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- Overview
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Target Overview
EGFR (epidermal growth factor receptor) and c-MET (hepatocyte growth factor receptor) are proteins expressed simultaneously on the surface of many cancer cells, unlike normal tissues. Overexpression or mutation of these receptors is correlated with the development, progression, and metastasis of cancer as well as poor prognosis.1,2 EGFR and c-MET share overlapping biology, with a functional cross-talk between the receptors that translates into clinically relevant phenotypes. In EGFR-mutated NSCLC, c-MET gene amplification has been identified as the most common mechanism of resistance to third-generation EGFR inhibitors, such as osimertinib.3,4,5
Compound Overview
Tilatamig samrotecan (AZD9592) is an antibody-drug conjugate. The antibody is a bispecific human IgG1 monoclonal antibody that can bind to EGFR and c-MET simultaneously on the surface of cells that express both of these receptors. Attached to the antibody are 6 molecules of a topoisomerase I inhibitor (TOP1i) warhead (AZ’0132). After binding to the tumor cells, AZD9592 gets internalized and the released warhead causes DNA damage and apoptotic cell death. In addition, the cell-permeable warhead can also diffuse out of EGFR/c-MET-positive tumor cells and kill neighboring tumor cells that express little or no EGFR/c-MET. This mechanism is called the bystander effect.6
Mechanism of Action
References
1. Benedettini E, Sholl LM, Peyton M, et al. Am J Pathol. 2010;177(1):415-423. 2. Engelman JA, Zejnullahu K, Mitsudomi T, et al. Science. 2007;316(5827):1039-1043. 3. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Br J Cancer. 2019;121(9):725-737. 4. Passaro A, Jänne PA, Mok T, Peters S. Nat Cancer. 2021;2(4):377-391. 5. Zhang Z, Yang S, Wang Q. Biomark Res. 2019;7:27. 6. Giugliano F, Corti C, Tarantino P, Michelini F, Curigliano G. Curr Oncol Rep. 2022;24:809-817.
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Abbreviations
ADC
antibody drug conjugate
c-MET
hepatocyte growth factor receptor
CRC
colorectal cancer
EGFR
epidermal growth factor receptor
EGFRm
epidermal growth factor receptor mutation
EGFRwt
epidermal growth factor receptor wild type
HNSCC
head and neck squamous cell carcinoma
NSCLC
non-small cell lung cancer
TOP1i
topoisomerase 1 inhibitor
Target Overview
EGFR (epidermal growth factor receptor) and c-MET (hepatocyte growth factor receptor) are proteins expressed simultaneously on the surface of many cancer cells, unlike normal tissues. Overexpression or mutation of these receptors is correlated with the development, progression, and metastasis of cancer as well as poor prognosis.1,2 EGFR and c-MET share overlapping biology, with a functional cross-talk between the receptors that translates into clinically relevant phenotypes. In EGFR-mutated NSCLC, c-MET gene amplification has been identified as the most common mechanism of resistance to third-generation EGFR inhibitors, such as osimertinib.3,4,5
Compound Overview
Tilatamig samrotecan (AZD9592) is an antibody-drug conjugate. The antibody is a bispecific human IgG1 monoclonal antibody that can bind to EGFR and c-MET simultaneously on the surface of cells that express both of these receptors. Attached to the antibody are 6 molecules of a topoisomerase I inhibitor (TOP1i) warhead (AZ’0132). After binding to the tumor cells, AZD9592 gets internalized and the released warhead causes DNA damage and apoptotic cell death. In addition, the cell-permeable warhead can also diffuse out of EGFR/c-MET-positive tumor cells and kill neighboring tumor cells that express little or no EGFR/c-MET. This mechanism is called the bystander effect.6
Mechanism of Action
References
1. Benedettini E, Sholl LM, Peyton M, et al. Am J Pathol. 2010;177(1):415-423. 2. Engelman JA, Zejnullahu K, Mitsudomi T, et al. Science. 2007;316(5827):1039-1043. 3. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Br J Cancer. 2019;121(9):725-737. 4. Passaro A, Jänne PA, Mok T, Peters S. Nat Cancer. 2021;2(4):377-391. 5. Zhang Z, Yang S, Wang Q. Biomark Res. 2019;7:27. 6. Giugliano F, Corti C, Tarantino P, Michelini F, Curigliano G. Curr Oncol Rep. 2022;24:809-817.
Clinical trial information
Select trial for more information
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Abbreviations
ADC
antibody drug conjugate
c-MET
hepatocyte growth factor receptor
CRC
colorectal cancer
EGFR
epidermal growth factor receptor
EGFRm
epidermal growth factor receptor mutation
EGFRwt
epidermal growth factor receptor wild type
HNSCC
head and neck squamous cell carcinoma
NSCLC
non-small cell lung cancer
TOP1i
topoisomerase 1 inhibitor