Drug Information

Drug (ID: DG01249) and It's Reported Resistant Information

• Name: Capmatinib
• Synonyms: Capmatinib; 1029712-80-8; INCB28060; INC-280; INC280; 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide; INCB-28060; NVP-INC280; UNII-TY34L4F9OZ; NVP-INC280-NX; Capmatinib (INCB28060); INC28060; 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide; TY34L4F9OZ; INCB 28060; BenzaMide, 2-fluoro-N-Methyl-4-[7-(6-quinolinylMethyl)iMidazo[1,2-b][1,2,4]triazin-2-yl]-; 2-Fluoro-N-methyl-4-[7-[(quinolin-6-yl)methyl]imidazo[1,2-b]-[1,2,4]triazin-2-yl]benzamide; C23H17FN6O; Tabrecta; Benzamide, 2-fluoro-N-methyl-4-[7-(6-quinolinylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-;Benzamide, 2-fluoro-N-methyl-4-[7-(6-quinolinylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-; benzamide hcl; INCB-28060 FREE BASE; Capmatinib [USAN]; Capmatinib (USAN/INN); Capmatinib [USAN:INN]; Capmatinib(INCB28060); INCB28060(Capmatinib); NYP-INC280-NX; MLS006010965; GTPL7904; SCHEMBL1426819; CHEMBL3188267; DTXSID90145595; EX-A446; AMY18553; AOB87335; BCP23444; BDBM50146167; MFCD18633285; NSC777878; NSC800067; s2788; ZINC43195321; AKOS025396439; BCP9000785; CCG-268791; CS-1541; DB11791; NSC-777878; NSC-800067; QC-7530; SB16608; NCGC00346702-01; NCGC00346702-02; NCGC00346702-05; AC-25890; AS-74142; DA-33530; HY-13404; SMR004702769; FT-0746310; Y0337; D10696; J-509516; Q27075685; 2-Fluoro-N-methyl-4-[7-(6-quinolinylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide; 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazolo[1,2-b][1,2,4]triazin-2-yl]benzamide; 2-fluoro-N-methyl-4-{7-[(quinolin-6-yl)methyl]imidazo[1,2-b][1,2,4]triazin-2-yl}benzamide
• Indication:
  In total 3 Indication(s)
  Hepatocellular carcinoma [ICD-11: 2C12]; Approved; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
  Recurrent glioblastoma [ICD-11: 2A00]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Gastric cancer [ICD-11: 2B72]; [2]
  Lung cancer [ICD-11: 2C25]; [3]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [4]
• Target: Proto-oncogene c-Met (MET); MET_HUMAN; [1]
• Formula: C23H17FN6O
• IsoSMILES: CNC(=O)C1=C(C=C(C=C1)C2=NN3C(=CN=C3N=C2)CC4=CC5=C(C=C4)N=CC=C5)F
• InChI: 1S/C23H17FN6O/c1-25-22(31)18-6-5-16(11-19(18)24)21-13-28-23-27-12-17(30(23)29-21)10-14-4-7-20-15(9-14)3-2-8-26-20/h2-9,11-13H,10H2,1H3,(H,25,31)
• InChIKey: LIOLIMKSCNQPLV-UHFFFAOYSA-N
• PubChem CID: 25145656
• TTD Drug ID: D07OJZ
• DrugBank ID: DB11791

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Hepatocyte growth factor receptor (MET) [5]

• Molecule Alteration: Missense mutation; p.Y1230H (c.3688T>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic female mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.

Key Molecule: Hepatocyte growth factor receptor (MET) [5]

• Molecule Alteration: Missense mutation; p.D1228N (c.3682G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic female mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: MET mutations Y1248H and D1246N are resistance mechanisms for type I MET-TKIs. NIH3T3 cells expressing either mutation showed resistance to both INC280 and crizotinib but not cabozantinib, indicating the potential of sequential use of MET inhibitors may lead to a more durable response.

