Erlotinib

Rachel Boone

Drug: Erlotinib

Background:

     Erlotinib is an orally active first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). The synthetic anti-cancer drug is used to treat non-small-cell lung cancer (NSCLC) as well as advanced-stage pancreatic cancer and several other cancer types. Molecular targeted cancer medications such as erlotinib have rapidly grown and expanded over the recent decades. This newer, more specific approach to cancer treatment has shown improvements in survival rates and quality of life over traditional chemotherapy strategies.  

     The program, which began in the early to mid-1990s, led to the discovery of Erlotinib [2]. Erlotinib completed Phase III trials and achieved FDA approval as a monotherapy treatment strategy in November 2004 [2]. Marketed under the trade name Tarceva in a hydrochloride salt form (erlotinib hydrochloride), this compound has the distinction of being the first EGFR inhibitor to show survival benefits in lung cancer patients (drugdevelopment-technology.com).

     Erlotinib’s chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)- 4-quinazolinamine. It belongs to the class of organic compounds known as quinazolinamines, which are heterocyclic, aromatic compounds containing a quinazoline moiety with one or more amine group substituents. Erlotinib contains a functionalized aniline as a substituent on the quinazoline core. Quinazoline derivatives tend to have a wide array of biological properties including antifungal, anit-inflammatory, anticancer among others [5]. The greatest solubility is achieved in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The compound is slightly soluble in polar protic solvents like water, methanol and ethanol, and nearly insoluble in aprotic solvents such as acetone, ethyl acetate, acetonitrile and others. This molecule has a moderate degree of oral bioavailability (approximately 60%) with 100% bioavailability attainable if taken after ingesting food. Erlotinib is well-tolerated via the oral delivery route due to its pH dependent solubility.  Solubility is increased by the protonation of the secondary amine at highly acidic pH, with greatest solubility achieved near a pH of 2. The compound is primarily eliminated by hepatic metabolism and is susceptible to oxidation particularly at the acetylene moiety and aromatic hydroxylation [4].

     Erlotinib was originally approved for treatment after failure of at least one chemotherapy treatment. In recent years, it has been proven effective as first-line treatment in patients with EGFR mutation-positive NSCLC.  Gefitinib (marketed under the trade name Iressa), is the other first-generation reversible, selective EGFR inhibitor approved just 6 months prior to Erlotinib. Though these compounds have the same core, the structural moieties of erlotinib have shown to provide longer half-life with longer median survival [3,10].  Erlotinib competes with ATP to reversibly bind to the catalytic region of tyrosine kinase receptors expressed on the surface of both normal and cancer cells to inhibit EGFR phosphorylation. Inhibition of intracellular phosphorylation prevents further downstream signaling, resulting in cell death (Lexicomp).

     A limitation of these therapies is that they are both only effective in cancer patients exhibiting mutation in EGFR.  Also, many patients lose response during treatment due to acquired resistance, leading to the necessity of improved therapies to combat secondary resistance mutations in EGFR genes. Although rare, some severe hepatotoxicity complications have been sited.

     While gefitnib and erlotinib have shown success in treatment, their limitations prompted the development of second-generation EGFR-TKIs with better efficacy such as afatinib. However, these more potent inhibitors present issues of toxicity because, while getinib and erlotinib are reversible EGFR inhibitors, afatinib is an irreversible, covalent bonding ErbB-family-blocker. This newer mechanism of action has been shown to increase incident and severity of side effects like rash and diarrhea, due to its “more potent and irreversible” inhibition of EGFR signaling. Since erlotinib was reasonably tolerated and effective in treatments, there could be potential for improvement and modifications for extended use.

