Abstract
Background
Epidermal growth factor receptor (EGFR) mutation positive (M+) non‐small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non‐squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours.
Objectives
To assess the clinical effectiveness of single‐agent or combination EGFR therapies used in the first‐line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression‐free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health‐related quality of life.
Search methods
We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles.
Selection criteria
Parallel‐group randomised controlled trials comparing EGFR‐targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy‐naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent.
Data collection and analysis
Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta‐analyses using a fixed‐effect model unless there was substantial heterogeneity, in which case we also performed a random‐effects analysis as a sensitivity analysis.
Main results
Twenty‐two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin.
Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR‐targeted treatments against cytotoxic chemotherapy or placebo.
Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively).
For progression‐free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high‐certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high‐certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate‐certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high‐certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine‐kinase inhibitor (TKI) compared to chemotherapy.
Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies.
Seven trials reported on health‐related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy.
The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy.
Authors' conclusions
Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health‐related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent‐TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.
Plain language summary
First‐line treatment of advanced non‐small cell lung cancer identified as being EGFR mutation positive
Background
Lung cancer is the most common cancer in the world. It has often spread by the time it is diagnosed. Therefore, surgery is usually not possible and drug treatment, typically chemotherapy, is needed. The commonest type of lung cancer is non‐small cell lung cancer (NSCLC). Around 10% to 15% of people with NSCLC will have a specific kind of cancer known as epidermal growth factor receptor positive (EGFR M+), in which there are changes in the cancer cells to the genes controlling tumour growth. In this review, we looked at new treatments that can target EGFR M+ NSCLC to find out how well they work.
Objectives
The purpose of this review was to find out whether people given treatments targeted at EGFR M+ NSCLC live longer and have a better health‐related quality of life than people having standard chemotherapy.
Trial characteristics
We found 22 trials that looked at five different EGFR‐targeted drugs and compared them with standard chemotherapy treatment: erlotinib, gefitinib, afatinib, icotinib and the antibody cetuximab. We included trials reporting results up to 27 July 2020.
Results
Our results showed that people given erlotinib, gefitinib,afatinib or icotinib have a longer time before the cancer progresses and experience fewer side effects than those people given standard chemotherapy. However, we could not be sure whether people given erlotinib, afatinib or icotinib live any longer than those given standard chemotherapy.
Conclusion
Erlotinib, gefitinib, afatinib and icotinib delay further spread of EGFR M+ lung cancer and improve health‐related quality of life. Giving cetuximab with chemotherapy is no better at controlling this type of cancer or extending life than chemotherapy alone.
Summary of findings
Background
Description of the condition
Lung cancer (along with breast cancer) is the most common cancer in the world and the third most common cancer diagnosed in the UK (Cancer Research UK). Globally, in 2018, two million people were diagnosed with lung cancer, representing 11.6 % of all cancers (GLOBOCAN 2018). In the UK annually, 47,800 new cases of lung cancer are diagnosed, 13% of all new cancers (Cancer Research UK 2019). In both men and women, smoking is the primary cause of lung cancer (Cancer Research UK 201a). Prognosis is poor, as early‐stage lung cancer is often asymptomatic and the majority of patients are diagnosed at a late stage (Cancer Research UK 2019). Between 2015 and 2017, 35,000 people in the UK died of lung cancer, representing 21% of all deaths from cancer in the UK (Cancer Research UK 2019a).
Non‐small cell lung cancer (NSCLC) accounts for the majority (80% to 85%) of lung cancer cases in the UK and comprises two main histological subgroups: squamous cell carcinoma and non‐squamous cell carcinoma (Cancer Research UK 2019c). Squamous cell carcinoma accounts for 25% to 30% of all NSCLC cases, whilst non‐squamous cell carcinoma (including adenocarcinoma and large cell carcinoma) accounts for 29% of NSCLC cases. Approximately 12% to 13% of patients have NSCLC that is ‘not‐otherwise specified’ with the diagnosis based on cytology alone (NLCA 2015; Schiller 2002). The prognosis for people with advanced NSCLC is poor, with a median survival of the order of six months without treatment.
Treatment for people with NSCLC depends not only on the histological subtype and genetic subtype of the tumour, but also on disease stage, comorbidity, and performance status. Chemotherapy, in most cases comprising a cisplatin doublet, for advanced disease can extend overall survival by several months compared to best supportive care and improves health‐related quality of life (Brown 2013).
In recent years, the biological subtypes of NSCLC have become relevant to the selection of treatment regimens. Attention has been drawn to tumours that harbour the epidermal growth factor receptor mutation (EGFR M+). The EGFR, a protein located on the cell surface, binds to and activates epidermal growth factor. This binding induces receptor dimerisation and tyrosine kinase autophosphorylation, leading through signal transduction to cell proliferation (Han 2012; NCBI). It is estimated that 10% to 15% of people with non‐squamous NSCLC have tumours that are EGFR M+ (Peters 2012; Rosell 2012). An EGFR mutation is more frequently observed in never‐smokers than ever‐smokers (51% versus 10%) in adenocarcinomas compared to cancers of other histologies (40% versus 3%), in people of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females rather than males (42% versus 14%) (Rosell 2009; Scoccianti 2012; Ulivi 2012).
The identification of people with EGFR M+ tumours has led to the development of targeted therapies comprising small molecule tyrosine kinase inhibitors (TKIs) directed at the signal transduction pathway between the cell membrane and the nucleus, while monoclonal antibodies (MABs) bind to and inactivate the receptor on the cell membrane. Since the majority of the phase III trials in this review were started, it has become apparent that activating mutations in exons 19 and 21 are associated with response to the TKIs, while the 1% of tumours with the exon 20 T790M mutation are resistant. The TKIs are orally administered agents, while the MABs are given intravenously. People of interest to this review were chemotherapy‐naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC who were not suitable for treatment with curative intent, such as surgery or radical radiotherapy.
Description of the intervention
In Europe, there are five licensed treatments that target EGFR M+ NSCLC: afatinib, dacomitinib, erlotinib, gefitinib and osimertinib. Icotinib is only available in China. These drugs are TKIs of EGFR and target proteins on the cancer cells related to activation of the signal transduction pathway. These treatments (tablets) are taken orally daily until the disease progresses.
In the UK, the National Institute for Health and Care Excellence has recommended the use of monotherapy erlotinib (NICE 2012), gefitinib (NICE 2010), afatinib (NICE 2014), and dacomitinib NICE 2019 for the first‐line treatment of EGFR M+ NSCLC. In Europe, the European Society for Medical Oncology guidelines recommend first‐line treatment with monotherapy erlotinib, or gefitinib, afatinib, dacomitinib and osimertinib (ESMO 2018). There is no consensus over which agent is preferred (ESMO 2018). In the USA, the Food and Drug Administration has approved the use of monotherapy erlotinib (FDA 2013), afatinib (FDA 2014), dacomitinib (FDA 2018(a)), and osimertinib (FDA 2018). Globally, there is considerable variation in the use of each of these drugs to treat people with NSCLC and in the availability and quality control of mutation testing, which determines patient selection. Cetuximab is not approved for EGFR M+ NSCLC in any jurisdiction.
Why it is important to do this review
Treatments for people with NSCLC have been evolving rapidly following the Medical Research Council meta‐analysis that demonstrated improved survival for chemotherapy compared with best supportive care (MRC 1995). Until early 2000, people with NSCLC were offered standard cytotoxic chemotherapy treatments (for example cisplatin, docetaxel, vinorelbine, paclitaxel, and gemcitabine), often given in two‐drug platinum‐based combinations (Brown 2013). However, in recent years patients have been treated with drugs according to their histological subtype (for example pemetrexed plus cisplatin for non‐squamous disease). Even more recently, as understanding of NSCLC has evolved, targeted treatments have been developed to treat specific groups of patients based on molecular criteria, for example TKIs and MABs. It is estimated that around 10% (n = 4000 annually) of all lung cancer patients in the UK have locally advanced or metastatic EGFR M+ NSCLC (NICE 2010), with a higher prevalence in Asian populations. It is therefore important to synthesise evidence for the clinical effectiveness and toxicity of these new treatments to ensure that patients are being treated with the most clinically effective drugs for their specific disease subtype.
Objectives
To assess the clinical effectiveness of single‐agent or combination EGFR therapies used in the first‐line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy agents used alone or in combination, or best supportive care (BSC). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, response rate, symptom palliation, toxicity, and health‐related quality of life.
Methods
Criteria for considering studies for this review
Types of studies
Parallel‐group randomised controlled trials (RCTs).
Types of participants
Chemotherapy‐naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent with surgery or radical radiotherapy. We included studies that included or excluded exon 20 T790 in the review.
Types of interventions
EGFR M+ targeted agents, alone or in combination with cytotoxic agents, compared with cytotoxic agents used alone or in combination or BSC.
We excluded trials comparing single‐agent or combinations of cytotoxic chemotherapy without a targeted therapy in either arm and trials with targeted therapy in both arms, and we did not evaluate maintenance or second‐line strategies. We also excluded cross‐over trials.
Types of outcome measures
Primary outcomes
Overall survival
Progression‐free survival
Secondary outcomes
Tumour response
Toxicity and adverse effects of treatment
Health‐related quality of life (e.g. Functional Assessment of Cancer Therapy ‐ Lung (FACT‐L) and Trial Outcome Index (TOI))
Symptom palliation
Search methods for identification of studies
Electronic searches
We searched the following electronic databases for relevant published literature up to 27 July 2020. We did not restrict searches by language.