Key Molecule: Hepatocyte growth factor receptor (MET) [4]

• Molecule Alteration: Missense mutation; p.D1228V (c.3683A>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: There is a patient with metastatic NSCLC with MET-mediated resistance to EGFR TKI who responded to treatment with a type I MET inhibitor, savolitinib, given in combination with a third-generation EGFR inhibitor, osimertinib. The patient then developed acquired resistance mediated by a novel MET kinase domain mutation.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [6]

• Molecule Alteration: Missense mutation; p.Y1003F (c.3008A>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vitro Model: Gp2-293 cells; Fetal kidney; Homo sapiens (Human); CVCL_WI48
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Hepatocyte growth factor receptor (MET) [6]

• Molecule Alteration: Missense mutation; p.D1010Y (c.3028G>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: WEHI-3 cells; Peripheral blood; Mus musculus (Mouse); CVCL_3622
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vitro Model: Gp2-293 cells; Fetal kidney; Homo sapiens (Human); CVCL_WI48
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: CCK-8 assay

Gastric cancer [ICD-11: 2B72]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [2]

• Molecule Alteration: Missense mutation; p.Y1230C (c.3689A>G)
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NCI-H441 cells; Lung; Homo sapiens (Human); CVCL_1561
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: SNU638 cells; Ascites; Homo sapiens (Human); CVCL_0102
• In Vitro Model: NCI-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vitro Model: Hs746T cells; Skeletal muscle; Homo sapiens (Human); CVCL_0333
• In Vivo Model: Nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Molecule Alteration: Missense mutation; p.D1228H
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Mechanism Description: Capmatinib is approved for MET exon 14-altered NSCLC based on activity in targeted therapy-na ve patients. A secondary MET mutation was detected in plasma from 4 (36%) patients with crizotinib-resistant NSCLC. The detected mutations included MET D1228H (n=2), Y1230H (n=1), and D1228N +Y1230H (n=1).

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Molecule Alteration: Missense mutation; p.Y1230H
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Mechanism Description: Capmatinib is approved for MET exon 14-altered NSCLC based on activity in targeted therapy-na ve patients. A secondary MET mutation was detected in plasma from 4 (36%) patients with crizotinib-resistant NSCLC. The detected mutations included MET D1228H (n=2), Y1230H (n=1), and D1228N +Y1230H (n=1).

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Molecule Alteration: Missense mutation+Missense mutation; p.D1228N+p.Y1230H
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next generation sequencing assay
• Mechanism Description: Capmatinib is approved for MET exon 14-altered NSCLC based on activity in targeted therapy-na ve patients. A secondary MET mutation was detected in plasma from 4 (36%) patients with crizotinib-resistant NSCLC. The detected mutations included MET D1228H (n=2), Y1230H (n=1), and D1228N +Y1230H (n=1).

Key Molecule: Hepatocyte growth factor receptor (MET) [7]

• Molecule Alteration: Missense mutation; p.Y1230H (c.3688T>C)
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [3]

• Molecule Alteration: Missense mutation; p.D1228N (c.3682G>A)
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Molecule Alteration: Missense mutation; p.Y1003N (c.3007T>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Molecule Alteration: Missense mutation; p.Y1003C (c.3008A>G)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Molecule Alteration: Missense mutation; p.Y1003F (c.3008A>T)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Molecule Alteration: Missense mutation; p.D1010N (c.3028G>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Molecule Alteration: Missense mutation; p.D1010H (c.3028G>C)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Hepatocyte growth factor receptor (MET) [8]

• Molecule Alteration: Missense mutation; p.D1010Y (c.3028G>T)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

References

• Ref 1: A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor .J Thorac Oncol. 2021 May;16(5):850-859. doi: 10.1016/j.jtho.2021.01.1605. Epub 2021 Feb 3. 10.1016/j.jtho.2021.01.1605
• Ref 2: Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothioneinCancer Cell Int. 2004 Oct 19;4(1):6. doi: 10.1186/1475-2867-4-6.
• Ref 3: Acquired Resistance to Crizotinib in NSCLC with MET Exon 14 Skipping. J Thorac Oncol. 2016 Aug;11(8):1242-1245. doi: 10.1016/j.jtho.2016.06.013. Epub 2016 Jun 22.
• Ref 4: Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov. 2016 Dec;6(12):1334-1341. doi: 10.1158/2159-8290.CD-16-0686. Epub 2016 Sep 30.
• Ref 5: Acquired MET Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non-Small Cell Lung CancerClin Cancer Res. 2017 Aug 15;23(16):4929-4937. doi: 10.1158/1078-0432.CCR-16-3273. Epub 2017 Apr 10.
• Ref 6: Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In VitroJ Thorac Oncol. 2019 Oct;14(10):1753-1765. doi: 10.1016/j.jtho.2019.06.023. Epub 2019 Jul 3.
• Ref 7: Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to CrizotinibJ Thorac Oncol. 2018 Apr;13(4):e49-e53. doi: 10.1016/j.jtho.2017.10.028. Epub 2017 Nov 8.
• Ref 8: Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skippingCancer Discov. 2015 Aug;5(8):842-9. doi: 10.1158/2159-8290.CD-14-1467. Epub 2015 May 13.