ROLE OF ERLOTINIB IN NON-SMALL CELL LUNG CANCER AS WELL AS PANCREATIC CANCER: A REVIEW

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About Authors:
Satyanand Tyagi*
*President, Tyagi Pharmacy Association & Scientific Writer,
Chattarpur, New Delhi, India-110074.
Prof. Satyanand Tyagi is a life time member of various pharmacy professional bodies like IPA, APTI and IPGA. He has published various research papers and review articles. His academic works include 49 Publications (41 Review Articles and 08 Research Articles of Pharmaceutical, Medicinal and Clinical Importance, published in standard and reputed National and International Pharmacy journals; Out of 49 publications, 11 are International Publications).
*sntyagi9@yahoo.com
, +91-9871111375 / 9582025220

ABSTRACT:
Erlotinib is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible 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. In lung cancer, it extends life by an average of 3.3 months at a cost of CDN $ 95,000. The hydrochloride salt of a quinazoline derivative of the drug shows antineoplastic properties. Competing with adenosine triphosphate, erlotinib reversibly binds to the intracellular catalytic domain of epidermal growth factor receptor (EGFR) tyrosine kinase, thereby reversibly inhibiting EGFR phosphorylation and blocking the signal transduction events and tumorigenic effects associated with EGFR activation. Erlotinib hydrochloride is approved to be used alone or with other drugs to treat:
* Non-small cell lung cancer that is locally advanced or has metastasized (spread to other parts of the body). It is used in patients who have already been treated with other chemotherapy.
* Pancreatic cancer. It is used with gemcitabine hydrochloride in patients whose disease cannot be removed by surgery or has metastasized.

Erlotinib hydrochloride is also being studied in the treatment of other types of cancer. The aim of present article is to provide in depth knowledge about the drug Erlotinib as well as its role in treatment of non-small cell lung cancer as well as pancreatic cancer.The review has also focused about chemistry, pharmacology as well as clinical trial studies of the Erlotinib.


REFERENCE ID: PHARMATUTOR-ART-1469

INTRODUCTION:
Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.
It is a reversible 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. In lung cancer, it extends life by an average of 3.3 months at a cost of CDN$95,000. Chemically it is N-(3-ethynylphenyl)-6, 7-bis (2-methoxyethoxy) quinazolin-4-amine hydrochloride  (Fig.1).

Fig.1:Chemical Structure of Erlotinib


MECHANISM OF ACTION:
Erlotinib is an EGFR inhibitor. The drug follows Iressa (gefitinib), which was the first drug of this type. Erlotinib specifically targets the epidermal (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 receptor1. 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.

CLINICAL APPLICATIONS:
Erlotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. The SATURN (Sequential Tarceva in Unresectable NSCLC) study found that erlotinib added to chemotherapy improved overall survival by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone2, 3. The manufacturer estimated that erlotinib can extend life by approximately 3.3 months. This is at a cost of CDN$95,000, which some researchers call "marginally”, cost effective4. In a draft guidance, NICE has recommended Tarceva for lung cancer5. The U.S. Food and Drug Administration (FDA) has 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 FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer6.

In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in the group of patients with EGFR mutations.

A test for the EGFR mutation in cancer patients has been developed by Genzyme. The response rate among EGFR mutation positive patients is approximately 60%. Patients who are non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC are more likely to have EGFR mutations, but mutations can occur in all types of patients. 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 EGFR positive patients are generally KRAS negative. The drug's US patent will expire in 20208. In May 2012, the US District Court of Delaware passed an order in favour of OSI Pharmaceutical LLC against Mylan Pharmaceuticals upholding the validity of the patent for Erlotinib. In India, generic pharmaceutical firm Cipla is battling with Roche against the Indian patent for this drug.

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