Erlotinib

Erlotinib

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Systematic (IUPAC) name
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Tarceva US FDA: Erlotinib
Pregnancy category	US: D (Evidence of risk)
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Identifiers
CAS Number	183321-74-6
ATC code	L01XE03 (WHO)
PubChem	CID 176870
DrugBank	APRD00951
ChemSpider	154044
Chemical data
Formula	C22H23N3O4
Molar mass	393.436 g/mol[[]]
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Erlotinib hydrochloride (Tarceva) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR). It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche.

Mechanism

Erlotinib is an EGFR inhibitor. The drug follows Iressa gefitinib, which was the first drug of this type. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change in their intracellular structure, exposing a further binding site for binding proteins that cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped.

Development

Erlotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. It has been approved for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen. In November 2005, the U.S. Food and Drug Administration (FDA) approved the use of erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

A test for the EGFR mutation in cancer patients has been developed by Genzyme. The response rate among EGFR positive patients is approximately 60%. EGFR positive patients are primarily non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC. The tests provides useful information about who is likely to respond to erlotinib and other tyrosine kinase inhibitors. Beyond smoking status, responses among patients with lung cancer are seen most often in females and Asians. EGFR positive patients are generally KRAS negative.

Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.

The drug's US patent will expire in 2020. In India, generic pharmaceutical firm Cipla is battling with Roche against the Indian patent for this drug. In April 2009, the Delhi High Court granted a final approval to Cipla to manufacture and sell its generic version of Erlotinib in India. Meanwhile, another generic pharmaceutical firm - Natco is also seeking to manufacture the generic version of Erlotinib in India but sell it to patients in Nepal using the TRIPS Agreements' Doha Declaration.

Administration

Oral tablets

Side effects

Common side effects

• Rash occurs in the majority of patients. This resembles acne and primarily involves the face and neck. It is self-limited and resolves in the majority of cases, even with continued use. Interestingly, some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed. The Journal of Clinical Oncology reported in 2004 that "cutaneous [skin] rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies." The newsletter Lung Cancer Frontiers reported in its October 2003 issue, "Patients with moderate to severe cutaneous reactions [rashes] have a far better survival, than those with only mild reactions and much better than those with no cutaneous manifestations of drug effects."
• Diarrhea
• Loss of appetite
• Fatigue
• Rarely, interstitial pneumonitis, which is characterized by cough and increased dyspnea. This may be severe and must be considered among those patients whose breathing acutely worsens.
• Rarely, ingrown hairs, such as eyelashes
• It has also been suggested that erlotinib can cause hearing loss.
• Partial hair loss (by strands, not typically in clumps)

Rare Side Effects

In spring 2009, the US Food and Drug Administration issued a warning on erlotinib. The FDA reported serious gastrointestinal tract, skin, and ocular disorders in patients taking the drug. In addition, according to a letter released by Genentech and OSI Pharmaceuticals, some people prescribed erlotinib have developed serious or fatal gastrointestinal tract perforations; "bullous, blistering, and exfoliative skin conditions, some fatal; and serious eye problems such as corneal lesions. Some of the cases, including ones which resulted in death, were suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis.

Resistance to treatment

A key issue with EGFR-directed treatments is that after a period of time, frequently 8–12 months, the cancer cells become resistant to the treatment. The primary source of resistance is a second mutation called T790M. A second source of resistance is the MET mutation.

Chemically resistance appears to occur by recruiting a mutated IGF-1 receptor to act as one of the EGFR partners in the homodimer, so forming a heterodimer. This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538 or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541.

Pan-inhibitors show some promise in combatting resistance, at least in cell studies. Today (3/10) the most promising approach to combatting resistance appears to be a dual approach, combining pan-inhibitors like HKI 272 with Erbitux. "Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab (Erbitux) and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance." Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer, J Clin Invest. 2009 October 1; 119(10). Tang, Dual MET EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer, Br J Cancer. 2008 September 16; 99(6)

Tarceva studies and availability

In November 2008 a study undertaken by Roche Holding of Switzerland claimed that Tarceva given immediately after chemotherapy may prove to stem the progress of lung cancer. Tarceva blocked the spread of advanced non-small cell lung cancer, researchers found.. However, the report of this study, called SATURN, does not indicate the extent of increase in survival-time.

Notes

http://www.cancer.gov/clinicaltrials/results/lung-and-erlotinib0604l http://www.roche.com/med-cor-2007-10-22 http://www.roche.com/med-cor-2009-05-30b http://www.cipla.com/whatsnew/news.htm#27apr09 http://www.cipla.com/whatsnew/news.htm#20mar08

External links

• Official Tarceva website
• Tarceva Discussion Group for Cancer Patients
• Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-7. PMID 15284455.
• Genzyme "Genzyme Launches Exclusive Lung Cancer Test" Press Release September 27, 2005
• "Determinants of Tumor Response and Survival With Erlotinib in Patients With Non-Small-Cell Lung Cancer, Journal of Clinical Oncology, August 15, 2004.
• October 2003 issue of Lung Cancer Frontiers on rash/effectiveness correlation
• "Is Rash a Good Thing with EGFR Inhibitors?", Dr. Howard West, M.D., OncTalk, November 25, 2006 (directed toward the layperson).

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