Icotinib

Icotinib (trade name Conmana) is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Icotinib is approved for use in China as first-line monotherapy in patients with non-small-cell lung cancer with somatic EGFR mutations.

Icotinib
Clinical data
Trade namesConmana
Other namesBPI-2009H
Routes of
administration		By mouth tablets
ATC code
Pharmacokinetic data
Bioavailability52%
MetabolismLiver (mainly CYP3A4, less CYP1A2)
Elimination half-life5.5 hrs (median)
Excretion>98% as metabolites, of which >90% via faeces, 9% via urine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC22H21N3O4
Molar mass391.427 g·mol−1
3D model (JSmol)
SMILES
  • C#Cc1cccc(Nc2ncnc3cc4c(cc23)OCCOCCOCCO4)c1
InChI
  • InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25) Y
  • Key:QQLKULDARVNMAL-UHFFFAOYSA-N Y
  (verify)

Development

Icotinib was first synthesized in 2002 by the company Betta Pharma.[1] The US patent application for the preparation of icotinib and icotinib hydrochloride was filed on December 28, 2012, and granted on July 21, 2015.[2]

Mechanism of action

Icotinib is a quinazoline derivative that competitively inhibits the ATP binding site of the EGFR receptor protein. EGFR drives malignant growth of cells when mutations occur within the tyrosine kinase domain of this protein. Such mutations cause unchecked cell proliferation, which inappropriately activates the anti-apoptotic Ras signaling pathway. By blocking the binding of ATP to EGFR, icotinib prevents activity of the signal transduction cascade that initiates mitosis.[3]

Indications

Icotinib is approved in China for the treatment of non-small cell lung cancer in patients with an EGFR mutation who have advanced or metastatic disease.[4]

Clinical research

The ICOGEN trial was a double-blind, head-to-head phase III study comparing icotinib with gefitinib in 399 patients across 27 centers in China. Results showed icotinib to have a median progression-free survival of 4.6 months (95% CI 3.5 – 6.3) as compared to gefitinib which has a PFS of 3.4 months (95% CI 2.3 – 3.8). Post-hoc analysis found fewer adverse events with icotinib than gefitinib (61% versus 70% respectively, p = 0.046).[5]

The ISAFE trial was a phase IV study evaluating the safety and toxicity of icotinib in 5,549 patients. It showed an overall adverse event rate of 31.5% and response rate of 30% to the drug.[6]

After receiving approval from the FDA to study icotinib in NSCLC patients,[7] a phase 1 study was planned to be conducted at Roswell Park Comprehensive Cancer Center in New York State, however the trial was withdrawn prior to enrollment. No further pursuits of US-based studies of icotinib have transpired since.[8]

Regulatory approvals

Icotinib was approved in China by the SFDA in June, 2011.[9] An indication for icotinib was approved in China by the SFDA in November 2014 as first-line treatment for patients with advanced-stage NSCLC with EGFR mutation.[10]

References
  1. "About Us". Beta Pharma. Retrieved 31 October 2017.
  2. US 9085588, Hu S, Long W, Wang F, Li Z, "Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof", issued 21 July 2015, assigned to Betta Pharmaceuticals Co Ltd
  3. Sordella R, Bell DW, Haber DA, Settleman J (August 2004). "Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways". Science. 305 (5687): 1163–7. Bibcode:2004Sci...305.1163S. doi:10.1126/science.1101637. PMID 15284455. S2CID 34389318.
  4. "Product: Icotinib". Betta Pharma. Retrieved 1 November 2017.
  5. Shi Y, Zhang L, Liu X, Zhou C, Zhang L, Zhang S, et al. (September 2013). "Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial". The Lancet. Oncology. 14 (10): 953–61. doi:10.1016/S1470-2045(13)70355-3. PMID 23948351.
  6. Tan F, Gu A, Zhang Y, Jiao SC, Wang CL, He J, et al. (2013). "Safety and efficacy results of a phase IV, open-label, multicenter, safety-monitoring study of icotinib in treating advanced non-small cell lung cancer (NSCLC): ISAFE study". ASCO 2013 Meeting: e19161.
  7. "Icotinib & Phase IV ISAFE Trial Poster" (PDF). Beta Pharma. Retrieved 1 November 2017.
  8. Clinical trial number NCT02033148 for "Icotinib Hydrochloride in Treating Patients With Advanced Cancers" at ClinicalTrials.gov
  9. Chen X, Zhu Q, Liu Y, Liu P, Yin Y, Guo R, et al. (16 May 2014). "Icotinib is an active treatment of non-small-cell lung cancer: a retrospective study". PLOS ONE. 9 (5): e95897. Bibcode:2014PLoSO...995897C. doi:10.1371/journal.pone.0095897. PMC 4023939. PMID 24836053.
  10. "Betta Pharmaceuticals received marketing approval of Icotinib indicating for first-line treatment of patients with advanced-stage NSCLC with EGFR mutation". Betta Pharmaceuticals. Retrieved 1 November 2017.
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