Cochrane Central Register of Controlled Trials (CENTRAL) (2020, Issue 7) (Appendix 1);
MEDLINE (from 1980) (accessed via PubMed and OvidSP) (Appendix 2);
Embase (from 1946) (OvidSP) (Appendix 3);
ISI Web of Science (from 1899) (Appendix 4).
We ran an initial search in October 2012. We ran an updated search (updated by the Cochrane Lung Cancer Group Information Specialist) in January 2014 and June 2015. As the updated search (Appendix 2) included amendments to the initial search strategy, we conducted a PubMed search from inception to 27 July 2020 to ensure that no relevant articles had been missed. We compared the results of the overall PubMed search with the results of all other searches and examined any non‐duplicate articles for possible inclusion in the review. We identified no relevant publications.
Searching other resources
We searched bibliographies of identified sources and use of Evidence Review Group (ERG) reports to the National Institute for Health and Care Excellence. We searched the proceedings of relevant conferences such as the American Society for Clinical Oncology and the European Society for Medical Oncology up to July 2020. If data were available, we considered including them in the review.
We developed a database of relevant references using EndNote X8 software (Thomson Reuters).
Data collection and analysis
Selection of studies
Two review authors independently took part in all stages of trial selection (FV and VB: Search 1; VB and JG: Search 2; JAG and YD, JAG and JG: Search 3). Review authors first independently scanned the titles and abstracts of references identified by the search strategy. We obtained full details of possibly relevant trials and independently assessed these for inclusion in the review. In case of disagreement, the review authors attempted to reach consensus by discussion, or by involving a third review author (AB or YD). We excluded trials that did not meet all of the inclusion criteria and listed their bibliographic details with reasons for exclusion. We listed ongoing trials that did not report relevant data but met the inclusion criteria for future use. We included trials published in abstract form only if it was clear that the trial was eligible. If it was not clear, we contacted authors for further information and placed the trial in ‘Studies awaiting classification’ until we received a reply.
Data extraction and management
Two review authors carried out the data extraction (FV and VB: Search 1; VB and JG: Search 2; JAG and JG: Search 3) using pre‐tested data extraction forms, and a third review author (KD who has left the team or MC) independently checked the extracted data for accuracy. We extracted data relating to the outcome measures as well as information on trial design and participants (for example, baseline characteristics). Where data from trials were presented in multiple publications, we extracted and reported these as a single trial with all other relevant publications listed.
Assessment of risk of bias in included studies
We assessed each included trial for risk of bias using criteria outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (see domains listed below) (Higgins 2011). Two review authors (FV and JG: Search 1; JG and KD: Search 2; JG and MC: Search 3) independently carried out the assessments. Any disagreements were resolved through discussion.
Random sequence generation (selection bias).
Allocation concealment (selection bias).
Blinding of participants (performance bias).
Blinding of outcome assessment (detection bias).
Incomplete outcome data (attrition bias).
Selective outcome reporting (reporting bias).
Any other identified bias, including inappropriate influence of funders.
We reported bias as either high, low, or unclear (further details of reporting bias are outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)). We assessed the domains of blinding and incomplete outcome data at the outcome level.
Summary of findings and assessment of the certainty of the evidence
We presented four 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4) with each outcome graded accordingly using the GRADE approach (GRADE Working Group 2004).
Summary of findings 1. Erlotinib vs control.
| First‐line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive (M+) non‐squamous non‐small cell lung cancer (NSCLC): erlotinib comparisons | ||||||
|
Patient or population: EGFR M+ patients with NSCLC Settings: oncology Intervention: erlotinib Comparison: control (cytotoxic chemotherapy) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Erlotinib | |||||
| Overall survival | 56 per 100 | 54 per 100 (46 to 63) | HR 0.95 (0.75, 1.22) | 429 (3 studies) | High | All trials were open‐label but included blinded independent review. |
| Progression‐free survival | 73 per 100 | 33 per 100 (28 to 40) | HR 0.31 (0.25, 0.39) | 583 (4 studies) | High | All trials were open‐label but included blinded independent review. |
| *The basis for the assumed risk is calculated as the event rate in the treatment group The corresponding risk is calculated as the assumed risk x the risk ratio (RR) of the intervention where RR = (1 ‐ exp(HR x ln(1 ‐ assumed risk)) )/assumed risk CI: confidence interval; RR: risk ratio; HR: hazard ratio | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
Summary of findings 2. Gefitinib vs paclitaxel + carboplatin.
| First‐line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive (M+) non‐squamous non‐small cell lung cancer (NSCLC): gefitinib comparisons | ||||||
|
Patient or population: EGFR M+ patients with NSCLC Settings: oncology Intervention: gefitinib Comparison: paclitaxel + carboplatin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Paclitaxel + carboplatin | Gefitinib | |||||
| Overall survival | 67 per 100 | 66 per 100 (58 to 73) | HR 0.95 (0.77 to 1.18) | 489 (2 studies) | High | Both trials were open‐label. IPASS did not report independent blinded review. |
| Progression‐free survival | 89 per 100 | 57 per 100 (50 to 65) | HR 0.39 (0.32 to 0.48) | 485 (2 studies) | High | Both trials were open‐label. IPASS did not report independent blinded review. |
| *The basis for the assumed risk is calculated as the event rate in the treatment group The corresponding risk is calculated as the assumed risk x the risk ratio (RR) of the intervention where RR = (1 ‐ exp(HR x ln(1 ‐ assumed risk)) )/assumed risk CI: confidence interval; RR: risk ratio; HR: hazard ratio | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
Summary of findings 3. Gefitinib vs pemetrexed + carboplatin with pemetrexed maintenance.
| First‐line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive (M+) non‐squamous non‐small cell lung cancer (NSCLC): gefitinib comparisons | ||||||
|
Patient or population: EGFR M+ patients with NSCLC Settings: oncology Intervention: gefitinib Comparison: pemetrexed + carboplatin | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of Participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Pemetrexed + carboplatin | Gefitinib | |||||
| Overall survival | 568 per 1000 | 505 per 1000 (410 to 606) | HR 0.84 (0.63 to 1.11) | 371 (2 studies) | Moderatea | Both trials were conducted in single centres. Both trials were open‐label with no independent blinded review. |
| Progression‐free survival | 924 per 1000 | 782 per 1000 (695 to 852) | HR 0.59 (0.46 to 0.74) | 371 (2 studies) | Moderateb | Both trials were conducted in single centres. Both trials were open‐label with no independent blinded review. |
| *The basis for the assumed risk is calculated as the event rate in the treatment group The corresponding risk is calculated as the assumed risk x the risk ratio (RR) of the intervention where RR = (1 ‐ exp(HR x ln(1 ‐ assumed risk)) )/assumed risk CI: confidence interval; RR: risk ratio; HR: hazard ratio | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
a downgraded by one due to imprecise estimate that includes beneficial and non‐beneficial effect
bdowngraded by one due to risk of bias. Both trials were open‐label with no independent blinded review
Summary of findings 4. Afatinib vs chemotherapy.
| First‐line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive (M+) non‐squamous non‐small cell lung cancer (NSCLC): afatinib comparisons | ||||||
|
Patient or population: EGFR M+ patients with NSCLC Settings: oncology Intervention: afatinib Comparison: cytotoxic chemotherapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Cytotoxic chemotherapy | Afatinib | |||||
| Overall survival | 66 per 100 | 63 per 100 (56 to 70) | HR 0.91 (0.75 to 1.10) | 709 (2 studies) | High | Both trials were open‐label but included blinded independent central review. |
| Progression‐free survival | 56 per 100 | 29 per 100 (24 to 35) | HR 0.42 (0.34 to 0.53) | 709 (2 studies) | High | Both trials were open‐label but included blinded independent central review. |
| *The basis for the assumed risk is calculated as the event rate in the treatment group The corresponding risk is calculated as the assumed risk x the risk ratio (RR) of the intervention where RR = (1 ‐ exp(HR x ln(1 ‐ assumed risk)) )/assumed risk CI: confidence interval; RR: risk ratio; HR: hazard ratio | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
The following outcomes were included in each table: OS and PFS.
Measures of treatment effect
For binary outcomes, where sufficient data were available, we presented relative treatment effects in the form of risk ratios with 95% confidence intervals (CIs). Where studies provided measures of effect rather than raw data, we considered it pragmatic to present meaures of treatment effect other than RR (i.e. OR). For continuous outcomes, we calculated mean differences and 95% CIs provided there was no evidence that the data were subject to skew. If statistical tests used in the original paper were for skewed data, or if median and interquartile ranges were reported, we assumed the data were skewed. We calculated standardised mean differences for health‐related quality of life variables, where appropriate. For time‐to‐event outcomes, we extracted log hazard ratios (log HRs) when available, with 95% CIs. If the log HR was not reported, we requested data from authors.
All trials allowed participant cross over to another treatment after progression, but no details were provided regarding how this was dealt with in any of the analyses of overall survival (OS). We considered trials for inclusion in the review that: (1) provided only unplanned, interim findings; and (2) were continuing to recruit participants, but we did not include these in the meta‐analysis.
Unit of analysis issues
We did not include trials designed as cross‐over trials, as the use of more than one treatment would impact on the assessment of OS (our primary outcome). However, we noted that many of the RCTs included in our review allowed participants from the control arm access to the intervention treatment when their disease progressed; we acknowledge that this limits our assessment of OS.
Dealing with missing data
We contacted authors (and sponsors) of trials for missing data. In cases where authors did not respond, we categorised the studies as awaiting classification and recorded details in the 'Characteristics of studies awaiting classification' table.
Assessment of heterogeneity
We assessed statistical heterogeneity between trials visually by inspection of the forest plots and using the Chi2 test (P < 0.1 was considered significant due to the low power of the test). We also calculated the I2 statistic, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). Values of I2 range from 0 to 100, with 0 representing no heterogeneity and 100 representing considerable heterogeneity.
