Icotinib

Icotinib

Clinical data
Trade names	Conmana, Icotinib
Routes of administration	Oral tablets
Pharmacokinetic data
Bioavailability	52%
Metabolism	Hepatic (mainly CYP3A4, less CYP1A2)
Biological half-life	5.5 hrs (median)
Excretion	>98% as metabolites, of which >90% via faeces, 9% via urine
Identifiers
CAS Number	1204313-51-8 Y
PubChem	CID: 22024915
IUPHAR/BPS	7641
ChemSpider	10762174 Y
UNII	9G6U5L461Q Y
ChEMBL	CHEMBL2087361
Chemical data
Formula	C22H21N3O4
Molecular mass	391.420 g/mol
SMILES C#CC1=CC(=CC=C1)NC2=NC=NC3=CC4=C(C=C32)OCCOCCOCCO4
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
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Icotinib Hydrochloride (BPI-2009H), or Icotinib, is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). EGFR is an oncogenic driver and patients with somatic mutations, particularly an exon 19 deletion or exon 21 L858R mutation, within the tyrosine kinase domain have activating mutations that lead to unchecked cell proliferation. Overexpression of EGFR causes inappropriate activation of the anti-apoptotic Ras signaling pathway, found in many different types of cancer. Icotinib is a quinazoline derivative that binds reversibly to the ATP binding site of the EGFR protein, preventing completion of the signal transduction cascade.

Clinical Evaluation

Icotinib is indicated for the treatment for EGFR mutation-positive, advanced or metastatic non-small cell lung cancer (NSCLC) as a second-line or third-line treatment, for patients who have failed at least one prior treatment with platinum-based chemotherapy. The ICOGEN trial was a double-blind, head-to-head phase III study comparing icotinib with gefitinib in all-comers. From 27 centers in China, 399 patients were randomized between the two treatments testing for a primary objective of progression-free survival and secondary objectives of overall survival, time to progression, quality of life, percentage of patients who achieved an objective response, and toxic effects. The ICOGEN results showed icotinib to have a median PFS 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). After the study was completed, post-hoc analysis revealed that in the icotinib treatment group, patients with activating EGFR mutations showed improved PFS as compared to patients with wild-type EGFR. Icotinib also was associated with fewer adverse events than gefitinib when considering all grades of reactions together (61% versus 70% respectively, p = 0.046). The phase IV ISAFE trial evaluated 5,549 patients and showed icotinib to have an overall response rate of 30% and a low adverse event rate of 31.5%.

Regulatory Approvals

Icotinib was approved in China by the SFDA in June, 2011. Since approval, Icotinib has treated over 40,000 patients in China successfully and is now undergoing global development.

January 2014, Beta Pharma, Inc. was given a “May Proceed” from the US FDA to conduct a Phase I study for the evaluation of icotinib as a treatment of EGFR+ Non-Small Cell Lung Cancer (NSCLC).