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      Drug Design, Development and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

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      Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC)

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          Abstract

          Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor. Epidermal growth factor receptor (EGFR)-targeted therapies, such as gefitinib, have been subjected to comprehensive clinical development. Several phase II and III trials evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemotherapy-naive patients. A phase III trial (ISEL) in heavily pretreated advanced NSCLC patients demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant within the overall population. A large phase III trial in pretreated patients (INTEREST) demonstrated the non-inferiority of gefitinib in comparison with docetaxel for overall survival, together with an improved quality of life and tolerability profiles. In a large phase III trial (IPASS) in Asian chemotherapy-naive, never or former light-smoker patients with adenocarcinoma, gefitinib was more effective than carboplatin–paclitaxel in prolonging progression-free survival, particularly in patients harboring EGFR gene mutations. Gefitinib was a generally well tolerated treatment, with skin rash and diarrhea being the most common treatment adverse events. As a result, gefitinib is expected to have a large impact on the management of patients with advanced NSCLC, in particular in EGFR mutated patients.

          Most cited references78

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          EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

          W Pao, V. Miller, M Zakowski … (2004)
          Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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            Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

            Tony Mok, Yi-Long Wu, Sumitra Thongprasert … (2009)
            Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.) 2009 Massachusetts Medical Society
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              Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

              Thomas Lynch, Daphne Bell, Raffaella Sordella … (2004)
              Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (publisher-id): Drug Design, Development and Therapy
                Title: Drug design, development and therapy
                Publisher: Dove Medical Press
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 25 May 2010
                Publication date Collection: 2010
                Volume: 4
                Pages: 81-98
                Affiliations
                Medical Oncology Unit, University, Hospital of Parma, Parma, Italy
                Author notes
                Correspondence: Marcello Tiseo Medical Oncology Unit, University, Hospital of Parma, Via Gramsci, 14, 43100 Parma, Italy, Tel +39 0521 702316, Fax +39 0521 995448, Email mtiseo@ 123456ao.pr.it
                Article
                Publisher ID: dddt-4-081
                DOI: 10.2147/DDDT.S6594
                PMC ID: 2880339
                PubMed ID: 20531963
                SO-VID: d7d20b3f-5728-4400-a564-2241c6126d0a
                Copyright statement: © 2010 Tiseo et al, publisher and licensee Dove Medical Press Ltd.
                License:

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: non-small-cell lung cancer,gefitinib,egfr
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: non-small-cell lung cancer, gefitinib, egfr

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