/23; 22%). 1 pt each had SCLC transformation, PIK3CA E545K/PIK3CA amp and FGFR1 D60N/FGFR1 amp. 2 pts had 2 distinct post-osi tissue bx showing heterogeneity. Pt 8 had plasma and a lung nodule with C797S/T790M while a mediastinal LN was wt at both loci. Pt 22 had MET-amp in pleural fluid but no MET amp on lung bx. Plasma identified AR mech not seen in tissue in 2/11 pts with both bx types. Among 7 pts with MET amp, 3 received combo EGFR/ MET TKI; all 3 had a RECIST PR. Conclusions: In this osi-resistant cohort, we commonly saw MET amp (30%) and C797S (22%). MET amp seems more common post-osi than after 1 -line TKIs, and 3/3 pts responded to EGFR+MET TKIs. AR heterogeneity was seen in 2 pts with matched tissue/plasma and 2 with >1 tissue bx, underscoring the complementary roles of plasma and tissue. (Table Presented).