For this review:
0% to 29%, heterogeneity might not be important;
30% to 49% may represent moderate heterogeneity;
50% to 74% may represent substantial heterogeneity; and
75% to 100%, considerable heterogeneity.
Assessment of reporting biases
If we had identified a sufficient number of trials, we would have constructed a funnel plot. If asymmetry was present in the funnel plot, we would have explored possible causes of bias, such as heterogeneity or outcome reporting bias. As there were not enough trials (at least 10) included in any one meta‐analysis, we did not include funnel plots in this update of the review.
Data synthesis
We have summarised individual trial data in structured tables and as a narrative description. As a major clinical issue is the toxicity of platinum‐based doublet chemotherapy (cytotoxic chemotherapy), we presented subgroups separately with comparators cytotoxic chemotherapy, single‐agent vinorelbine in elderly participants, and placebo. We dealt with the comparison of the combination of an EGFR‐targeted therapy and cytotoxic chemotherapy with cytotoxic chemotherapy alone as a separate comparison in view of concerns about interactions between chemotherapy and a tyrosine kinase inhibitor. We combined data for time‐to‐event outcomes using the generic inverse variance method. We used the Mantel‐Haenszel method for dichotomous outcomes. In future versions of this review, where data are available, we may combine continuous outcomes using the inverse variance method.
We conducted meta‐analyses using the fixed‐effect model, unless there was substantial heterogeneity (I2 > 50%), in which case we used a random‐effects model as a sensitivity analysis. If there was considerable heterogeneity (I2 > 75%) some data have been combined, but our conclusions highlighted the amount of heterogeneity present.
Indirect comparisons and network meta‐analysis
We considered that a network meta‐analysis (NMA) was not appropriate because of the different populations across the included trials. We identified other barriers to conducting NMA: some trials reported adjusted analyses, whereas all other trials reported unadjusted analyses and combining these is statistically unsound; participants in all trials were allowed to switch treatment after progression, and we had no information about how this was handled in the analysis for OS. Finally, the Kaplan‐Meier plots shown in the trial reports crossed in four of the trials, indicating that using a Cox proportional hazards model may not be appropriate.
If in future versions of this review we identify trials comparing different interventions that are similar enough in their populations and outcomes, we may make indirect comparisons for competing interventions that have not been compared directly. Multiple‐treatments meta‐analysis (also referred to as network meta‐analysis) may combine direct and indirect comparisons using multivariate meta‐analysis, as this will also take into account any multi‐arm trials. We will use a random‐effects model within STATA to conduct analyses using code from www.mtm.uoi.gr.
We will evaluate transitivity (the trials making different direct comparisons must be sufficiently similar in all respects other than the treatments being compared) clinically. We will compare the distributions of possible effect modifiers (smoking status, age, gender, ethnicity, and performance status) across comparisons using subgroup analysis. As the review only considers first‐line treatment, indications are similar.
We will evaluate consistency using a loop‐specific approach (Salanti 2009), and use a design interaction consistency model (Higgins 2012). If we identify inconsistency, we will not present the network meta‐analysis.
We will assess estimates of treatment effect by pairwise meta‐analysis. We will conduct network meta‐analysis where appropriate.
Prior to analysis we will draw a diagram of the network for all relevant interventions, indicating the number of trials per comparison. We will derive and display ranking probabilities for each treatment using the Surface Under the Cumulative RAnking curve (SUCRA) plot and rankograms (Salanti 2011).
We will discuss the possible effects of risk of bias on the clinical effectiveness data and review findings.
Subgroup analysis and investigation of heterogeneity
In an update of this review when enough trials are included and if data are available, we may conduct analyses to investigate any differential effects in terms of:
smoking status
age
sex
ethnicity
performance status
type of mutation (exon 19/exon 21)
type of histology
Sensitivity analysis
In an update of this review when sufficient trials are included, we will conduct sensitivity analyses based on the overall risk of bias of the included trials. We will base overall risk of bias on sequence generation, allocation concealment, and blinding (for the specific outcome), and will base the summary assessment on recommendations in Table 8.7a of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Summary of findings and assessment of the certainty of the evidence
We presented four 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4) with each outcome graded accordingly using the GRADE approach (GRADE Working Group 2004).
The following outcomes are included in each table: OS and PFS.
Results
Description of studies
Results of the search
The database search strategy yielded 12,481 non‐duplicate papers. We identified a further eight records via handsearching of reference lists. Of these, we screened 386 full‐text records for inclusion in the review. We screened all of the potentially relevant references and included 22 eligible RCTs (reported in 59 publications) comparing EGFR‐targeted therapy to chemotherapy as first‐line treatment in NSCLC patients in our review (Figure 1).
1.
Study flow diagram.
We classified two trials as 'awaiting classification' and have not yet included them in the review (TALENT; TRIBUTE). We contacted the authors of TALENT and TRIBUTE and asked them to provide data on the EGFR M+ population. We have not received a response.
Included studies
See Characteristics of included studies. The 22 trials that met the inclusion criteria were published or updated between 2003 and 2017 (BMSO99; CHEN; CONVINCE; ENSURE; EURTAC; FASTACT 2; First‐SIGNAL; FLEX; GTOWG; Han 2017; INTACT 1; INTACT 2; IPASS; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL;Patil 2017; TOPICAL; TORCH; WJTOG3405; Yu 2014). With the exception of GTOWG, all trials were published as peer‐reviewed papers. The overall number of people recruited to the trials ranged between 113 in CHEN and 1217 in IPASS. The median length of follow‐up (where reported) ranged from 15.7 months, in CONVINCE, to 59 months, in WJTOG3405.
Ten trials included EGFR M+ participants only (CONVINCE; ENSURE; EURTAC; Han 2017; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; Patil 2017; WJTOG3405). The number of participants recruited to the EGFR M+ only trials ranged from 121 in Han 2017 to 364 in LUX‐Lung 6, with a total population of 2371. The remaining 12 trials recruited a 'mixed' population of participants ‐ that is, participants were not selected for inclusion in the trial on the basis of their EGFR mutation status. These latter trials reported results for the subgroup of participants with EGFR M+ mutation status. The numbers of participants reported in these subgroups ranged from 10 in GTOWG to 261 in IPASS, with a combined total of 645. The combined total of participants with EGFR M+ NSCLC was 3023, of whom approximately 2563 were of Asian origin.
Three trials were conducted exclusively in Europe (EURTAC; GTOWG; TOPICAL); 13 were conducted exclusively in Asia (CHEN; CONVINCE; ENSURE; FASTACT 2; First‐SIGNAL; Han 2017; IPASS; LUX‐Lung 6; NEJSG; OPTIMAL; Patil 2017; WJTOG3405; Yu 2014); and one was conducted in the USA (BMSO99). The remaining trials were more international: (TORCH), (INTACT 2), LUX‐Lung 3, INTACT 1, and FLEX. The 10 trials that recruited exclusively EGFR M+ patients were conducted in Asia: CONVINCE; ENSURE; Han 2017; LUX‐Lung 6; NEJSG; OPTIMAL; Patil 2017; WJTOG3405; and Europe: EURTAC, with one international trial: (LUX‐Lung 3).
Four of the trials were placebo‐controlled and double‐blinded (FASTACT 2; INTACT 1; INTACT 2; TOPICAL); the remainder were specifically reported as being open‐label or did not report blinding status. In the latter case, we assumed these to be open‐label due to the nature of the interventions and comparator (that is, oral versus intravenous treatments). Four trials were phase II (CHEN; GTOWG; Han 2017; Yu 2014), whilst the others were phase III. Sixteen trials were partially or totally funded by a pharmaceutical company (BMSO99; CHEN; CONVINCE; ENSURE; EURTAC; FASTACT 2; First‐SIGNAL; FLEX; INTACT 1; INTACT 2; IPASS; LUX‐Lung 3; LUX‐Lung 6; OPTIMAL; TOPICAL; TORCH); the Han 2017; NEJSG; and WJTOG3405 trials were funded by scientific groups.The Patil 2017 trial was funded by a hospital grant. The funding source for the GTOWG and Yu 2014 trials was not reported.
Four categories of comparisons for all four agents were described:
targeted agent versus established platinum‐based combinations (e.g. cisplatin or carboplatin and gemcitabine or docetaxel) ‐ the term platinum‐based refers to cisplatin or carboplatin‐based combinations, both drugs being metabolised to the same active moiety;
targeted agent versus single‐agent chemotherapy drug vinorelbine, for which clinical interest is limited to the elderly population due to its favourable toxicity profile;
cytotoxic chemotherapy with the targeted agent versus chemotherapy alone; and
erlotinib versus placebo.
Population characteristics
All trials provided data for age, sex, performance status, and smoking status except for the INTACT 1, INTACT 2, and GTOWG trials (no details of smoking history). The median age of the overall population of all participants in the included trials ranged from 56 to 77 years; the median age of participants in the EGFR M+ only trials ranged from 56 to 65 years. Two trials only included people aged over 70 years (CHEN; GTOWG), and NEJSG, Patil 2017, and Yu 2014 only reported mean age. There were more females (than males) in 11 trials (CONVINCE; ENSURE; EURTAC; First‐SIGNAL;Han 2017; IPASS; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; WJTOG3405), and more males (than females) in seven trials (BMSO99; CHEN; FLEX; GTOWG; INTACT 1; INTACT 2; Patil 2017; TORCH). The majority of participants were of good performance status (ECOG or WHO 0 or 1). The GTOWG abstract did not report performance status.
