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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
P1.01-018 - Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression (ID 10014)
09:30 - 16:00 | Author(s): H. Yan
MET exon14 skipping mutation has been regarded the driver mutation for MET activation, but with relatively low frequency of occurrence. MET overexpression can be a promising biomarker to predict the response to crizotinib. However, little is known about acquired resistance to treatments in tumors with de novo MET overexpression.
This prospective observational study included 33 NSCLC patients with MET IHC overexpression received crizotinib treatment From January 2013 to June 2017, 23 eligible patients evaluable for response . MET expression level were detected by immunohistochemistry (IHC) with antibody SP44, and ≥50% tumor cells with moderate to high intensity staining were defined as positive. Gene copy numbers were detected by FISH (Met probes from KREATECHTM.), and referring to Cappuzzo scoring system or MET/CEP7 ratio, ≥5 copies were positive or MET/CEP7 ratio ≥1.8 (low ≥1.8-≤2.2, Intermediate >2.2-<5 and High ≥5) was defined as MET amplification;. The status of EGFR, ALK, KRAS and ROS1 were also tested at baseline. Biopsy specimens obtained both at baseline and at the time of progression using targeted next-generation sequencing to assess for mechanisms of resistance.
Response were evaluable for 23 NSCLC patients with MET overexpression (4 female, 19 male). Fifteen of them achieved partial response (PR, 65.2%), 2 were stable disease (SD) and 6 were progressive disease (PD). All responders had high MET expression , and 12(52.2%) with FISH positive. The PFS and OS in the ITT population were 3.2 and 13.2 month respectively. Median PFS was 7.4m(95% CI,4.5-10.4) for MET IHC (100%+++) patients vs. MET IHC (50%++~100%+++) 1.9m (95% CI 0.9-2.9,P=0.053), For FISH positive patients, mPFS was 8.2 m(95% CI,5.2-11.1) m v.s. FISH negative 1.3m(95% CI,0.2-1.7,p=0.002). Two acquired resistance mechanisms were found after resistance, a 64 male patient with MET IHC 100%×3,FISH (+),crizotinib first line and the best response PR, rebiopsy after resistance showed the MET D1228N mutation by NGS, and the second patient was 50 years old male with MET IHC 100%×3,FISH (+),crizotinib first line and the best response was PR, EGFR amplification were found upon progression when rebiopsy after resistance. The patient acheived PR with subsequent treatment of cetuximab plus Taxel.
Multiple mechanisms of acquired resistance to crizotinib were found in de novo MET overexpressed patients. A secondary mutation in the MET gene and EGFR amplification may be the two main mechanisms. MET overexpression could be as a biomarker for de novo MET positive NSCLC. FISH seems better in predicting efficacy for MET inhibitor.
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