Development & Approval, Financial History:

     This small molecular, once-a-day, orally active EGFR-TKI was initially formulated by OSI Pharmaceuticals (formerly Oncogene Science) in partnership with Pfizer for treatment of solid tumors, however, in June 2000 Pfizer merged with Warner-Lambert. For the newly formed merger to comply with Federal Trade Commission requirements, Pfizer granted all marketing and developmental rights for erlotinib to OSI. The following year, OSI partnered with HopeLink Corporation, enabling the administration of phase III NSCLC and pancreatic clinical trials through an internet-based service as part of the HopeLink Syndicated Network. That same year, OSI partnered with US NCI and Therradex® for additional aid in monitoring and conducting clinical trials of erlotinib in a variety of cancers including ovarian, head and neck. As part of the collaborative research agreement, OSI also supplied erlotinib to US NCI for investigation as treatment of multiple tumor types including gastrointestinal and genitourinary, gynecological, epithelial and brain. In July 2001, phase III combination trials of erlotinib with chemotherapy drugs carboplatin and paclitaxel were conducted by Genentech. Just months later, the healthcare company Roche began front-line combination clinical trials in NSCLC in Europe.  The collaboration that formed between the three companies OSI, Roche, and Genentech in 2001 initiated several years of collaboration for the clinical co-development of erlotinib as an oral tablet and would eventually lead to an alliance for global development and commercialization.

     In September 2002, OSI received fast track designation by the US FDA for treatment with erlotinib as a second- or third-line treatment in advanced stage NSCLC with failure of at least one chemotherapy regimen. This same year, the Wall Street Journal analysts reported annual sales predictions of over $1 billion ($US).  However, at the same time, approximately 12 new anticancer agents of similar types were set to commercialize and provide strong competition for erlotinib with strongest competitors developed by AstraZeneca and ImClone. Meanwhile, development partners Genentech and Roche were estimated to purchase OSI’s stock for as much as $35 million ($US).  

     

     The FDA granted OSI the approval for erlotinib in treatment of patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. With this approval in November 2004, the drug would become OSI’s flagship product and first drug produced from the company to gain FDA approval. Genentech, Roche and OSI began measures for global production, distribution, marketing and commercialization of the drug erlotinib, which would be marketed under the trade name Tarceva® in a hydrochloride salt form. Under the alliance formed, overall development costs were split equally amongst the three shareholders, with Genentech and OSI splitting costs and profits for U.S. commercialization and Roche managing regulations and commercialization aspects for outside territories with royalties owed to OSI based on net sales. Details in the original agreement outlined specific roles and responsibilities of each company. Initially, Genentech would be responsible for marketing, launch and promotion of Tarceva® in the US. OSI oversaw additional U.S. promotion by manufacturing and supplying at least 25 percent of the combined U.S. sales force.      All companies were responsible for continued development and improvement of Tarceva® post-launch.

     The companies worked under the agreement until 2010, when OSI was acquired by Astellas Holding US Inc. In 2008, Roche bought over half of Genentech’s shares with the remaining purchase completed in 2009. As part of the merger agreement, Genentech (now a member of the Roche group), combined their pharmaceutical operations in the US, with Genentech’s San Francisco location serving as the new headquarters for Roche in the United States. From this point forward, Astellas Oncology and Genentech (now a member of the Roche group) jointly market Tarceva® in the U.S with Roche conducting global initiatives for manufacturing, commercialization and development outside of the U.S.  Genentech continues to pursue independent pursuits in early development collaborations with a separate budget, with Roche serving as the global infrastructure for late-stage drug candidates.

     The second FDA approval for Tarceva® was made in April 2010 for maintenance treatment of advanced NSCLC. This approval was later modified, however, for limit only to patients whose tumors exhibit specific EGFR mutations. It is estimated that between ten to thirty percent of people with lung cancer have tumors that are positive for these specific EGFR mutations. This modifying decision was made after trial results of erlotinib against a placebo as maintenance treatment in patients with metastatic NSCLC without EGFR mutations showed no survival benefits.  Ultimately this decision granted Tarceva® approval as initial treatment in patients exhibiting metastatic, mutation-positive NSCLC, no longer maintenance therapy contingent upon prior chemotherapy treatment.

     In 2016, U.S. partners Genentech and OSI faced a lawsuit claiming false allegations and misleading statements of the effectiveness of Tarceva® for treatment of patients with NSCLC. The allegations claimed inaccurate information was promoted in misleading marketing campaigns for treatment of these patients when there was little evidence of the effectiveness in treating patients who smoked or did not exhibit the EGFR mutation. To resolve these False Claims Act allegations, the companies agreed to pay $67 million settlement, with $62.6 million provided to the federal government and the remaining funds to Medicaid program.

