EGFR-TKIs like osimertinib are widely used to treat advanced EGFR-mutant NSCLC, however tumors inevitably acquire resistance. Amplification of MET occurs in ~20% of EGFR-TKI resistant tumors. Previous studies have used a variety of technologies (FISH, IHC, NGS, ctDNA) with mixed success in identifying MET-driven tumors. Thus, there is an urgent need to better understand the reliability of these assays for the detection of MET-driven EGFR-TKI resistance in NSCLC.

In the TATTON study (NCT02143466), the combination of osimertinib and savolitinib (AZD6094, HMPL-504, volitinib), a potent and selective MET-TKI, has demonstrated encouraging anti-tumor activity in patients with NSCLC and MET-driven EGFR-TKI resistance. During screening, MET testing (central, or local with central confirmation) was performed on tumor tissue collected after the most recent therapy. Informative central MET FISH screening/confirmation results were generated for 254 consented patients. MET overexpression and amplification were further assayed centrally using tissue IHC (n=81), tissue NGS (n=117; Foundation Medicine), and ctDNA NGS (n=199; Guardant Health). Standard NGS provider MET amplification calls were used. Central IHC positivity was defined as 3+ in ≥50% of tumor cells. Central FISH+ was defined as either amplification (MET:CEP7 ratio ≥2) or polysomy (gene copy number ≥5 if MET:CEP7 <2). MET FISH was used as the common comparator across assays.

Central MET FISH+ was found in 123/254 tumors (48%; 75 with amplification, 48 with polysomy), an elevated prevalence likely related to local MET+ prescreening. Comparison of tissue NGS with FISH (n=95) identified high negative-percent agreement (NPA, 98%) but modest positive-percent agreement (PPA, 48%). Further investigation indicated NGS PPA is highly dependent on the FISH result, with higher PPA for amplification (88%) but low PPA for polysomy (4%). Similarly, comparison of ctDNA NGS with FISH (n=112) yielded modest NPA (90%) and PPA of only 25% (43% for amplification; 10% for polysomy). PPA improved to 50% (64% for amplification; 30% for polysomy) when limited to 46 patients with an EGFR mutation detected at >5% allelic fraction in ctDNA. Comparison of IHC with FISH (n=52) identified a 63% NPA and 72% PPA. Notably, of 28 IHC 3+ tumors, 10 (36%) were negative by FISH.

Tissue NGS identifies a subset of MET FISH+ tumors, however MET polysomy is largely missed by NGS assays. MET IHC 3+ staining overlaps extensively with MET FISH+ but also identifies additional potentially MET-dependent tumors. When combined with future clinical efficacy data, this technical comparison will help inform a prospective biomarker strategy for the detection of MET-driven EGFR-TKI resistance in NSCLC.

Citation Format: Ryan J. Hartmaier, Ji-Youn Han, Byoung Chul Cho, Melanie M. Frigault, Aleksandra Markovets, Anne L’Hernault, David Duncan, Pierre Lao-Sirieix, J. Carl Barrett, Remy B. Verheijen, Dana Ghiorghiu, Jonathan Wessen, Geoffrey R. Oxnard. Detection of MET-mediated EGFR tyrosine kinase inhibitor (TKI) resistance in advanced non-small cell lung cancer (NSCLC): biomarker analysis of the TATTON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4897.