Drug Information

Drug (ID: DG01263) and It's Reported Resistant Information

• Name: Larotrectinib
• Synonyms: Larotrectinib; LOXO-101; 1223403-58-4; ARRY-470; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; LOXO 101; UNII-PF9462I9HX; LOXO101; PF9462I9HX; (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide; BAY2757556; BAY-2757556; Vitrakvi; ARRY 470; 1-Pyrrolidinecarboxamide, N-(5-((2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxy-, (3S)-; 1-Pyrrolidinecarboxamide, N-[5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxy-, (3S)-; ARRY-470; larotrectinib; Larotrectinib (USAN/INN); Larotrectinib [USAN:INN]; ARRY470; AMY264; GTPL8909; SCHEMBL2241012; CHEMBL3889654; BDBM136597; BCP16262; EX-A1981; MFCD28902192; NSC785570; NSC801004; s5860; Larotrectinib (LOXO-101 free base); example 14 [US8865698 B2]; ZINC118399834; CS-5722; DB14723; NSC-785570; NSC-801004; AC-33660; AS-35231; HY-12866; J3.628.138C; D11137; US8865698, 14; Q27081513; ARRY-470;ARRY 470 : LOXO-101; LOXO101; Larotrectinib; ARRY470;ARRY-470;ARRY 470;LOXO 101;LOXO101;Larotrectinib; (3S)-N-(5-((2R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine- 1-carboxamide; (S)-N-(5 -((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin -1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3 yl)-3-hydroxypyrrolidine-1-carboxamide
• Indication:
  In total 3 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Colorectal cancer [ICD-11: 2B91]; [2]
  Rhabdomyosarcoma [ICD-11: 2B55]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [3]
• Target: BDNF/NT-3 growth factors receptor (TrkB); NTRK2_HUMAN; [1]
• Target: NT-3 growth factor receptor (TrkC); NTRK3_HUMAN; [1]
• Target: Tropomyosin-related kinase A (TrkA); NTRK1_HUMAN; [1]
• Formula: C21H22F2N6O2
• IsoSMILES: C1C[C@@H](N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CC[C@@H](C4)O)C5=C(C=CC(=C5)F)F
• InChI: 1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
• InChIKey: NYNZQNWKBKUAII-KBXCAEBGSA-N
• PubChem CID: 46188928
• TTD Drug ID: D07TOK

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

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

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tropomyosin-related kinase A (TrkA) [3]

• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: NT-3 growth factor receptor (TrkC) [3]

• Molecule Alteration: Missense mutation; p.G623R (c.1867G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• 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: NT-3 growth factor receptor (TrkC) [4]

• Molecule Alteration: Other; .
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: NT-3 growth factor receptor (TrkC) [5]

• Molecule Alteration: Other; .
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay

Rhabdomyosarcoma [ICD-11: 2B55]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tropomyosin-related kinase A (TrkA) [1]

• Molecule Alteration: Missense mutation; p.G595R
• Resistant Disease: Metastatic undifferentiated sarcoma [ICD-11: 2B55.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: NTHY-ORI-3-1 cells; Thyroid gland; Homo sapiens (Human); CVCL_2659
• Mechanism Description: After 6 months on study, restaging scans identified an isolated area of progression in the right hepatic lobe, which was resected (S3), followed by resumption of larotrectinib. NGS from S3 identified an NTRK1 G595R solvent-front mutation. Three months later, diffuse disease was noted on restaging scans.

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tropomyosin-related kinase A (TrkA) [2]

• Molecule Alteration: Missense mutation; p.G595R (c.1783G>A)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: KM-12 cells; Colon; Homo sapiens (Human); CVCL_1331
• In Vivo Model: Balb-c nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blotting analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 assay

Key Molecule: Tropomyosin-related kinase A (TrkA) [2]

• Molecule Alteration: Missense mutation; p.G667C (c.1999G>T)
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: KM-12 cells; Colon; Homo sapiens (Human); CVCL_1331
• In Vivo Model: Balb-c nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blotting analysis
• Experiment for Drug Resistance: CellTiter Glo assay; IC50 assay

References

• Ref 1: Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1 .JCO Precis Oncol. 2020;4:79-90. doi: 10.1200/po.19.00287. Epub 2020 Feb 14. 10.1200/po.19.00287
• Ref 2: Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged CancersMol Cancer Ther. 2017 Oct;16(10):2130-2143. doi: 10.1158/1535-7163.MCT-16-0909. Epub 2017 Jul 27.
• Ref 3: A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid TumorsCancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3.
• Ref 4: Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation studyAnn Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539.
• Ref 5: Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangementBlood Adv. 2020 Jan 14;4(1):106-111. doi: 10.1182/bloodadvances.2019000769.