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Icotinib
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<h2 id="development">Development</h2> <p>Icotinib was first synthesized in 2002 by the company Betta Pharma.<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a> The US patent application for the preparation of icotinib and icotinib hydrochloride was filed on December 28, 2012, and granted on July 21, 2015.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> </p> <h2 id="mechanism-of-action">Mechanism of action</h2> <p>Icotinib is a <a href="/facts/Quinazoline/1Ho3cd9r">quinazoline</a> derivative that <a href="/facts/Competitive_inhibition/AQ3PLzBe">competitively inhibits</a> the <a href="/facts/Adenosine_triphosphate/nB9bwgcU">ATP</a> binding site of the <a href="/facts/Epidermal_growth_factor_receptor/NLmnXKYY">EGFR receptor protein</a>. EGFR drives malignant growth of cells <a href="/facts/Oncogene/WLFu6Ma5">when mutations</a> occur within the <a href="/facts/Tyrosine_kinase/26Ln0qJ4">tyrosine kinase</a> <a href="/facts/Protein_domain/oUpFcSsl">domain</a> of this protein. Such mutations cause unchecked cell proliferation, which inappropriately activates the <a href="/facts/Apoptosis/8dVzSm4y">anti-apoptotic</a> <a href="/facts/Ras_GTPase/JB883YoM">Ras</a> signaling pathway. By blocking the binding of ATP to EGFR, icotinib prevents activity of the signal transduction cascade that initiates <a href="/facts/Cellular_division/n5MrunWj">mitosis</a>.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <h2 id="indications">Indications</h2> <p>Icotinib is approved in China for the treatment of <a href="/facts/Non-small_cell_lung_cancer/9T47knRp">non-small cell lung cancer</a> in patients with an EGFR mutation who have advanced or metastatic disease.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p> <h2 id="clinical-research">Clinical research</h2> <p>The ICOGEN trial was a <a href="/facts/Double-blind/6ALSxX8M">double-blind</a>, head-to-head phase III study comparing icotinib with <a href="/facts/Gefitinib/qnjmhugq">gefitinib</a> in 399 patients across 27 centers in China. Results showed icotinib to have a median <a href="/facts/Progression-free_survival/6SIDoGTV">progression-free survival</a> of 4.6 months (95% CI 3.5 – 6.3) as compared to <a href="/facts/Gefitinib/qnjmhugq">gefitinib</a> which has a PFS of 3.4 months (95% CI 2.3 – 3.8). Post-hoc analysis found fewer <a href="/facts/Adverse_event/6zKwT4g5">adverse events</a> with icotinib than gefitinib (61% versus 70% respectively, p = 0.046).<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p><p>After receiving approval from the <a href="/facts/Food_and_drug_administration/rCEnh9WB">FDA</a> to study icotinib in NSCLC patients,<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> a phase 1 study was planned to be conducted at <a href="/facts/Roswell_Park_Comprehensive_Cancer_Center/8bHnqzMY">Roswell Park Comprehensive Cancer Center</a> in <a href="/facts/New_York_State/mnl67G1G">New York State</a>, however the trial was withdrawn prior to enrollment. No further pursuits of US-based studies of icotinib have transpired since.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="regulatory-approvals">Regulatory approvals</h2> <p>Icotinib was approved in China by the <a href="/facts/SFDA/WUUNUafn">SFDA</a> in June, 2011.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> 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.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"About Us". Beta Pharma. Retrieved 31 October 2017. <a href="http://betapharma.com/about-us/icotinib/" target="_blank">http://betapharma.com/about-us/icotinib/</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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 <a href="https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US9085588" target="_blank">https://worldwide.espacenet.com/textdoc?DB=EPODOC&IDX=US9085588</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>"Product: Icotinib". Betta Pharma. Retrieved 1 November 2017. <a href="http://en.bettapharma.com/Product.aspx?cId=58" target="_blank">http://en.bettapharma.com/Product.aspx?cId=58</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>"Icotinib & Phase IV ISAFE Trial Poster" (PDF). Beta Pharma. Retrieved 1 November 2017. <a href="http://betapharma.com/wp-content/uploads/2016/04/APLCC-Poster-final.pdf" target="_blank">http://betapharma.com/wp-content/uploads/2016/04/APLCC-Poster-final.pdf</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Clinical trial number NCT02033148 for "Icotinib Hydrochloride in Treating Patients With Advanced Cancers" at ClinicalTrials.gov <a href="https://www.clinicaltrials.gov/show/NCT02033148" target="_blank">https://www.clinicaltrials.gov/show/NCT02033148</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023939" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023939</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>"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. <a href="http://en.bettapharma.com/NewsDetail.aspx?cId=48&id=1499" target="_blank">http://en.bettapharma.com/NewsDetail.aspx?cId=48&id=1499</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> </ol>