It is notable that, with the exception of Patil 2017, in all of the trials that recruited EGFR M+ patients only, the proportion of females was greater than males (CONVINCE; ENSURE; EURTAC;Han 2017; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; WJTOG3405).
Interventions
Erlotinib
Eight trials used erlotinib (n = 754 EGFR M+) as the EGFR‐targeted therapy (CHEN; ENSURE; EURTAC; FASTACT 2; GTOWG; OPTIMAL; TOPICAL; TORCH). CHEN and GTOWG used the drug vinorelbine as a single agent or with carboplatin, respectively, in elderly populations. In FASTACT 2, erlotinib was used in combination with a platinum doublet containing gemcitabine. We classified trials using erlotinib into the following comparison groups.
Erlotinib versus platinum‐based chemotherapy: One trial compared erlotinib versus gemcitabine plus carboplatin (OPTIMAL), two trials compared erlotinib versus gemcitabine plus cisplatin (ENSURE; TORCH), and one trial compared erlotinib versus docetaxel plus cisplatin or gemcitabine plus cisplatin (EURTAC).
Erlotinib versus vinorelbine +/‐ other chemotherapy: One trial compared erlotinib versus vinorelbine (CHEN); one trial compared erlotinib versus carboplatin plus vinorelbine (GTOWG).
Erlotinib plus chemotherapy versus chemotherapy plus placebo: One trial compared erlotinib plus gemcitabine plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin plus placebo (FASTACT 2).
Erlotinib versus placebo: One trial considered this comparison (TOPICAL).
Gefitinib
Nine trials used gefitinib (n = 1184 EGFR M+) as the EGFR‐targeted therapy (First‐SIGNAL; Han 2017; INTACT 1; INTACT 2; IPASS; NEJSG; Patil 2017; WJTOG3405; Yu 2014). The Han 2017 trial included three treatment arms. Four trials used gefitinib in combination with chemotherapy (Han 2017; INTACT 1; INTACT 2; Yu 2014). We classified trials using gefitinib into the following comparison groups.
Gefitinib versus gemcitabine plus cisplatin: One trial considered this comparison (First‐SIGNAL).
Gefitinib versus paclitaxel plus carboplatin: Two trials considered this comparison (IPASS; NEJSG).
Gefitinib versus docetaxel plus cisplatin: One trial considered this comparison (WJTOG3405).
Gefitinib versus pemetrexed plus carboplatin and maintenance pemetrexed. Two trials considered this comparison (Han 2017; Patil 2017).
Gefitinib and carboplatin plus paclitaxel or cisplatin plus gemcitabine versus cytotoxic chemotherapy alone: Two trials considered this comparison (INTACT 1; INTACT 2). However, as EGFR M+ specific data from both trials were analysed as though from one trial, data were only presented narratively.
Gefitinib plus pemetrexed and cisplatin versus pemetrexed plus cisplatin: One trial considered this comparison (Yu 2014).
Gefitinib plus pemetrexed and carboplatin versus pemetrexed plus carboplatin. One trial considered this comparison (Han 2017).
Afatinib
Two trials compared afatinib (n = 709) with cytotoxic chemotherapy (LUX‐Lung 3; LUX‐Lung 6). These trials differed principally in the selection of the cytotoxic chemotherapy comparator, LUX‐Lung 3 comparing afatinib with cisplatin and pemetrexed in an ethnically diverse population, and LUX‐Lung 6 comparing afatinib with cisplatin and gemcitabine in an Asian population. We combined these trials in a meta‐analysis for progression‐free survival, overall survival, and response.
Icotinib
One trial compared icotinib (n = 285) with cytotoxic chemotherapy. The CONVINCE trial compared icotinib with four cycles of pemetrexed with cisplatin, followed by pemetrexed alone as maintenance therapy.
Cetuximab
Two trials (n = 81) compared cetuximab plus chemotherapy with combination chemotherapy (BMSO99; FLEX).
Of the nine trials that recruited only people with EGFR M+ NSCLC, two trials used afatinib (LUX‐Lung 3; LUX‐Lung 6), three used erlotinib (ENSURE: EURTAC; OPTIMAL), three used gefitinib (Han 2017; NEJSG; WJTOG3405) and one used icotinib (CONVINCE). Seven EGFR M+ only trials compared targeted treatment with cytotoxic chemotherapy (ENSURE; EURTAC; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; WJTOG3405), one trial with cytotoxic chemotherapy followed by maintenance chemotherapy. The three‐arm trial (Han 2017) compared targeted treatment with cytotoxic chemotherapy and with targeted treatment combined with cytotoxic chemotherapy.
Outcomes
The primary outcome for the majority of trials was progression‐free survival with secondary outcomes of overall survival, tumour response rate, symptom palliation, health‐related quality of life, and safety. Overall survival was the primary outcome in six trials (First‐SIGNAL; FLEX; INTACT 1; INTACT 2; TOPICAL; TORCH).
Excluded studies
See Characteristics of excluded studies.
We excluded 327 records after the selection procedure (Figure 1). The main reasons for exclusion were the use of non‐randomised designs (including systematic reviews and reports from conferences), non‐assessment of participants' EGFR mutation status, and non‐administration of treatments as first‐line therapy. We excluded other trials if they were designed to assess maintenance treatment, or if an EGFR‐targeted therapy was used in both trial arms. We were unable to easily exclude articles at the screening stage, as we could not be certain from the abstract whether subgroup analyses of outcomes of participants with EGFR M+ tumours were reported. In the Characteristics of excluded studies table, we have listed the 20 trials that appeared to meet the inclusion criteria, but on closer examination were not a complete match. Participants in five trials were not tested for EGFR mutations (Crino 2008; Gatzemeier 2003; Goss 2009; Lilenbaum 2008; Rosell 2004). Two trials tested for EGFR expression only (Rosell 2008; Thatcher 2014). Three trials included too few participants with EGFR M+ tumours to warrant analysis (FASTACT; Heigener 2014; White), and in eight trials tyrosine kinase inhibitors treatment was included in both trial arms (Hirsh 2011; Janne 2012; JO25567; Massuti 2014; NEJ005 2014; NEJ009; Xie 2015; Yang 2015). One trial only assessed outcomes of patients who had survived at one year (Boutsikou 2013), and in another trial there were insufficient samples available for testing (ECOG 4508).
Risk of bias in included studies
Allocation
Of the 22 included trials, 14 reported adequate information about the methods used to generate the randomisation sequence (CONVINCE; EURTAC; FASTACT 2; FLEX; Han 2017; IPASS; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; Patil 2017;TOPICAL; TORCH; WJTOG3405). We considered these trials to be at low risk of bias and the remaining 8 trials to be at unclear risk of bias. We considered that 13 trials (CONVINCE; EURTAC; FASTACT 2; FLEX; IPASS; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; Patil 2017;TOPICAL; TORCH; WJTOG3405) provided adequate information about allocation concealment procedure; we considered these trials to be at low risk of bias. We considered the risk of bias for the remaining eight trials to be unclear due to lack of reported information (BMSO99; CHEN; ENSURE; First‐SIGNAL; GTOWG;Han 2017; INTACT 1; INTACT 2; Yu 2014).
Blinding
Performance bias
Only four of the 22 included trials reported employing blinding procedures (INTACT 1; INTACT 2; NEJSG; TOPICAL). The remaining trials explicitly stated they were open‐label or did not report blinding status. In the latter case, we assumed these trials were open‐label due to the differences between interventions and comparator (that is, oral versus intravenous).
Detection bias
We considered 12 of the trials to be at low risk of detection bias for the outcome of progression‐free survival, as they incorporated independent verification procedures, in BMSO99; CONVINCE; ENSURE; EURTAC; FASTACT 2; First‐SIGNAL; LUX‐Lung 3; LUX‐Lung 6; and NEJSG;, or blinded outcome assessment, in INTACT 1; INTACT 2, and TOPICAL. None of the remaining trials reported any independent assessment procedures and were considered to be at high risk of bias for the outcome of progression‐free survival.
Incomplete outcome data
We considered one trial (CONVINCE) to be at high risk of bias as 11 participants did not receive treatment in the chemotherapy arm, but the reasons were not reported and a per protocol analysis was conducted. In all other trials, all participants were accounted for in the analyses. There did not appear to be any major imbalances in dropout rates between trial arms in any of the trials and therefore we considered all trials to be at low risk of bias.
Selective reporting
We considered two trials to be at high risk of reporting bias (CHEN; CONVINCE). The trial protocol for CHEN stated time to progression as a secondary outcome of the trial, but the published paper did not report this outcome. The trial protocol was not available for the CONVINCE trial. The trial outcomes listed at NCT01719536 for the CONVINCE trial were PFS (primary), OS and objective response rate. No data were presented for objective response rate. We considered two trials to be at unclear risk of bias as the available information was insufficient to judge selective reporting (FLEX; GTOWG) and one trial (Patil 2017) did not report the HRQoL outcomes that were measured. We considered all other trials to be at a low risk of bias, as either trial protocols were available, or all outcomes stated in the methods section of the papers were reported.
Other potential sources of bias
Eighteen trials were sponsored fully or in part by pharmaceutical companies. One trial was terminated early as the non‐inferiority of the intervention arm was demonstrated by the first planned interim analysis (TORCH). Two trials were terminated early for benefit (ENSURE; EURTAC).
Effects of interventions
See: Table 1; Table 2; Table 3; Table 4
Pairwise meta‐analysis
Erlotinib versus placebo, platinum‐based chemotherapy, or other cytotoxic agents
1. Overall survival
Data from four trials were available for overall survival (OS) (CHEN; ENSURE; EURTAC; TORCH). Two trials presented limited data (OPTIMAL; TOPICAL), and one trial presented no data (GTOWG).
