We conducted an analysis of gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) to assess the antitumor efficacy of this epidermal growth factor receptor tyrosine kinase inhibitor.
Methods
Our single-center, prospective landmark analysis included 183 patients with advanced NSCLC who received 250 mg of gefitinib orally once daily in an expanded-use program at our institution. Thirty-three of the 183 patients were previously untreated. The patients included in this analysis had all received at least 12 weeks of gefitinib.
Results
The objective tumor response rate was 3.8%, but an additional 53.5% of patients experienced clinically meaningful disease stabilization. Median progression-free survival time was 3.6 months, and median overall survival time was 8.8 months. The 1-year survival rate for the entire cohort was 35%. Predictors of longer survival included female gender, adenocarcinoma or bronchoalveolar carcinoma histology, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea.
Conclusions
In this single-center experience, gefitinib demonstrated clinically significant antitumor activity and provided good palliation in a predominantly pretreated group of patients. Our results, which are likely to be reproducible in a community setting, demonstrated a 1-year survival rate of 35% in a cohort of patients who were able to take the drug for at least 12 weeks.
References
1.
KlapperL.N., KirschbaumM.H., SelaM.. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors.Adv Cancer Res.2000; 77: 25–79.
2.
LemmonM.A., SchlessingerJ.. Regulation of signal transduction and signal diversity by receptor oligomerization.Trends Biochem Sci.1994; 19: 459–463.
3.
AlbanellJ., RojoF., AverbuchS.. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition.J Clin Oncol.2002; 20: 110–124.
4.
KeL.D., Adler-StorthzK., ClaymanG.L.. Differential expression of epidermal growth factor receptor in human head and neck cancers.Head Neck.1998; 20: 320–327.
5.
SalomonD.S., BrandtR., CiardielloF.. Epidermal growth factor-related peptides and their receptors in human malignancies.Crit Rev Oncol Hematol.1995; 19: 183–232.
6.
TysnesB.B., HauglandH.K., BjerkvigR.. Epidermal growth factor and laminin receptors contribute to migratory and invasive properties of gliomas.Invasion Metastasis.1997; 17: 270–280.
7.
KulikG., KlippelA., WeberM.J.. Antiapoptotic signaling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt.Mol Cell Biol.1997; 17: 1595–1606.
8.
AkimotoT., HunterN.R., BuchmillerL.. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.Clin Cancer Res.1999; 5: 2884–2890.
9.
WosikowskiK., SilvermanJ.A., BishopP.. Reduced growth rate accompanied by aberrant epidermal growth factor signaling in drug resistant human breast cancer cells.Biochim Biophys Acta.2000; 1497: 215–226.
10.
RansonM., HammondL.A., FerryD.. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.J Clin Oncol.2002; 20: 2240–2250.
CiardielloF., CaputoR., BiancoR.. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor.Clin Cancer Res.2000; 6: 2053–2063.
13.
SwaislandH., LaightA., StaffordL.. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers.Clin Pharmacokinet.2001; 40: 297–306.
14.
HerbstR.S., MaddoxA.M., RothenbergM.L.. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.J Clin Oncol.2002; 20: 3815–3825.
15.
BaselgaJ., RischinD., RansonM.. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.J Clin Oncol.2002; 20: 4292–4302.
16.
LorussoP.M.. Phase I studies of ZD1839 in patients with common solid tumors.Semin Oncol.2003; 30(1 suppl 1): 21–29.
17.
FukuokaM., YanoS., GiacconeG.. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer.J Clin Oncol.2003; 21: 2237–2246.
18.
KaplanE.L., MeierP.L.. Nonparametric estimation from incomplete observations.J Am Statistical Assoc.1958; 53: 457–481.
19.
GreenwoodM.. The natural duration of cancer.Reports on Public Health and Medical Subjects.London, England: His Majesty's Stationery Office; 1926: 33; 1–26.
20.
National Cancer Institute.Cancer Therapy Evaluation Program: Common Toxicity Criteria v2.0. Available at: http://ctep.cancer.gov/reporting/ctc.html. Accessed August 5, 2003.
21.
JohnsonD.H., ArteagaC.L.. Gefitinib in recurrent non-small-cell lung cancer: an IDEAL trial?J Clin Oncol.2003; 21: 2227–2229.
22.
FranklinW.A., VeveR., HirschF.R.. Epidermal growth factor receptor family in lung cancer and premalignancy.Semin Oncol.2002; 29(1 suppl 4): 3–14.
23.
HirschF.R., Varella-GarciaM., FranklinW.A.. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas.Br J Cancer.2002; 86: 1449–1456.
24.
MoasserM.M., BassoA., AverbuchS.D.. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells.Cancer Res.2001; 61: 7184–7188.
25.
MoulderS.L., YakesF.M., MuthuswamyS.K.. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo.Cancer Res.2001; 61: 8887–8895.
26.
LangerC.J., ManolaJ., BernardoP.. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial.J Natl Cancer Inst.2002; 94: 173–181.
27.
LilenbaumR.C., HerndonJ., ListM.. Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness.Proc Annu Meet Am Soc Clin Oncol.2002: 2. Abstract.
28.
WakelingA.E., GuyS.P., WoodburnJ.R.. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy.Cancer Res.2002; 62: 5749–5754.
29.
SirotnakF.M., ZakowskiM.F., MillerV.A.. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase.Clin Cancer Res.2000; 6: 4885–4892.
30.
JanmaatM.L., KruytF.A., RodriguezJ.A.. Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways.Clin Cancer Res.2003; 9: 2316–2326.
