Brian J Byrne
Fellow in Hematology and Oncology
Duke University Medical Center
Lung cancer is the leading cause of cancer death in Europe.(1) Chemotherapy with a platinum-based doublet is the current standard of care for patients with a good performance status and advanced disease. However, even with therapy, prognosis is poor, with a one-year survival of 34% and a two-year survival of 12% in a large randomised trial.(2) This poor survival rate and our increased understanding of cancer biology have led to the development of targeted therapies for the treatment of cancer.
The epidermal growth factor receptor (EGFR), which is overexpressed in 40ï¿½80% of all cases of lung cancer, is a promising area of research.(3) EGFR is a member of the tyrosine kinase family that includes Her2/neu, erb3 and erb4.4 When a ligand binds to the extracellular domain, phosphorylation of the tyrosine kinase occurs. This leads to cell proliferation, apoptosis, angiogenesis, adhesion and motility through pathways such as Ras/Mek/Erk and P13k/Akt.(5) Molecules that target and inhibit EGFR lead to cell death and are promising agents in cancer therapy. One method of inhibiting this enzyme is through small-molecule inhibitors, with agents such as ï¿½gefitinib and erlotinib. These are anilinoâ€‘quinazolines, which are specific, competitive inhibitors of ATP binding by EGFR.
Gefitinib and erlotinib
Gefitinib (Iressa) originally showed a benefit in patients with stage IIIB and IV nonsmall-cell lung cancer (NSCLC). In the two Iressa Dose Evaluation of Advanced Lung Cancer (IDEAL) trials, the rate of response was 18% in IDEAL-1 and 12% in IDEAL-2 (see Table 1).(6,7) In addition, the rate of response was quick, with 68% of responders declaring themselves within four weeks of starting the medication.(6) With a small response rate, both retrospective and prospective studies have been undertaken to identify the subset of patients who are most likely to benefit from the medication. Clinical characteristics associated with a good response to EGFR inhibitors included female sex, nonsmokers, good performance status, Asian race and adenocarcinoma histology.(8-11)
However, the role of gefitinib in NSCLC has been severely questioned with the results of the Iressa Survival Evaluation in Lung Cancer (ISEL) study.(12) This was a placebo- controlled trial that showed no significant survival advantage (5.6 vs 5.1 months) with treatment with gefitinib. When analysing subgroups, there was no difference in survival in patients with adenocarcinoma (6.3 vs 5.4 months; p=0.07), but there was a survival advantage in patients of Asian origin (9.5 vs 5.5 months; p=0.010) and never smokers (8.8 vs 6.1 p=0.012).(12) Following publication of this study, AstraZeneca withdrew its European Marketing Authorization Application and the FDA issued limitations to the prescribing of gefitinib.(12)
Unlike gefitinib, erlotinib has shown a survival advantage in a large phase III randomised controlled trial. The Canadian BR.21 study enrolled 731 patients in a 2:1 scheme.(13) The response rate was 8.9%; however, overall survival was improved by two months (6.7 vs 4.7 months; p<0.001). In a multiple logistic-regression analysis, never smokers, adenocarcinoma and EGFR expression were associated with increased response. However, there was a benefit in most of the subgroups analysed. Erlotinib has received approval from the FDA as a second- or third-line agent in patients with advanced-stage lung cancer. Because of the response rate as second- or third-line therapy, research has been conducted combining these agents with chemotherapy as initial treatment. Preclinical data have shown a benefit in combining gefitinib with chemotherapy. In human tumour xenografts, it has enhanced the efficacy of cytotoxic agents.(14,15) However, disappointingly, in four large clinical trials adding a small tyrosine kinase inhibitor did not have any survival advantage.(16ï¿½19) In a subgroup analysis of the TRIBUTE trial, nonâ€‘smokers who received erlotinib had a 23-month overall survival versus 10 months in patients with placebo (HR 0.49 95% CI 0.28-0.85).(18) Further studies are being conducted to confirm this finding.
In a landmark article, Lynch et al found a mutation near the ATP cleft of the tyrosine kinase domain where 4-anilinoquinazoline compounds such as gefitinib and erlotinib bind.(20) It was thought that this mutation allowed for increased responsiveness to oral tyrosine kinase inhibitors, and eight of nine patients who had a prolonged response to gefitinib had a mutation. Subsequently, it was found that there was an increased rate of mutations in adenocarcinoma compared with other histologies (21% vs 2%), women compared with men (20% vs 9%), and a more frequent rate in Japanese individuals compared with Americans (26% vs 2%).(21) However, in BR.21, polysomy or amplification of EGFR was associated with response to erlotinib, but mutational status was not.(22) The role of mutational status and EGFR overexpression needs to be studied further.
Both gefitinib and erlotinib are well-tolerated medications. In the Iressa Expanded Access Program (EAP), 2.3% of patients had a serious treatment-related adverse event.(9) Discontinuation of the drug for side-effects occurred in 1.1% of patients, and 0.3% had an investigator-assessed, drug-related death. Five percent of patients in BR.21 stopped the drug secondary to side-effects.(13) The most common side-effects are diarrhoea and rash. Diarrhoea, which occurs in around 50% of patients, is of grade 1 and 2 severity and responds to antimotility agents.(6,7,13) Skin toxicity can include acne, rash, dry skin or pruritus. Seventy-six percent of patients on erlotinib and 47-62% of patients on gefitinib express a rash.(6,7,13) There is currently no proven correlation between rash and survival. The major life-threatening toxicity is interstitial lung disease (ILD). Japanese patients on gefitinib with an incidence of 1.9-6.8% appear to have a higher rate than the rest of the world (0.3%).(23-25) There was no increase in ILD in BR.21.(13) It is recommended that, if pulmonary symptoms worsen after starting this medication, it should be immediately stopped. If ILD is confirmed then it should not be restarted.
Inhibiting EGFR is a promising area of treatment for NSCLC. The small tyrosine kinase inhibitors have shown activity in patients with refractory disease. To date, only erlotinib has shown a survival benefit in patients. These agents are being studied in other tumour types. In a phase III trial, erlotinib was combined with gemcitabine in patients with advanced pancreatic cancer. The one-year survival was 24% in the combined group vs 17% in the single agent gemcitabine group. There was no difference in rates of grade III or IV toxicity.(26) Further studies in renal cell, liver, ovarian, head and neck and colon cancer are being conducted, and their use as anticancer drugs may be significantly increased in the coming years.
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