Erlotinib versus platinum‐based chemotherapy: The pooled treatment effect estimate for three trials (N = 429), hazard ratio (HR) of 0.95 (95% confidence interval (CI) 0.75 to 1.22; I2 = 0%) (Analysis 1.1) indicated no evidence of clinical benefit in OS between the groups (ENSURE; EURTAC; TORCH). OPTIMAL reported that OS did not differ between the two treatment arms (HR = 1.065, P = 0.6849). No standard error was reported, so the results could not be entered into a meta‐analysis.
1.1. Analysis.
Comparison 1: Erlotinib versus CTX, Outcome 1: Overall survival
Erlotinib versus vinorelbine: CHEN reported a HR of 2.16 (95% CI 0.58 to 8.10) for OS comparing erlotinib versus vinorelbine in elderly patients. As the CI was very wide, the possibility of no clinical benefit of erlotinib for OS could not be ruled out (Analysis 1.1).
Erlotinib versus placebo: TOPICAL reported the median overall survival, which was 10.4 months (95% CI 5.5 to 15.1) for erlotinib (n = 17) versus 3.7 months (95% CI 0.3 to 49.3) for placebo (n = 11).
2. Progression‐free survival
Five trials reported progression‐free survival (PFS) (CHEN; ENSURE; EURTAC; OPTIMAL; TORCH). One trial did not report hazard ratios and only presented limited data (TOPICAL), and one trial reported no data (GTOWG).
Erlotinib versus platinum‐based chemotherapy: The pooled treatment effect estimate for four trials (HR 0.31, 95% CI 0.25 to 0.39; fixed‐effect; I2 = 75%) favoured erlotinib (ENSURE; EURTAC; OPTIMAL; TORCH) (Analysis 1.2). As there was a substantial amount of heterogeneity, we performed a sensitivity analysis using the random‐effects model, and results were similar to the main analysis (HR 0.32, 95% CI 0.20 to 0.51).
1.2. Analysis.
Comparison 1: Erlotinib versus CTX, Outcome 2: Progression‐free survival
Erlotinib versus vinorelbine: CHEN reported a HR of 0.55 (95% CI 0.21 to 1.46) for PFS indicating no evidence of any difference between the treatments (Analysis 1.2).
Erlotinib versus placebo: TOPICAL reported the median PFS, which was 4.8 months (95% CI 1.6 to 8.8) for erlotinib (n = 17) and 2.9 months (95% CI 0.3 to 10.1) for placebo (n = 11).
ENSURE, EURTAC, and OPTIMAL showed an improvement in PFS for the exon 19 deletion in favour of erlotinib. We did not perform meta‐analysis of these preliminary data.
1. Tumour response
Erlotinib versus platinum‐based chemotherapy: The pooled treatment effect estimate for five trials favoured erlotinib (risk ratio (RR) 2.26, 95% CI 1.85 to 2.76; I2 = 57%) (ENSURE; EURTAC; GTOWG; OPTIMAL; TORCH). As there was a substantial amount of heterogeneity, we performed a sensitivity analysis using a random‐effects model, and results were similar (RR 2.20, 95% CI 1.53 to 3.17) (Analysis 1.3).
1.3. Analysis.
Comparison 1: Erlotinib versus CTX, Outcome 3: Tumour response
Erlotinib versus vinorelbine: CHEN reported a RR of 0.83 (95% CI 0.19 to 3.67; 24 participants) for tumour response, indicating no evidence of clinical benefit of erlotinib in tumour response.
TOPICAL did not report tumour response for EGFR M+ participants.
2. Toxicity and adverse effects of treatment.
The most commonly reported adverse effects of treatment (AEs) in participants treated with erlotinib as a monotherapy were rash, diarrhoea, and fatigue (CHEN; ENSURE; EURTAC; GTOWG; OPTIMAL; TOPICAL; TORCH) (Table 5). Other AEs included mouth ulcers, constitutional symptoms, nausea, increased alanine aminotransferase, dyspnoea, and pulmonary toxicities. Cytotoxic chemotherapy was associated with greater grade 3/4 myelosuppression, fatigue and anorexia.
1. Adverse events ‐ most commonly occurring grade 3 & 4.
| Study | Definition of AE | Population | Top AE (listed according to intervention) | Second top AE (listed according to intervention) | Third top AE (listed according to intervention) | Top 3 AEs (listed according to comparator) |
| Afatinib trials | ||||||
| LUX‐Lung 3 | Grade >= 3 CTC (V3) AEs that were reported in > 10% of participants in either group and if there was a >= 10% difference between the groups |
EGFR M+ only | Rash/acne: 16.2% (AFA) vs 0% (cytotoxic chemotherapy) |
Diarrhoea: 14.4% (AFA) vs 0% (cytotoxic chemotherapy) |
Paronychia: 11.4% (AFA) vs 0% (cytotoxic chemotherapy) |
Neutropenia: 18% vs 0.4% Fatigue: 12.6% vs 1.3% Leukopenia: 8.1% vs 0.4% |
| LUX‐Lung 6 | CTC (V3) Events were included if reported for >= 1% of participants in any treatment group. |
EGFR M+ only | Rash/acne: 14.6% (AFA) vs 0% (cytotoxic chemotherapy) |
Diarrhoea: 5.4% (AFA) vs 0% (cytotoxic chemotherapy) |
Stomatitis/mucositis: 5.4% (AFA) vs 0% (cytotoxic chemotherapy) |
Neutropenia: 26.5% vs 0.4% Vomiting: 19.4% vs 0.8% Leukopenia: 15.1% vs 0.4% |
| Erlotinib trials | ||||||
| CHEN | Incidence rate >= 10% | Unselected population | Rash: 64.9% (ERL) vs NR (cytotoxic chemotherapy) |
Diarrhoea: 29.8% (ERL) vs NR (cytotoxic chemotherapy) |
Mouth ulceration: 14% (ERL) vs NR (cytotoxic chemotherapy) |
Anorexia: 26.3% vs NR Diarrhoea: 12.3% vs NR Vomiting: 10.5% vs NR |
| ENSURE | Grade ≥ 3 ≥ 5% in either arm |
EGFR M+ only | Rash: 6.4% (ERL) vs 1% (cytotoxic chemotherapy) |
Neutropenia, leukopenia, anaemia: All 0.9% (ERL) vs 25%, 14.4%, 12.5% respectively (cytotoxic chemotherapy) |
‐ | Neutropenia: 25% vs 0.9% Leukopenia: 14.4% vs 0.9% Anaemia: 12.5% vs 0.9% |
| EURTAC | Grade 3/4 CTC (V3) Common AEs |
EGFR M+ only | Rash: 13% (ERL) vs 0% (cytotoxic chemotherapy) |
Fatigue: 6% (ERL) vs 20% (cytotoxic chemotherapy) |
Diarrhoea: 5% (ERL) vs 0% (cytotoxic chemotherapy) |
Neutropenia: 22% vs 0% Fatigue: 20% vs 6% Thrombocytopenia: 14% vs 0% |
| FASTACT 2 | Grade 3/4 CTC (V3) Most commonly reported |
Unselected population | Neutropenia: 29% (ERL) vs 25% (cytotoxic chemotherapy) |
Thrombocytopenia 14% (ERL) vs 14% (cytotoxic chemotherapy) |
Anaemia: 11% (ERL) vs 9% (cytotoxic chemotherapy) |
Neutropenia: 25% vs 29% Thrombocytopenia: 14% vs 14% Anaemia: 9% vs 11% |
| GTOWG | Grade 3/4 | Unselected population | Rash: 12% (ERL) vs 0% (cytotoxic chemotherapy) |
Diarrhoea: 6% (ERL) vs 2% (cytotoxic chemotherapy) |
Constitutional symptoms: 3% (ERL) vs 5% (cytotoxic chemotherapy) |
Neutropenia: 36% vs 0% Leukocytes: 33% vs 0% Haemoglobin: 11% vs 0.7% |
| OPTIMAL | Grade 3/4 CTC (V3) AEs occurred in 3% or more in either treatment group |
EGFR M+ only | Increased ALT: 4% (ERL) vs 1% (cytotoxic chemotherapy) |
Skin rash: 2% (ERL) vs 0% (cytotoxic chemotherapy) |
Diarrhoea: 1% (ERL) vs 0% (cytotoxic chemotherapy) |
Neutropenia: 42% vs 0% Thrombocytopenia: 40% vs 0% Anaemia: 13% vs 0% |
| TOPICAL | CTC (V3) Specific AEs grade 3 or 4 |
Unselected population | Dyspnoea: 59% (ERL) vs 64% (PLA) |
Fatigue: 23% (ERL) vs 23% (PLA) |
Diarrhoea: 8% (ERL) vs 1% (cytotoxic chemotherapy) |
Dyspnoea: 64% vs 59% Fatigue: 23% vs 23% Anorexia: 5% vs 5% |
| TORCH | Worst toxicity experienced with first‐line treatment alone | Unselected population | Skin rash: 11% (ERL) vs 0% (cytotoxic chemotherapy) |
Pulmonary toxicity: 9% (ERL) vs 6% (cytotoxic chemotherapy) |
Fatigue: 8% (ERL) vs 12% (cytotoxic chemotherapy) |
