|Metabolism||Hepatic (mainly CYP3A4, less CYP1A2)|
|Elimination half-life||5.5 hrs (median)|
|Excretion||>98% as metabolites, of which >90% via faeces, 9% via urine|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||391.420 g/mol g·mol−1|
|3D model (JSmol)|
Icotinib (trade name Conmana) is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Icotinib is approved for use as first-line monotherapy in patients with non-small-cell lung cancer with somatic EGFR mutations. Currently, it is solely approved and marketed in China.
Beta Pharma, an American specialty pharmaceutical company, first synthesized icotinib in 2002. Icotinib was subsequently developed, approved, and marketed in China through a joint venture with Chinese-based pharmaceutical company Betta Pharmaceuticals, Ltd. Since attaining approval by the Chinese Food and Drug Administration in 2011, icotinib, marketed under the brand name Conmana, has reported to have over a third of the Chinese market share in lung cancer therapies. The US patent application for the preparation of icotinib and icotinib hydrochloride was filed on December 28, 2012 and the patent was granted on July 21, 2015. There are currently no active or recruiting clinical trials for icotinib in the United States. Currently, icotinib is the only marketed drug product from Betta Pharmaceuticals, primarily accounting for the company’s $1.289 billion earnings in sales in 2016. Beta Pharma owns the international development and production rights of icotinib outside of China.
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.
Icotinib is approved for the treatment for EGFR mutation-positive, advanced or metastatic non-small cell lung cancer (NSCLC). Upon initial approval, icotinib was indicated as a second-line or third-line treatment for patients who have failed at least one prior treatment with platinum-based chemotherapy. In 2014, icotinib was approved to treat NSCLC patients with EGFR mutation regardless of past chemotherapy use. 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 an adverse event rate of 31.5%. This trial demonstrated consistent safety and toxicity profiles of icotinib observed in the ICOGEN trial. In 2014, after receiving approval from the FDA to study icotinib in NSCLC patients with EGFR mutation, a phase 1 study was planned to be conducted at the Roswell Park Cancer Institute. The following trial was submitted in January, 2014 and was to begin recruitment in August, 2014. However, the trial was withdrawn prior to enrollment and no further pursuits of US-based studies of icotinib have transpired. 
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.
Beta Pharma 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).