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      Gefitinib for advanced non-small cell lung cancer

      1 , 2 , 3 , 4 , 3 , 3
      Cochrane Lung Cancer Group
      Cochrane Database of Systematic Reviews
      Wiley

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          Abstract

          The role of gefitinib for the treatment of advanced non‐small cell lung cancer (NSCLC) is evolving. We undertook a systematic review to evaluate the available evidence from all randomised trials. To determine the effectiveness and safety of gefitinib as first‐line, second‐line or maintenance treatment for advanced NSCLC. We performed searches in CENTRAL, MEDLINE and Embase from inception to 17 February 2017. We handsearched relevant conference proceedings, clinical trial registries and references lists of retrieved articles. We included trials assessing gefitinib, alone or in combination with other treatment, compared to placebo or other treatments in the first‐ or successive‐line treatment of patients with NSCLC, excluding compassionate use. We used the standard Cochrane methodology. Two authors independently assessed the search results to select those with sound methodological quality. We carried out all analyses on an intention‐to‐treat basis. We recorded the following outcome data: overall survival, progression‐free survival, toxicity, tumour response and quality of life. We also collected data for the following subgroups: Asian ethnicity and positive epidermal growth factor receptor (EGFR) mutation. We included 35 eligible randomised controlled trials (RCTs), which examined 12,089 patients. General population Gefitinib did not statistically improve overall survival when compared with placebo or chemotherapy in either first‐ or second‐line settings. Second‐line gefitinib prolonged time to treatment failure (TTF) (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75 to 0.90, P < 0.0001) when compared with placebo. Maintenance gefitinib improved progression‐free survival (HR 0.70, 95% CI 0.53 to 0.91, P = 0.007) after first‐line therapy. Studies in patients of Asian ethnicity or that conducted subgroup analyses Second‐line gefitinib prolonged overall survival over placebo (HR 0.66, 95% CI 0.48 to 0.91, P = 0.01). In the first‐line setting, progression‐free survival was improved with gefitinib over chemotherapy alone (HR 0.65, 95% CI 0.43 to 0.98, P = 0.04, moderate quality of evidence). Gefitinib given in combination with a chemotherapy regimen improved progression‐free survival versus either gefitinib alone or chemotherapy alone (HR 0.69, 95% CI 0.49 to 0.96, P = 0.03; HR 0.69, 95% CI 0.62 to 0.77, P < 0.00001, respectively). In the second‐line setting, progression‐free survival was superior in patients given gefitinib over placebo or chemotherapy (HR 0.69, 95% CI 0.52 to 0.91, P = 0.009; HR 0.71, 95% CI 0.57 to 0.88, P = 0.002; moderate quality of evidence, respectively). Combining gefitinib with chemotherapy in the second‐line setting was superior to gefitinib alone (HR 0.65, 95% CI 0.43 to 0.97, P = 0.04). As maintenance therapy, gefitinib improved progression‐free survival when compared with placebo (HR 0.42, 95% CI 0.33 to 0.54, P < 0.00001). Patients with EGFR mutation‐positive tumours Studies in patients with EGFR mutation‐positive tumours showed an improvement in progression‐free survival in favour of gefitinib over first‐line and second‐line chemotherapy (HR 0.47, 95% CI 0.36 to 0.61, P < 0.00001; HR 0.24, 95% CI 0.12 to 0.47, P < 0.0001, respectively). Gefitinib as maintenance therapy following chemotherapy improved overall and progression‐free survival (HR 0.39, 95% CI 0.15 to 0.98, P = 0.05; HR 0.17, 95% CI 0.07 to 0.41, P < 0.0001, respectively) in one phase III study when compared to placebo. Toxicities from gefitinib included skin rash, diarrhoea and liver transaminase derangements. Toxicities from chemotherapy included anaemia, neutropenia and neurotoxicity. In terms of quality of life, gefitinib improved Functional Assessment of Cancer Therapy‐Lung (FACT‐L) (standardised mean difference (SMD) 10.50, 95% CI 9.55 to 11.45, P < 0.000001), lung cancer subscale (SMD 3.63, 95% CI 3.08 to 4.19, P < 0.00001) and Trial Outcome Index (SMD 9.87, 95% CI 1.26 to 18.48, P < 0.00001) scores when compared with chemotherapy. This systematic review shows that gefitinib, when compared with standard first‐ or second‐line chemotherapy or maintenance therapy, probably has a beneficial effect on progression‐free survival and quality of life in selected patient populations, particularly those with tumours bearing sensitising EGFR mutations. Patients with EGFR mutations lived longer when given maintenance gefitinib than those given placebo. One study conducted subgroup analysis and showed that gefitinib improved overall survival over placebo in the second‐line setting in patients of Asian ethnicity. All other studies did not detect any benefit on overall survival. The data analysed in this review were very heterogenous. We were limited in the amount of data that could be pooled, largely due to variations in study design. The risk of bias in most studies was moderate, with some studies not adequately addressing potential selection, attrition and reporting bias. This heterogeneity may have an impact