Neutropenia: 21% vs 0% Thrombocytopenia: 12% vs 0% Fatigue: 12% vs 8% |
| Gefitinib trials | ||||||
| First‐SIGNAL | Grade 3 or 4 CTCAE (V3) | Unselected population |
Rash: 29.3% (GEF) vs 2% (cytotoxic chemotherapy) |
Anorexia: 13.8% (GEF) vs 57.3% (cytotoxic chemotherapy) |
AST: 11.3% (GEF) vs 2% (cytotoxic chemotherapy) |
Anorexia: 57.3% vs 13.9% Neutropenia: 54% vs 1.9% Fatigue: 45.3% vs 10.1% |
|
Han 2017 (GEF vs CTX) |
Grade 3 to 4 CTCAE (V4) treatment‐related | EGFR M+ only | Rash: 9.8% (GEF) vs 0% (cytotoxic chemotherapy) |
Liver dysfunction: 2.4% (GEF) vs 0% (cytotoxic chemotherapy) | None | Neutropenia: 12.5% vs 0% Fatigue: 5% vs 0% |
|
Han 2017 (GEF+CTS vs CTX) |
Grade 3 to 4 CTCAE (V4) treatment‐related | EGFR M+ only | Rash: 10% (GEF + cytotoxic chemotherapy) vs 0% (CTX) |
Liver dysfunction: 10% (GEF + cytotoxic chemotherapy) vs 0% (cytotoxic chemotherapy) | Neutropenia: 10% (GEF + cytotoxic chemotherapy) vs 0% (cytotoxic chemotherapy) |
Neutropenia: 12.5% vs 10% Fatigue: 5% vs 7.5% |
| INTACT 1 | Grade 3/4 CTCAE Commonly occurring AEs |
Unselected population |
Thrombocytopenia*: 5.8% (GEF + cytotoxic chemotherapy) vs 5.6% (cytotoxic chemotherapy) |
Rash: 3.6% (GEF + cytotoxic chemotherapy) vs 1.1% (cytotoxic chemotherapy) |
Diarrhoea: 3.6% (GEF + cytotoxic chemotherapy) vs 2.3% (cytotoxic chemotherapy) |
Thrombocytopenia*: 5.6% vs 5.8% Leukopenia: 2.5% vs 3.3% Diarrhoea: 2.3% vs 3.6% |
| INTACT 2 | Grade 3/4 CTCAE (V2) Common drug‐related AEs |
Unselected population |
Diarrhoea: 9.9% (GEF + cytotoxic chemotherapy) vs 2.9% (cytotoxic chemotherapy) |
Neutropenia: 6.7% (GEF + cytotoxic chemotherapy) vs 5.9% (cytotoxic chemotherapy) |
Rash: 3.2% (GEF + cytotoxic chemotherapy) vs 1.5% (cytotoxic chemotherapy) |
Neutropenia: 5.9% vs 6.7% Diarrhoea: 2.9% vs 9.9% Vomiting: 2.3% vs 2% |
| IPASS | Grade 3, 4, or 5 CTCAE (V3) At least 10% of participants in either treatment group and at least a 5% difference between arms |
Unselected population |
Diarrhoea: 3.8% (GEF) vs 1.4% (cytotoxic chemotherapy) |
Any neutropenia: 3.7% (GEF) vs 67.1% (cytotoxic chemotherapy) |
Rash: 3.1% (GEF) vs 0.8% (cytotoxic chemotherapy) |
Any neutropenia: 67.1% vs 3.7% Leukopenia: 35% vs 1.5% Anaemia: 10.6% vs 2.2% |
| NEJSG | Grade >= 3 CTCAE (V3) At least 10% of participants in either treatment group and at least a 5% difference between arms |
EGFR M+ only | ATE: 26.3% (GEF) vs 0.9% (cytotoxic chemotherapy) |
Rash: 5.3% (GEF) vs 2.7% (cytotoxic chemotherapy) |
Appetite loss: 5.3% (GEF) vs 6.2% (cytotoxic chemotherapy) |
Neutropenia: 65.5% vs 0.9% Arthralgia: 7.1% vs 0.9% Neuropathy: 6.2% vs 0% Appetite loss: 6.2% vs 5.3% |
| Patil 2017 | Grade 3 or Grade 4 CTCAE (V4.03) 'Worst grade toxicity' reported |
EGFR M+ only | Rash: 69.7 (GEF) vs 28.4% (cytotoxic chemotherapy) |
Raised SGPT: 54.5% (GEF) vs 51.1% (cytotoxic chemotherapy) |
Raised SGOT: 53.1% (GEF) vs 40.4% (cytotoxic chemotherapy) Anaemia: 53.1% (GEF) vs 78.7% (cytotoxic chemotherapy) |
Anaemia: 78.7% vs 53.1% Raised SGPT: 51.1% vs 54.5% Thrombocytopaenia: 40.4% vs 6.9% Raised SGOT: 40.4% vs 53.1% |
| WJTOG3405 | Grade >= 3 CTCAE (V3) AEs occurred in 10% of either of the treatment groups |
EGFR M+ only | ALT/AST: 27.5% (GEF) vs 2.3% (cytotoxic chemotherapy) |
Rash: 2.3% (GEF) vs 0% (cytotoxic chemotherapy) |
Fatigue: 2.3% (GEF) vs 2.3% (cytotoxic chemotherapy) |
Neutropenia: 84% vs 0% Leucocytopenia: 50% vs 0% Anaemia: 17% vs 0% |
| Yu 2014 | Grade 3+ Participants with at least 1 AE |
Unselected population |
Rash: 16% (GEF + cytotoxic chemotherapy) vs 0% (cytotoxic chemotherapy) |
Vomiting: 10% (GEF) vs 8% (cytotoxic chemotherapy) |
Neutropenia: 10% (GEF) vs 12% (cytotoxic chemotherapy) |
Neutropenia: 12% vs 10% Nausea: 8% vs 5% Vomiting: 8% vs 10% |
| Icotinib trials | ||||||
| CONVINCE | Grade 3 or 4 CTCAE(V4) any drug‐related AE | EGFR M+ only | Rash: 14.9% (ICO) vs 1.5% (cytotoxic chemotherapy) |
Elevated AST: 8.1% (ICO) vs 10.9% (cytotoxic chemotherapy) |
Diarrhoea: 7.4% (ICO) vs 4.4% cytotoxic chemotherapy Leukopenia: 7.4% (ICO) vs 43.8% cytotoxic chemotherapy |
Nausea: 46% vs 2.7% Leukopenia: 43.8% vs 7.4% Neutropenia: 42.3% vs 3.4% |
| Cetuximab trials | ||||||
| BMSO99 | Grade 3/4 CTCAE (V3) Most frequent and relevant grade 3/4 AEs |
Unselected population | Neutropenia: 62.5% (CET + cytotoxic chemotherapy) vs 56% (cytotoxic chemotherapy) |
Leukopenia: 43.8% (CET + cytotoxic chemotherapy) vs 30.7% (cytotoxic chemotherapy) |
Fatigue: 15.1% (CET + cytotoxic chemotherapy) vs 12.2% (cytotoxic chemotherapy) |
Same AEs as intervention |
| FLEX | Grade 3/4 CTCAE (V2) AEs that were reported in > 5% of participants (G3/G4) or > 1% (G4) or AEs of special interest in either group |
EGFR M+ expressing | Neutropenia: 53% (CET + cytotoxic chemotherapy) vs 51% (cytotoxic chemotherapy) |
Leukopenia: 25% (CET + cytotoxic chemotherapy) vs 19% (cytotoxic chemotherapy) |
Febrile neutropenia: 22% (CET + cytotoxic chemotherapy) vs 15% (cytotoxic chemotherapy) |
Neutropenia: 52% vs 52% Leukopenia: 19% vs 25% Anaemia: 16% vs 1% |
AE: adverse event AFA: afatinib ATE: aminotransferase elevation ALT: alanine aminotransferase AST: aspartate aminotransferase CET: cetuximab CTC: common toxicity criteria CTCAE: Common Terminology Criteria for Adverse Events ERL: erlotinib EGFR M+: epidermal growth factor receptor mutation positive G3: Grade 3 G4: Grade 4 GEF: gefitinib ICO: Icotinib NR: not reported PLA: placebo SGOT: serum glutamic oxaloacetic transaminase SGPT: serum glutamic aspartate aminotransferase V2/3/4: Version 2,3 or 4 vs: versus
*Neutropenia was also reported as 5.8% for G3/4; as this rate was higher than the rate for all participants (5%) it was not included in the table.
3. Health‐related quality of life
Three trials reported on the health‐related quality of life (HRQoL) of EGFR M+ participants (ENSURE; OPTIMAL; TORCH). One trial used the Lung Cancer Symptom Scale (LCSS) to measure HRQoL, but compliance was so poor that the authors regarded the analysis as inconclusive (EURTAC).
HRQoL was measured but not reported in the trial reports in GTOWG, and was not available for the EGFR M+ subgroup in two trials (CHEN; TOPICAL).
TORCH used the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire ‐ Core 30 (QLQ‐C30) and the lung cancer‐specific module (EORTC QLQ‐LC13) to evaluate HRQoL. The number of participants who were improved/stable/worse was reported for selected and unselected participants receiving erlotinib and chemotherapy. Improvement in terms of global QoL and physical functioning was particularly evident in the small numbers of EGFR M+ participants (n = 36/39 available for analysis) for erlotinib compared to cytotoxic chemotherapy.
OPTIMAL used the Functional Assessment of Cancer Therapy‐Lung (FACT‐L), LCSS, and Trial Outcome Index (TOI) to assess HRQoL. The odds ratios (ORs) (with covariates EGFR mutation type, smoking history, and histological type) were in favour of erlotinib and were 6.69 (95% CI 3.01 to 14.85; P = 0.0001), 7.54 (95% CI 3.38 to 16.85; P = 0.0001), and 8.07 (95% CI 3.57 to 18.26; P = 0.0001), respectively.
