Erlotinib for the treatment of Non-small cell lung cancer

Erlotinib with brand name Tarceva was approved by US-FDA in May 14th 2013, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). This drug is intended for the patients whose tumors have epidermal growth factor receptor (EGFR) with gene substitution mutations. Tarceva was developed by Astellas Pharma Inc. in the US.

Lung cancer could be classified into two major categories. Small cell lung cancer, also known as oat cell carcinoma, accounts for about 15% of lung cancers and non small cell lung cancer (NSCLC) accounts for the majority of the lung cancer cases. Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy is increasingly being used both pre-operatively and post-operatively. The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there areseveral other types that occur less frequently, and all types can occur in unusual histological variants and as mixed cell-type combinations. Lung cancer in non-smokers is almost universally diagnosed with NSCLC, with a sizeable majority being adenocarcinoma. Adenocarcinoma of the lung is currently the most common type of lung cancer in “non- smokers”(especially never smokers). Adenocarcinoma account for approximately 40% of all the lung cancers. Squamous cell carcinoma (SCC) of the lung is more common in men than in women. It is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. The most prominent symptoms include persistent cough that may get worse over time, trouble breathing or shortness of breath, constant chest pain or discomfort, hoarseness, bloody phlegm or spit (sputum),infections such as bronchitis or pneumonia that won’t go away or that keep coming back , fatigue and weakness and unintentional weight loss.

Erlotinib is a reversible tyrosine kinase inhibitor, which inhibits epidermal growth factor receptor (EGFR). Erlotinib specifically targets the epidermal growth factor receptor (EGFR) (a tyrosine kinase), which is highly expressed and occasionally mutated in various forms of cancer. The drug binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. EGFR molecule dimerizes to form an active EGFRmoiety. The active dimeric form then use ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. By inhibiting the ATP, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.

The drug was approved based on the results of a randomized, multicenter open-label trial comparing Erlotinib (n=86) to platinum-based doublet chemotherapy (n=88) in patients with metastatic NSCLC. In this study the subjects were specially selected whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as determined by a clinical trial assay (CTA). Eligible patients were randomly assigned (1:1) to receive Erlotinib, 150 mg/day orally, or platinum-based doublet chemotherapy. Platinum-based doublet chemotherapy is the combination of platinum-based (cisplatin, carboplatin, which has platinum as their structural component) chemotherapy along with docetaxel, paclitaxel, vinorelbine, gemcitabine or irinotecan (which are non platinum based agents).Tumor samples from 134 patients were tested retrospectively with reference to the EGFR mutation test. The trial’s primary endpoint was investigator-assessed progression-free survival of the subjects (PFS). Secondary endpoints included overall survival (OS) and objective response rate (ORR) within the subjects. The median PFS was 10.4 months in the Erlotinib arm versus 5.2 months in the platinum-based chemotherapy arm. The median OS was 22.9 months in the Erlotinib arm and 19.5 months in the platinum-based chemotherapy arm. The ORR was 65 percent in the Erlotinib arm and 16 percent in the platinum-based chemotherapy arm. Thus Erlotinib (Tarceva) showed much promising effect compared to platinum-based doublet chemotherapy.

The recommended daily dose of Erlotinib for the treatment of NSCLC is 150 mg, which should be taken orally at least one hour before or two hours after eating a meal. Treatment should continue until disease progression or unacceptable toxicity is observed in subjects. The most common side effect of Erlotinib treated subjects include rash, diarrhea, asthenia, cough, dyspnoea and decreased appetite. The most frequent severe adverse reactions of Erlotinib treatment were rash and diarrhea.

The first line of therapy for any type of cancer plays a pivotal role for the cure of the disease. If the first line of therapy provides sufficient efficacious result, sometimes the cancer could be cured totally or in other cases it would progress very slowly. On November 2004, Erlotinib hydrochloride got approval by US-FDA (Tarceva tablets, OSI Pharmaceuticals Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer. Next on April, 2010 FDA approved Erlotinib for maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).This was intended for the patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. In addition to these, approval of Erlotinib as first-line treatment of patients with metastatic non-small cell lung cancer on May 2013,make it a drug of choice for the treatment of all different stages of non-small cell lung cancer. Thus, Erlotinib has proven to be the most important drug for the treatment of a spectrum of non-small cell lung cancers.

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