Figures
- Figure 1.
Schematic representation of the role of epidermal growth factor receptor (EGFR) in cancer and its inhibition by gefitinib. Activation of the EGFR by ligand binding causes receptor dimerisation and the autophosphorylation of specific tyrosine residues of the intracellular tyrosine kinase (TK) domain. This leads to the stimulation of downstream signalling pathways, including the phosphatidylinositol 3-kinase (PI3K)–Akt and RAS–mitogen-activated protein kinase (MAPK) pathways, which promote the processes of cell proliferation, angiogenesis, invasion/metastasis and the inhibition of apoptosis. Gefitinib inhibits the TK activity of the EGFR TK domain, blocking the signalling pathways important in the survival and proliferation of tumour cells. PTEN: phosphatase and tensin homologue; STAT3: signal transducer and activator of transcription 3; GRB2: growth factor receptor-bound protein 2. Reproduced from [11] with permission from the publisher.
- Figure 2.
Forest plot of (left) overall survival and (right) progression-free survival for gefitinib versus docetaxel in the INTEREST (IRESSA NSCLC Trial Evaluating Response and Survival versus Taxotere) study (pretreated setting) by clinical characteristics and epidermal growth factor receptor (EGFR) biomarkers [37, 38]. ORR: objective response rate. #: unadjusted analysis – per-protocol population for clinical factors and intent-to-treat population for biomarker factors; ¶: adjusted analysis – evaluable for response (EFR) population; +: EFR population.
- Figure 3.
Kaplan–Meier curve for progression-free survival for gefitinib versus doublet chemotherapy in three phase III trials in first-line nonsmall cell lung cancer harbouring an activating epidermal growth factor receptor (EGFR) mutation: a) patients with EGFR mutation-positive status in the IRESSA Pan-Asia Study (IPASS; first-line setting) (
: gefitinib; : carboplatin plus paclitaxel) (reproduced from [39] with permission from the publisher; © 2009 Massachusetts Medical Society. All rights reserved), b) the overall population (all EGFR mutation-positive) in the WJTOG3405 study (first-line setting) (: gefitinib; : cisplatin plus docetaxel) (reproduced from [44] with permission from the publisher; © 2010, with permission from Elsevier) and c) the overall population (all EGFR mutation-positive) in the NEJ002 study (first-line setting) (: gefitinib (n = 114); : carboplatin plus paclitaxel (n = 110)) (reproduced from [45] with permission from the publisher; © 2009 Massachusetts Medical Society. All rights reserved). PFS: progression-free survival; HR: hazard ratio. #: HR <1.00 favours gefitinib. - Figure 4.
Kaplan–Meier curve for progression-free survival for non-Asian patients with epidermal growth factor receptor (EGFR) mutation-positive status in the INTEREST (IRESSA NSCLC Trial Evaluating Response and Survival versus Taxotere) study (pretreated setting).
: gefitinib; : docetaxel. PFS: progression-free survival; HR: hazard ratio. #: HR <1.00 favours gefitinib. Reproduced from [53] with permission from the publisher.
Tables
- Table 1 Summary of efficacy end-points for gefitinib from the IPASS, INTEREST and ISEL studies
Study Population Subjects n Objective response rates Progression-free survival# Overall survival#,¶ IPASS+ Gefitinib versus carboplatin/paclitaxel in chemo-naïve, never- or former light-smokers with adenocarcinoma in East Asia Overall 1217 43.0% versus 32.2% HR 0.74 HR 0.91 OR 1.59 95% CI 0.65–0.85 95% CI 0.76–1.10 95% CI 1.25–2.01 5.7 versus 5.8 months 18.6 versus 17.3 months p<0.001 p<0.001 EGFR mutation-positive 261 71.2% versus 47.3% HR 0.48 HR 0.78 OR 2.75 95% CI 0.36–0.64 95% CI 0.50–1.20 95% CI 1.65–4.60 9.5 versus 6.3 months NR versus 19.5 months p = 0.0001 p<0.001 EGFR mutation-negative 176 1.1% versus 23.5% HR 2.85 HR 1.38 OR 0.04 95% CI 2.05–3.98 95% CI 0.92–2.09 95% CI 0.01–0.27 1.5 versus 5.5 months 12.1 versus 12.6 months p = 0.0013 p<0.001 INTEREST§ Gefitinib versus docetaxel in previously treated patients Overall 1466 9.1% versus 7.6% HR 1.04 HR 1.020 OR 1.22 95% CI 