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 solid ...

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 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.

Indications

Icotinib is approved in China for the treatment of

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

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 targ ...

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 p ...

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 An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can ther ...

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. The ...

New York State New York, officially the State of New York, is a state in the Northeastern United States. It is often called New York State to distinguish it from its largest city, New York City. With a total area of , New York is the 27th-largest U.S. stat ...

, 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 The National Medical Products Administration (NMPA, , formerly the China Food and Drug Administration, or CFDA) was founded on the basis of the former State Food and Drug Administration (SFDA). In March 2013, the former regulatory body was rebra ...

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