ENSURE used the Functional Assessment of Cancer Therapy‐Lung (FACT‐L), LCSS, and Trial Outcome Index (TOI) to assess HRQoL. Deterioration in TOI was 11.4 months for erlotinib compared to 4.2 months for chemotherapy (HR 0.51, 95% CI 0.34 to 0.76; P = 0.0006), and time to deterioration in HRQoL was 8.2 months for erlotinib compared to 2.8 months for chemotherapy (HR 0.64, 95% CI 0.44 to 0.93; P = 0.0168).
4. Symptom palliation
In the TORCH trial, the time to deterioration curves for cough, dyspnoea, and pain in the first 20 weeks were visually assessed for erlotinib versus chemotherapy, and no major differences were observed. No statistical analyses were provided by the authors.
The OPTIMAL trial reported that the time to improvement of symptoms on the FACT‐L, TOI, and LCSS (sometimes abbreviated to Lung Cancer Subscale (LCSS)) was significantly shorter for erlotinib compared to chemotherapy: FACT‐L 1.51 versus 3.19 months (P = 0.0067); TOI 2.79 versus 3.48 months (P = 0.003); LCSS 1.48 versus 3.15 months (P = 0.0010). There was also significant correlation between overall response and improvement in symptom scores (P = 0.0006, 0.0002, and 0.0213 for FACT‐L, TOI, and LCSS, respectively).
In the ENSURE trial, preliminary data using the FACT‐L showed that time to symptomatic progression was 13.8 months for erlotinib compared to 5.5 months for chemotherapy (HR 0.56, 95% CI 0.36 to 0.87; P = 0.0076).
Erlotinib plus platinum‐based chemotherapy versus platinum‐based chemotherapy plus placebo
The FASTACT 2 trial compared erlotinib plus gemcitabine plus carboplatin or cisplatin versus placebo plus gemcitabine plus carboplatin or cisplatin.
1. Overall survival
FASTACT 2 reported a HR of 0.48 (95% CI 0.27 to 0.85) for OS indicating a clinical benefit of erlotinib plus gemcitabine plus carboplatin or cisplatin in a trial of 91 participants (Analysis 2.1).
2.1. Analysis.
Comparison 2: Erlotinib plus CTX versus CTX, Outcome 1: Overall survival
2. Progression‐free survival
FASTACT 2 demonstrated a clinical benefit for PFS favouring erlotinib plus gemcitabine plus carboplatin or cisplatin (HR 0.25, 95% CI 0.16 to 0.39) (Analysis 2.2).
2.2. Analysis.
Comparison 2: Erlotinib plus CTX versus CTX, Outcome 2: Progression‐free survival
1. Tumour response
FASTACT 2 observed an objective response in 41 (84%) of 49 participants with EGFR‐activating mutations in the erlotinib plus gemcitabine plus carboplatin or cisplatin group, and 7 (15%) of 48 participants in the placebo plus gemcitabine plus carboplatin or cisplatin group. The corresponding RR was 5.74 (95% CI 2.86 to 11.50) (Analysis 2.3).
2.3. Analysis.
Comparison 2: Erlotinib plus CTX versus CTX, Outcome 3: Tumour response
2. Toxicity and adverse effects of treatment.
Commonly reported AEs in the FASTACT 2 trial were neutropenia, thrombocytopenia, and anorexia (Table 5).
3. Health‐related quality of life
HRQoL was not available for the EGFR M+ subgroup in FASTACT 2.
4. Symptom palliation
The FASTACT 2 trial did not report data on symptom palliation.
Gefitinib versus platinum‐based chemotherapy
1. Overall survival
We could not combine data for all six trials comparing gefitinib to platinum‐based chemotherapy (First‐SIGNAL; IPASS; NEJSG; WJTOG3405, Han 2017; Patil 2017), as two trials reported only adjusted analyses (IPASS; NEJSG). It is not advisable to combine adjusted and unadjusted estimates.
Gefitinib versus gemcitabine plus cisplatin: One trial, First‐SIGNAL, reported a HR of 1.04 (95% CI 0.50 to 2.20) (Analysis 3.1).
3.1. Analysis.
Comparison 3: Gefitinib versus CTX, Outcome 1: Overall survival
Gefitinib versus carboplatin and paclitaxel: Pooled analysis of the two trials indicated no evidence of a difference in OS between the groups (HR 0.95, 95% CI 0.77 to 1.18; I2 = 0) (IPASS; NEJSG) (Analysis 3.1).
Gefitinib versus docetaxel plus cisplatin: WJTOG3405 reported a HR of 1.25 (95% CI 0.88 to 1.78), indicating no evidence of a difference in OS between the groups (Analysis 3.1).
Gefitinib versus pemetrexed plus carboplatin with premetrexed maintenance: Pooled analysis of the two trials indicated no evidence of a difference in OS between the groups (HR 0.84, 95% CI 0.63 to 1.11, I2 = 0) (Han 2017; Patil 2017) (Analysis 3.1).
2. Progression‐free survival
We could not combine data for all six trials comparing gefitinib to platinum‐based chemotherapy (First‐SIGNAL; IPASS; NEJSG; WJTOG3405, Han 2017; Patil 2017), as two trials reported only adjusted analyses (IPASS; NEJSG). It is not advisable to combine adjusted and unadjusted estimates.
Gefitinib versus gemcitabine plus cisplatin: First‐SIGNAL reported a HR of 0.54 (95% CI 0.27 to 1.10). The wide CI indicates that the possibility of no difference in PFS between the groups cannot be ruled out (Analysis 3.2).
3.2. Analysis.
Comparison 3: Gefitinib versus CTX, Outcome 2: Progression‐free survival
Gefitinib versus paclitaxel plus carboplatin: The pooled treatment effect estimate for two trials showed a clinical benefit in PFS between the groups, favouring gefitinib (HR 0.39, 95% CI 0.32 to 0.48; I2 = 73%) (IPASS; NEJSG) (Analysis 3.2). As there was a substantial amount of heterogeneity, we performed a sensitivity analysis using a random‐effects model, and results were similar (HR 0.39, 95% CI 0.26 to 0.59).
Gefitinib versus docetaxel plus cisplatin: WJTOG3405 reported a clinical benefit in PFS favouring gefitinib (HR 0.49, 95% CI 0.34 to 0.71) (Analysis 3.2).
Gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance: The pooled treatment effect estimate for two trials showed a clinical benefit in PFS between the groups, favouring gefitinib (HR 0.59, 95% CI 0.46 to 0.74; I2 = 77%) (Han 2017; Patil 2017) (Analysis 3.2).
IPASS and NEJSG both showed an improvement in PFS for the exon 19 deletion in the gefitinib population.
1. Tumour response
The pooled treatment effect estimate for six trials, First‐SIGNAL, IPASS, NEJSG, WJTOG3405, Han 2017 and Patil 2017 favoured gefitinib (RR 1.74, 95% CI 1.53 to 1.97; I2 = 54%) (Analysis 3.3). There was considerable heterogeneity between the two trials that investigated gefitinib versus paclitaxel+carboplatin, although both trials favoured treatment with gefitinib and so the heterogeneity is quantitative in nature.
3.3. Analysis.
Comparison 3: Gefitinib versus CTX, Outcome 3: Tumour response
Response at cross‐over after progression on first‐line treatment
NEJSG reported that 28.2% of 52 participants responded to carboplatin and paclitaxel after progressing on gefitinib, and 58.5% of 106 participants responded to gefitinib after progressing on carboplatin and paclitaxel.
2. Toxicity and adverse effects of treatment
The most commonly reported AE for gefitinib monotherapy was rash, followed by liver toxicity, anorexia, and diarrhoea (Table 5). Cytoxic chemotherapy was associated with greater grade 3/4 myelosuppression in all comparisons and greater anorexia in one trial (First‐SIGNAL).
3. Health‐related quality of life
Two trials reported on HRQoL (IPASS; NEJSG). HRQoL was not measured in one trial (WJTOG3405), and not available for the EGFR M+ subgroup in one trial (First‐SIGNAL).
IPASS used the FACT‐L and TOI symptom improvement by the LCSS and achieved 89.5% compliance for the cytotoxic chemotherapy group and 94.8% for the gefitinib group. Gefitinib was significantly favoured over carboplatin plus paclitaxel in the proportion of participants showing improvement in FACT‐L total score, TOI, and LCSS (FACT‐L total score: 70.2% versus 44.5% (OR 3.01, 95% CI 1.79 to 5.07), TOI: 70.2% versus 38.3% (OR 3.96, 95% CI 2.33 to 6.71), LCSS: 75.6% versus 53.9% (OR 2.70, 95% CI 1.58 to 4.62)). The time‐to‐deterioration data showed a median of 15.6 months for gefitinib compared to 3.0 months for cytotoxic chemotherapy for FACT‐L; 16.6 months for gefitinib compared to 2.9 months for cytotoxic chemotherapy for TOI; and 11.3 months for gefitinib compared to 2.9 months for cytotoxic chemotherapy for LCSS. In the 131 participants in the gefitinib group who improved, the median time to improvement in all three scores was either eight or 11 days.
NEJSG assessed HRQoL weekly using the Care Notebook and achieved compliance in 72 participants (63%) on chemotherapy and 76 participants (69%) on gefitinib. They used three categories of physical, mental, and 'life' well‐being, each of which had three subcategories. The number of participants who were improved/stable/worse was also reported, and there was no difference between the treatment arms in mental well‐being. However, the physical and life scales were all better for gefitinib than for cytotoxic chemotherapy. The data for daily functioning was quoted as HR 0.32 (95% CI 0.17 to 0.59; P < 0001).
4. Symptom palliation
In the NEJSG trial, participants who received gefitinib had a significantly longer time to deterioration in the time up to 20 weeks than participants who received paclitaxel plus carboplatin using both 9.1% and 27.3% levels of deterioration. The data for 27.3% deterioration for pain and shortness of breath showed a HR of 0.28 (95% CI 0.17 to 0.46; P = 0.0001) in favour of gefitinib.
