Gefitinib (Iressa)

A reversible inhibitor of the epidermal growth factor receptor.

A tyrosine kinase inhibitor.

A reversible inhibitor of the kinase activity of the wild-type and activating mutations of EGFR

Approved for the first line treatment of patients with metastatic non-small cell lung cancer with EGFR exon 19 deletions or exon 21 (L858R)substitution mutations, as detected by companion diagnostic test.

Activating EGFR mutations such as exon 19 deletion and exon 21 point mutation L858R A non-small cell lung cancer promotes tumor cell growth, inhibits apoptosis, up regulates angiogenic factors, and promotes metastases.

This drug is a reversible inhibitor of the kinase activity of wild-type and activating mutations of EGFR preventing autophosphorylation of tyrosine residues resulting inhibition of downstream signaling and EGFR-dependent proliferation.

The binding affinity of this drug is higher for mutated EGFR than for wild-type EGFR and also inhibits insulin-like growth factor and platelet derived growth factor.

Asians treated with non-small cell small cell cancer have longer survival than non-Asians so treated.

Mutations in the EGFR tyrosine kinase domain are observed in approximately 15% of NSCLC adenocarcinomas in the US, and are more common in Asians and non-smokers.

Associated with a 10% response rate in advanced non-small-cell lung cancer after chemotherapy failure.

Has a toxicity profile similar to erlotinib, except for hepatic toxicity.

Rash of all grades occurrs in 47% of patients, diarrhea of all grades occurs in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials.

Elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.

Close monitoring of liver function is clinically warranted.

Iressa Survival Evaluation in Lung Cancer (ISEL)-250 mg per day vs. best supportive care in NSCLC patients that failed previous chemotherapy had no improvement in survival.

In phase 2 studies of this agent in patients with advanced non-small cell lung cancer and EGFR mutations, a response rate of more than 70% and progression free survival of 9 to 10 months has been reported (Inoue A et al, Asashina H et al, Sutani A et al).

Clinical responses have been observed most frequently in females, nonsmokers, patients with adenocarcinoma, and of Asian ethnicity.

Gefitinib in phase II studies of patients with previously treated non-small cell lung cancer the response rate is 9-19% (Schiller JH, Ohe Y).

In a randomized controlled study of 230 patients with metastatic, non-small cell lung cancer and EGFR mutations and who had not previously received chemotherapy, received gefitinib or carboplatin-paclitaxel: progression free survival was significantly longer in the gefitinib group with a median progression free survival of 10.8 months versus 5.4 months in the chemotherapy group, a higher response rate of 73% versus 23% in the chemotherapy group (Makoto M et al).

Indicated for the first-line treatment of patients with metastatic non-small cell lung cancer who have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Deletions in exon 19 and L858R point mutation in exon 21 are the 2 most common activating mutations.

EGFR mutations significantly predeict for increased response to TKI mamgement and a favorable prognosis in adenocarcinoma of the lung.

IFUM study revealed a 50% objective response rate and a 70% overall sponsoring the median duration of response of 6-8.3 months.

IPASS study 3-1/2 month improvement in progression free survival versus chemotherapy overall response rate 67% with a median duration of response 9.6 months.

Fewer than 3% of patients treated have serious adverse events.

Approximate 5% of patients discontinue therapy due to an adverse event the most frequent which are nausea, vomiting, and diarrhea.

Associated with about a 1% risk 0f interstitial lung disease, which can lead to fatalities.

Dosing 250 mg tablet daily with or without food.

Approved with the companion diagnostic test EGFR RGQ PCR kit (Qiagen).

The drug is administered until disease progression or unacceptable toxicity.

The drug should be withheld for up to 14 days for acute worsening of pulmonary symptoms of dyspnea, cough or fever or grade 2 or greater liver function abnormalities or diarrhea, or signs of symptoms of ocular disorders.

Daily dose can be increased to 500 mg in the absence of severe adverse drug reactions when used concomitantly with strong CYP3A4 inducers such as phenytoin or tricyclic antidepressants with treatment resumed at 250 mg after discontinuation of the associated drugs.

Drugs that elevate gastric pH should not be given concomitantly and not a same time with proton pump inhibitors or H2 receptor antagonist or antacids.

Patients taking warfarin need regular monitoring of INR as elevations in INR and hemorrhage have been reported with gefitinib.

The most common adverse reactions are skin reactions, diarrhea, decreased appetite, and vomiting.

The drug carries warnings for interstitial lung disease, hepatotoxicity, gastrointestinal perforation, ocular disorders, skin disorders and embryofetal toxicity.

Incidence of interstitial lung disease is 1.3%

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