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.

Development

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

Mechanism of action

Icotinib is a

quinazoline Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline so ...

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 A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

domain A domain is a geographic area controlled by a single person or organization. Domain may also refer to: Law and human geography * Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...

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 Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

Indications

Icotinib is approved in China for the treatment of

non-small cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

in patients with an EGFR mutation who have advanced or metastatic disease.

Clinical research

The ICOGEN trial was a

double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

, head-to-head phase III study comparing icotinib with

gefitinib Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targe ...

in 399 patients across 27 centers in China. Results showed icotinib to have a median

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is ...

of 4.6 months (95% CI 3.5 – 6.3) as compared to

which has a PFS of 3.4 months (95% CI 2.3 – 3.8). Post-hoc analysis found fewer

adverse event In pharmaceuticals, an adverse event (AE) is any unexpected or harmful medical occurrence that happens to a patient during medical treatment or a clinical trial. Unlike direct side effects, an adverse event does not necessarily mean the medicati ...

s with icotinib than gefitinib (61% versus 70% respectively, p = 0.046). 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. After receiving approval from the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

to study icotinib in NSCLC patients, a phase 1 study was planned to be conducted at

Roswell Park Comprehensive Cancer Center Roswell Park Comprehensive Cancer Center is a cancer research and treatment center located in Buffalo, New York. Founded by surgeon Roswell Park in 1898, the center was the first in the United States to specifically focus on cancer research. Th ...

New York State New York, also called New York State, is a state in the northeastern United States. Bordered by New England to the east, Canada to the north, and Pennsylvania and New Jersey to the south, its territory extends into both the Atlantic Ocean and ...

, however the trial was withdrawn prior to enrollment. No further pursuits of US-based studies of icotinib have transpired since.

Regulatory approvals

Icotinib was approved in China by the SFDA in June, 2011. 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.

References

{{Growth factor receptor modulators Tyrosine kinase inhibitors Quinazolines