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erlotinib
Tuesday 2 June 2009
(trade name Tarceva)
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Definition: Erlotinib hydrochloride (Tarceva) acts on the epidermal growth factor receptor (EGFR). It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).
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Folliculitis-perifolliculitis related to erlotinib therapy
Erlotinib hydrochloride (Tarceva) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.
Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.
Erlotinib is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche under the tradename Tarceva.
In lung cancer, it extends life by an average of 3.3 months at a cost of CDN$ 95,000.
Targets
Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer.
Erlotinib 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.
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.
Erlotinib 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.
Indications
Erlotinib hydrochloride (originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.
Lung cancer
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 alone.
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 effective.
In a draft guidance, NICE has recommened Tarceva for lung cancer.
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 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.
JAK2
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.
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.
Pancreatic cancer
In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.
Patent
The drug’s US patent will expire in 2020.
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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See also
tyrosine kinase inhibitors ("-nib")
- receptor tyrosine kinase
- ErbB: HER1/EGFR (erlotinib, gefitinib, vandetanib) · HER1/EGFR and HER2/neu (afatinib, lapatinib, neratinib)
- RTK class III: C-kit and PDGFR (axitinib, pazopanib, sunitinib, sorafenib, toceranib) · FLT3 (lestaurtinib)
- VEGFR (axitinib, cediranib, pazopanib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, vandetanib)
