Abstract CT127: Tumor response and MET-detection methods exploratory biomarker analysis of Part B of the Ph 1b TATTON study
Authors: Ryan Hartmaier, Ji-Youn Han, Byoung Chul Cho, Aleksandra Markovets, Nisha Kurian, Mireille Cantarini, Pasi A. Janne
Journal: Cancer Research (2021)

Abstract Background/Purpose Following disease progression on osimertinib, a third generation (3G), irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), ≤22% of patients (pts) with EGFR mutation positive (EGFRm) non-small cell lung cancer (NSCLC) develop MET-amplification as a resistance mechanism to treatment. In the Ph1b TATTON (NCT02143466) Part B expansion cohort, pts with MET-amplified EGFRm advanced NSCLC and progression on a prior EGFR-TKI received osimertinib + savolitinib, an oral, potent and highly selective MET TKI. Previous analyses have compared MET patient selection assays and found that different methods identify different but partially overlapping proportions of pts with MET amplification or overexpression. Here, we report the response rates observed in the subgroups defined by the different central MET assays in TATTON Part B. Methods MET testing (central, or local with central confirmation) was performed on tumor tissue collected after the most recent therapy. MET assays included FISH (MET gene copy number ≥5 or MET-CEP7 ratio ≥2) and IHC (MET +3 expression in ≥50% of tumor cells). TATTON Part B was split into 3 pt cohorts: pts previously treated with a 3G EGFR TKI and not previously treated with a 3G EGFR TKI (T790M positive/negative). This analysis uses the final study data (cutoff 4 March 2020) to compare the objective response rate (ORR) of subgroups identified by each assay. Results For pts who had received prior treatment with a 3G EGFR TKI, ORR by MET assay was as follows: FISH-positive overall (n=53) 30%; FISH polysomy (n=18) 28%; FISH amplification (n=35) 31%; IHC (n=13) 46%. For FISH-positive tumors, ORR trended higher for tumors with ≥10 MET gene copies (n=29, 35%) vs tumors with 5-9 copies (n=24, 25%). For pts with no prior treatment with a 3G EGFR TKI (T790M negative), ORR was as follows: FISH-positive overall (n=34) 65%; FISH polysomy (n=14) 57%; FISH amplification (n=20) 70%; IHC (n=4) 75%. For FISH-positive tumors, ORR trended higher for tumors with ≥10 MET gene copies (n=14, 79%) vs tumors with 5-9 copies (n=20, 55%). In tumors with both central FISH and IHC data available (n=34), IHC positivity (n=20) and FISH positivity (n=27) were correlated, specifically IHC and FISH amplification: 13/16 cases of FISH amplification were also IHC positive. In FISH-positive tumors IHC expression tended to increase with increasing gene copy number (≥10), but outcomes were largely comparable. Conclusions Overall, the MET assays were comparable with regards to ORR, thus supporting continued use of both FISH and IHC for detection of MET in pts following disease progression on any 3G EGFR TKI, though IHC data were limited. Further study is warranted in this area: the SAVANNAH (NCT03778229; FISH and IHC) and ORCHARD (NCT03944772; NGS) studies will provide opportunity for further analyses. Citation Format: Ryan Hartmaier, Ji-Youn Han, Byoung Chul Cho, Aleksandra Markovets, Nisha Kurian, Mireille Cantarini, Pasi A. Janne. Tumor response and MET-detection methods exploratory biomarker analysis of Part B of the Ph 1b TATTON study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT127.