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Poster session 08

2295P - Pan-cancer prevalence of MET fusions and clinical response to MET- targeted therapy

Date

21 Oct 2023

Session

Poster session 08

Topics

Translational Research;  Molecular Oncology

Tumour Site

Presenters

Morana Vojnic

Citation

Annals of Oncology (2023) 34 (suppl_2): S1152-S1189. 10.1016/S0923-7534(23)01927-0

Authors

I. Odintsov1, Z. Liu2, D. Lu3, M. Harshan4, A. Ameri5, S. Machnicki6, X. Xiao7, W. Lockwood3, M. Ladanyi8, R. Somwar9, M. Vojnic10

Author affiliations

  • 1 Department Of Pathology, Brigham and Women's Hospital, 2115 - Boston/US
  • 2 Department Of Pathology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 200127 - Shanghai/CN
  • 3 Department Of Pathology And Laboratory Medicine, UBC - The University of British Columbia, V5Z 1M9 - Vancouver/CA
  • 4 Department Of Pathology, Lenox Hill Hospital, 10075 - New York/US
  • 5 Department Of Hematology/oncology, Lenox Hill Hospital, 10075 - New York/US
  • 6 Department Of Radiology, Lenox Hill Hospital, 10075 - New York/US
  • 7 Department Of Oncology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 200001 - Shanghai/CN
  • 8 Department Of Pathology, MSKCC - Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 9 Department Of Pathology, MSKCC - Memorial Sloan Kettering Cancer Center, 10017 - New York/US
  • 10 Lenox Hill Hospital, Northwell Health Cancer Institute, 10065 - New York/US

Resources

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Abstract 2295P

Background

MET rearrangements are found in multiple cancers. Despite the availability of effective MET drugs there is no approved treatment for these tumors. We determined the prevalence of MET fusions, explored MET therapy in preclinical models and assessed efficacy of MET tyrosine kinase inhibitors (TKI) in a colorectal cancer (CRC) patient with MET fusion.

Methods

We analyzed the AACR project GENIE registry (release V13, 167,423 samples from 148,268 patients) for intergenic MET fusions. We also identified 2 CRC patients (Lenox Hill Hospital, New York, NY, and Renji Hospital Shanghai, China, respectively) by RNA-based NGS. MET expression was assessed by IHC. Sensitivity of SJ-GBM2 (CLIP::MET, glioblastoma), and H1993 and EBC1 (MET amplified lung cancer) cells to type 1 and type 2 MET TKIs were assessed.

Results

We identified 44/148,286 patients (0.03%) with an intergenic MET fusion; cancer types included brain (n=12; with 8 high-grade gliomas), NSCLC (n = 11 with 9 adenocarcinomas), gastrointestinal tract (n = 8; with 3 esophageal adenocarcinomas, 3 cholangiocarcinomas), etc. Recurrent fusion partners accounted for 18/44 (40.1%) cases and included 7 PTPRZ1, 5 ST7, 3 CTTNBP2, 2 CAPZA2 and 2 DOCK4. Two CRC patients with MET fusions (SYNRG2::MET, ZKSCAN1::MET) were found from routine NGS screening and both showed strong MET expression. Treatment with type 2 (cabozantinib) or type 1 (crizotinib, capmatinib, savolitinib) MET TKIs blocked growth of SJ-GBM2 cells with IC50 values of 0.3, 0.2, 0.1 and 0.04 μM, respectively, reflecting the sensitivity observed in H1993 and EBC1. MET TKIs blocked MET, AKT, ERK and S6 phosphorylation in SJ-GBM2 cells. These results were recapitulated with MET shRNAs. The CRC patient (SYNRG2::MET fusion) failed several lines of chemotherapy and was then treated with crizotinib, achieving a mixed response, with stable disease in lung metastases. Upon progression the patient was treated with capmatinib and a decrease in CEA from was observed after 3 weeks on therapy.

Conclusions

Our findings indicate MET fusions are widely distributed among tumor types and are sensitive to type 1 and type 2 MET TKIs. Clinical trials evaluating MET inhibitors for patients whose cancers are driven by MET fusions are ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

NIH.

Disclosure

M. Ladanyi: Financial Interests, Advisory Board: Merck, Bristol Myers Squibb, Takeda, Bayer, Lilly Oncology, Janssen, Paige.AI; Non-Financial Interests, Research Grant: Merus, Loxo Oncology, Elevation Oncology Inc., Hellsin. R. Somwar: Non-Financial Interests, Research Grant: Merus, Loxo Oncology, Elevation Oncology Inc., Hellsin. All other authors have declared no conflicts of interest.

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