     Globalization partner Astellas reported a decline of 16.5% in Tarceva-related revenues in the fiscal 2016 period to $325 million (US$) profit, split evenly amongst co-promoters Genentech and Roche. They suspect this is largely due to increasing competition in the drug market. Currently, Tarceva® has four U.S. patents to protect from generic formulations. These patents, which expire in 2020, now belong to Astellas following the acquisition of OSI. The company has formulated a business strategy to overcome impacts from these expirations of these patent and other product patents with the likelihood of generic competitors being formed soon.

Bibliography

[1] Tarceva Small Molecule EGFR-Tyrosine Kinase Inhibitor for Cancer. (n.d.). Retrieved from https://www.drugdevelopment-technology.com/projects/tarceva/

[2] Petit-Jean, E., Buclin, T., Guidi, M., Quoix, E., Gourieux, B., Decosterd, L. A., ... & Widmer, N. (2015). Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature. Therapeutic drug monitoring, 37(1), 2-21.

[3] Erlotinib. (2005). Retrieved from https://www.sciencedirect.com/topics/chemistry/erlotinib

[4] Johnson, K., Miao, Z., Rakhit, A., Pantze, M., Hamilton, M., Lum, B., & Prakash, C. (2005). Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug metabolism and disposition.

[5] Jafari, E., Khajouei, M. R., Hassanzadeh, F., Hakimelahi, G. H., & Khodarahmi, G. A. (2016). Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities. Research in pharmaceutical sciences, 11(1), 1.

[6] Schettino, C., Bareschino, M. A., Ricci, V., & Ciardiello, F. (2008). Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment. Expert review of respiratory medicine, 2(2), 167-178.

[7] Tarceva (erlotinib) FDA Approval History. Retrieved from https://www.drugs.com/history/tarceva.html

[8] Muir, V. J., & Dhillon, S. (2011). Erlotinib. BioDrugs, 25(3), 139–146. Retrieved from http://ezproxy.uky.edu/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=a9h&AN=65180052&site=ehost-live&scope=site

[9] Yoneda, K.Y., and C.E. Cross. “Erlotinib.” NeuroImage, Academic Press, 2010, www.sciencedirect.com/topics/chemistry/erlotinib.

[10] Yang, Z., Hackshaw, A., Feng, Q., Fu, X., Zhang, Y., Mao, C., & Tang, J. (2017). Comparison of gefitinib, erlotinib and afatinib in non‐small cell lung cancer: A meta‐analysis. International journal of cancer, 140(12), 2805-2819.

[11] Showing metabocard for Erlotinib (HMDB0014671). (n.d.). Retrieved from http://www.hmdb.ca/metabolites/HMDB0014671

[12] http://www.lexicomp.com

[13] Limited, A. I. (2003). Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415. Drugs in R&D, 4(4), 243–248. http://ezproxy.uky.edu/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=a9h&AN=10219556&site=ehost-live&scope=site

[14] https://www.gene.com/partners/our-relationship-with-roche

[15] Erlotinib. (2003). Drugs in R & D, 4(4), 243-248.

[16] http://www.astellasoncology.com/us/partnership.html

[17] Allen, D. J. M., Norris, T., Raggon, J. W., Santafianos, D. P., & Shanker, R. M. (2004). U.S. Patent No. 6,706,721. Washington, DC: U.S. Patent and Trademark Office.

[18] https://www.gene.com/media/press-releases/7527/2004-06-16/osi-pharmaceuticals-and-genentech-enter-

[19] Norman, P. (2001). OSI-774 OSI Pharmaceuticals. Current opinion in investigational drugs (London, England: 2000), 2(2), 298-304.

[20] https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm525739.htm

[21] https://www.fda.gov/ICECI/CriminalInvestigations/ucm505813.htm

[22] Adis Editorial. (2003). Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415. Drugs in R & D, 4, 243-248.