on the applicability of the results Combining gefitinib with chemotherapy appears to be superior in improving progression‐free survival to either gefitinib or chemotherapy alone, however further data and phase III studies in these settings are required. Gefitinib has a favourable toxicity profile when compared with current chemotherapy regimens. Although there is no improvement in overall survival, gefitinib compares favourably with cytotoxic chemotherapy in patients with EGFR mutations with a prolongation of progression‐free survival and a lesser side effect profile. Review question Do patients with non‐small cell lung cancer live longer if they are given gefitinib? Background Non‐small cell lung cancer (the most common type of lung cancer) is a leading cause of cancer death worldwide. People diagnosed with advanced lung cancer may be offered chemotherapy. Some lung cancers have been found to have a gene mutation, which is an alteration in the chromosome sequence inside the cells. This mutation affects the epidermal growth factor receptor (EGFR), which is a switch on the surface of the cell leading to uncontrolled growth and spread. Gefitinib is a drug that targets cells with mutated EGFR, thus stopping their growth. Studies have found that this mutation is more commonly found in people who are non‐smokers, female, of Asian heritage and with adenocarcinoma (a type of lung cancer). Study characteristics We searched for relevant trials up to 17 February 2017. There were a total of 35 studies conducted between 2000 and 2017, evaluating 12,089 participants from multiple countries including North America, Europe and Asia. Key results This review showed that patients with advanced lung cancer do not live longer when treated with gefitinib when compared with no other treatment or chemotherapy. In people whose lung cancer has worsened after initial therapy, gefitinib may prolong the time before the cancer progresses further, but only in a selected group of patients of Asian ethnicity or with EGFR mutations. Combining gefitinib with chemotherapy probably increases the time to cancer progression over either gefitinib or chemotherapy alone. For EGFR‐mutation positive patients who are stable after chemotherapy, ongoing gefitinib has been shown to improve survival when compared to placebo. Severe side effects, such as low red and white blood cell counts and nerve symptoms, occurred more frequently in patients given chemotherapy compared to those given gefitinib. Side effects caused by gefitinib included a skin rash, diarrhoea and liver dysfunction. Quality of life may be improved in favour of gefitinib when compared with chemotherapy. Quality of the evidence When comparing gefitinib as a first‐ and second‐line treatment with chemotherapy, we downgraded the quality of the evidence to moderate for the outcomes overall survival and progression‐free survival because the results were not precise and they may not be applicable to all patients due to the inclusion of a population only over 70 years of age. However, the quality of the evidence when we compared toxicities from gefitinib with chemotherapy was high.

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          Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].

          To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily. Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]
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            Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.

            More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006). Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.
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              Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.

              Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy. We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (>/=one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m(2) intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388. 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1.020, 96% CI 0.905-1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1.09, 95% CI 0.78-1.51; p=0.62; median survival 8.4 vs 7.5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common. INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.
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                Author and article information

                Journal
                Cochrane Database of Systematic Reviews
                Wiley
                14651858
                January 16 2018
                Affiliations
                [1 ]GenesisCare Radiation Oncology; 1 Medical Place Urraween Queensland Australia 4655
                [2 ]The University of Queensland; UQ Thoracic Research Centre, School of Medicine; Brisbane Australia
                [3 ]The Prince Charles Hospital; Department of Thoracic Medicine; Brisbane Australia
                [4 ]University of Tasmania; School of Medicine; Hobart Tasmania Australia 7001
                Article
                10.1002/14651858.CD006847.pub2
                6491254
                29336009
                f2185ca4-58ed-49f3-9cfb-3a4bd6c4d470
                © 2018
                History

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