0.93–1.18 96% CI 0.905–1.150## 95% CI 0.82–1.84 2.2 versus 2.7 months 7.6 versus 8.0 months p = 0.33 p = 0.47 p = 0.7332 EGFR mutation-positive 44 42.1% versus 21.1% HR 0.16 HR 0.83 OR 25.22 95% CI 0.05–0.49 95% CI 0.41–1.67 95% CI 1.23–515.53 7.0 versus 4.1 months 14.2 versus 16.6 months p = 0.0361 p = 0.001 p = 0.60 EGFR mutation-negative 253 6.6% versus 9.8% HR 1.24 HR 1.02 OR 0.63 95% CI 0.94–1.64 95% CI 0.78–1.33 95% CI 0.23–1.73 1.7 versus 2.6 months 6.4 versus 6.0 months p = 0.3720 p = 0.14 p = 0.91 ISELƒ Gefitinib versus best supportive care in previously treated patients Overall 1692 8.0% versus 1.3% TTF HR 0.82 HR 0.89 OR 7.28 95% CI 0.73–0.92 95% CI 0.77–1.02 95% CI 3.1–16.9 3.0 versus 2.6 months 5.6 versus 5.1 months p<0.0001 p = 0.0006 p = 0.087 EGFR mutation-positive 26 37.5% versus 0% NC NC NC EGFR mutation-negative 189 2.6% versus 0% NC HR 1.16 NC 95% CI 0.79–1.72 3.7 versus 5.9 months p = 0.4449 Odds ratios >1 favour gefitinib. Hazard ratios <1 favour gefitinib. IPASS: IRESSA Pan-Asia Study; INTEREST: IRESSA NSCLC Trial Evaluating Response and Survival versus Taxotere; ISEL: IRESSA Survival Evaluation in Lung cancer; EGFR: epidermal growth factor receptor; NR: not reached; NC: not calculated; TTF: time to treatment failure. #: median month values are presented; ¶: IPASS overall survival follow-up is ongoing; +: values presented for IPASS are for gefitinib versus carboplatin/paclitaxel; §: INTEREST values are for gefitinib versus docetaxel; ƒ: ISEL values are for gefitinib versus placebo; ##: confidence interval entirely below non-inferiority margin of 1.154. Data are taken from [7, 28, 37, 38, 39] and previously unpublished studies.
- Table 2 Summary of multivariate logistic regression analysis to identify factors that independently predict for the presence of epidermal growth factor receptor (EGFR) mutations in non-Asian and Asian patients
Factors that predict for presence of EGFR mutation# Non-Asian patients¶ Asian patients+ Odds (95% CI) of EGFR mutation p-value Odds (95% CI) of EGFR mutation p-value Smoking status 6.6 (3.9–11.1) times higher in never-smokers than ever-smokers <0.0001 2.4 (0.9–5.9) times higher in never-smokers than ever-smokers 0.0702 Histology 3.8 (2.1–6.8) times higher in adenocarcinoma than non-adenocarcinoma <0.0001 4.7 (1.7–12.8) times higher in adenocarcinoma than non-adenocarcinoma 0.0022 Sex 1.9 (1.2–3.1) times higher in females than males 0.0103 2.2 (0.9–5.5) times higher in females than males 0.1007 WHO PS 1.9 (1.0–3.6) times higher in PS 0–1 than PS 2 0.0594 These data are previously unpublished. #: age (<65 years versus ≥65 years) and WHO PS (0–1 versus ≥2; Asians only) were not found to be significant predictors using p<0.2 selection criteria; ¶: analysis based on INTEREST, INVITE, ISEL, INSTEP, INTACT 1 and 2, and IDEAL 1 and 2 baseline data in non-Asian patients combined (n = 920); overall mutation-positive rate in non-Asian patients was 10%; +: analysis based on INTEREST, V-15-32, INTACT 1 and 2, and IDEAL 1 and 2 baseline data in Asian patients combined (n = 140); overall mutation-positive rate in Asian patients was 39%. WHO: World Health Organization; PS: performance status; INTEREST: IRESSA NSCLC Trial Evaluating Response and Survival versus Taxotere; INVITE: IRESSA in NSCLC versus Vinorelbine Investigation in the Elderly; ISEL: IRESSA Survival Evaluation in Lung cancer; INSTEP: IRESSA NSCLC Trial Evaluating Poor Performance Status Patients; INTACT: IRESSA NSCLC Trial Assessing Combination Treatment; IDEAL: IRESSA Dose Evaluation in Advanced Lung Cancer.
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- Article
- Abstract
- TARGETING THE EGFR WITH GEFITINIB
- DETERMINING THE OPTIMUM BIOLOGICAL DOSE
- IDENTIFYING POTENTIAL PREDICTORS OF RESPONSE TO GEFITINIB
- THE GEFITINIB MONOTHERAPY EXPERIENCE: FROM AN UNSELECTED PRETREATED POPULATION TO FIRST-LINE USE IN PATIENTS WITH EGFR MUTATION-POSITIVE NSCLC
- LESSONS LEARNED
- SUMMARY
- Acknowledgments
- Footnotes
- REFERENCES
- Figures & Data
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