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.