Gefitinib and platinum‐based chemotherapy versus platinum‐based chemotherapy.
1. Overall survival
Han 2017, a phase 2 trial, reported a HR of 0.46 (95% CI 0.24 to 0.87) indicating a clinical benefit in favour of gefinitib plus platinum‐based chemotherapy (Analysis 4.1). INTACT 1 and INTACT 2 reported a combined HR of 1.77 (95% CI 0.50 to 6.23). The wide CI indicates that the possibility of no difference in OS between the groups cannot be ruled out. Yu 2014 did not report on OS.
4.1. Analysis.
Comparison 4: Gefitinib plus CTX versus CTX, Outcome 1: Overall survival
2. Progression‐free survival
INTACT 1 and INTACT 2 reported a HR of 0.55 (95% CI 0.19 to 1.60); there was insufficient evidence to indicate any clinical benefit in PFS between the groups (combined total of 32 participants).
Yu 2014 reported a HR of 0.20 (95% CI 0.05 to 0.75) for PFS for comparison of gefitinib plus pemetrexed and cisplatin versus pemetrexed plus cisplatin, while Han 2017 reported a HR of 0.16 (95% CI 0.09 to 0.29) indicating a clinical benefit in favour of gefinitib plus platinum‐based chemotherapy (Analysis 4.2). We did not pool results from these two studies as it was not clear whether results from Han were unadjusted or adjusted.
4.2. Analysis.
Comparison 4: Gefitinib plus CTX versus CTX, Outcome 2: Progression‐free survival
1. Tumour response
Han 2017 reported a RR of 2.54 (95% CI 1.59 to 4.06), indicating a clinical benefit in favour of gefinitib plus platinum‐based chemotherapy (Analysis 4.3). INTACT 1 and INTACT 2 showed that the response rates for gefitinib plus cytotoxic chemotherapy were the same as for cytotoxic chemotherapy alone (30.4% versus 28.7%). Yu 2014 reported a response rate of 77% for cytotoxic chemotherapy plus gefitinib compared to cytotoxic chemotherapy alone (50%) (P = 0.13).
4.3. Analysis.
Comparison 4: Gefitinib plus CTX versus CTX, Outcome 3: Tumour response
Response at cross‐over after progression on first‐line treatment
INTACT 1 and INTACT 2 reported that 13 out of 18 (72%) of EGFR M+ participants responded to gefitinib plus cytotoxic chemotherapy, while 2 out of 5 (40%) of EGFR M+ participants responded to cytotoxic chemotherapy alone.
2. Toxicity and adverse effects of treatment
The commonly reported AEs for gefitinib plus cytotoxic chemotherapy were thrombocytopenia, rash, diarrhoea and neutropenia (INTACT 1; INTACT 2).
3. Health‐related quality of life
HRQoL was measured but not reported in the trial report in one trial (INTACT 2), and was not measured in one trial (INTACT 1),
4. Symptom palliation
No data were available on symptom palliation.
Afatinib versus cisplatin‐based chemotherapy
Afatinib versus pemetrexed plus cisplatin: One trial considered this comparison (LUX‐Lung 3).
Afatinib versus gemcitabine plus cisplatin: One trial considered this comparison (LUX‐Lung 6).
1. Overall survival
The pooled treatment effect estimate indicated no evidence of a difference in OS between the groups (HR 0.91, 95% CI 0.75 to 1.10; I2 = 0; 2 trials) (Analysis 5.1). A preliminary report of a pooled analysis of participants with an exon 19 deletion or L858R mutation showed improved survival for afatinib compared to cisplatin‐based chemotherapy in participants with an exon 19 deletion (HR 0.81, 95% CI 0.66 to 0.99; P = 0.037) (Yang 2014). We did not formally assess outcome by mutation site in this review.
5.1. Analysis.
Comparison 5: Afatinib versus CTX, Outcome 1: Overall survival
2. Progression‐free survival
The pooled treatment effect estimate showed a clinical benefit in PFS between the groups favouring afatinib (HR 0.42, 95% CI 0.34 to 0.53; I2 = 90%; 2 trials) (Analysis 5.2). As there was a substantial amount of heterogeneity, we performed a sensitivity analysis using a random‐effects model, and results were similar (HR 0.41, 95% CI 0.20 to 0.83).
5.2. Analysis.
Comparison 5: Afatinib versus CTX, Outcome 2: Progression‐free survival
1. Tumour response
The pooled treatment effect estimate favoured afatinib (RR 2.71, 95% CI 2.12 to 3.46; I2 = 0%; 2 trials) (Analysis 5.3).
5.3. Analysis.
Comparison 5: Afatinib versus CTX, Outcome 3: Tumour response
2. Toxicity and adverse effects of treatment
The most commonly reported grade 3/4 AEs in the afatinib‐treated participants were rash and diarrhoea, paronychia, and stomatitis/mucositis (LUX‐Lung 3; LUX‐Lung 6) (Table 5). Myelosuppression was consistently greater in the chemotherapy arms, while greater fatigue was seen in one comparison. Diarrhoea was worse with afatinib in both trials.
3. Health‐related quality of life
In LUX‐Lung 3, improvement was noted using the EORTC QLQ‐C30 scale in global health, physical, cognitive, and role function in favour of afatinib over cisplatin plus pemetrexed chemotherapy.
LUX‐Lung 6 also used the EORTC QLQ‐C30 scale and the lung cancer‐specific module QLQ‐LC13 with greater than 90% compliance. A greater percentage of participants showed improvement in global health scores/QoL scores (P < 0.0001), physical function (P < 0.0001), and social function (P < 0.0001) with afatinib when compared to cisplatin plus gemcitabine. Subgroup analysis showed delay in time to deterioration in cough, dyspnoea, and pain.
4. Symptom palliation
In the LUX‐Lung 3 trial, time‐to‐deterioration curves for cough and dyspnoea showed a significant effect in favour of afatinib (HR 0.60, 95% CI 0.41 to 0.87; P = 0.007) and (HR 0.68, 95% CI 0.50 to 0.93; P = 0.02), respectively. The HR for pain, 0.83 (95% CI 0.62 to 1.10), showed no evidence of a difference between the two groups (P = 0.19).
In the LUX‐Lung 6 trial, time‐to‐deterioration for cough (HR 0.45; P = 0.0003), dyspnoea (HR 0.54; P < 0.0001), and pain (HR 0.70; P = 0.003) showed a clinical benefit in favour of afatinib (HR 0.56, 95% CI 0.41 to 0.77; P = 0.0002).
Cetuximab plus platinum‐based chemotherapy versus platinum‐based chemotherapy
Cetuximab plus paclitaxel or docetaxel plus carboplatin versus paclitaxel or docetaxel plus carboplatin: One trial considered this comparison (BMSO99).
Cetuximab plus vinorelbine plus cisplatin versus vinorelbine plus cisplatin: One trial considered this comparison (FLEX).
1. Overall survival
We could not pool data for the two trials comparing cetuximab plus platinum‐based chemotherapy to platinum‐based chemotherapy alone, as one trial reported only an adjusted analysis (FLEX).
BMSO99 reported a HR of 1.62 (95% CI 0.54 to 4.84), indicating no evidence of clinical benefit in OS between the groups (Analysis 6.1).
6.1. Analysis.
Comparison 6: Cetuximab plus CTX versus CTX, Outcome 1: Overall survival
FLEX reported a HR of 1.48 (95% CI 0.77 to 2.82), indicating no evidence of clinical benefit in OS between the groups (Analysis 6.1).
2. Progression‐free survival
We could not pool data for the two trials comparing cetuximab plus platinum‐based chemotherapy to platinum‐based chemotherapy alone, as one trial reported only an adjusted analysis (FLEX).
BMSO99 reported a HR of 1.17 (95% CI 0.36 to 3.80), indicating no evidence of clinical benefit in PFS between the groups (Analysis 6.2).
6.2. Analysis.
Comparison 6: Cetuximab plus CTX versus CTX, Outcome 2: Progression‐free survival
FLEX reported a HR of 0.92 (95% CI 0.53 to 1.60), indicating no evidence of clinical benefit in PFS between the groups (Analysis 6.2).
1. Tumour response
The pooled treatment effect estimate (RR 1.43, 95% CI 0.83 to 2.47; I2 = 40%; 2 trials) indicated no evidence of clinical benefit between the groups (Analysis 6.3).
6.3. Analysis.
Comparison 6: Cetuximab plus CTX versus CTX, Outcome 3: Tumour response
2. Toxicity and adverse effects of treatment
The most commonly reported AEs in the cetuximab‐treated participants were neutropenia, leukopenia, febrile neutropenia, and fatigue (BMSO99; FLEX) (Table 5).
3. Health‐related quality of life
FLEX used the EORTC QLQ‐C30 and LCSS, and found no difference in HRQoL between the groups.
HRQoL was not available for the EGFR M+ subgroup in BMSO99.
4. Symptom palliation
Neither trial reported specifically on symptom palliation.
Icotinib versus platinum‐based chemotherapy
Icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy: one trial investigated this comparison (CONVINCE).
1. Overall survival
The CONVINCE trial reported a HR of 0.97 (95% CI: 0.72 to 1.31), indicating no difference in OS between the groups.
2. Progression‐free survival
The CONVINCE trial reported a HR of 0.61 (95% CI: 0.43 to 0.87), indicating a clinical benefit in PFS in favour of icotinib.
1. Tumour response
The CONVINCE trial did not report tumour response data.
2. Toxicity and adverse effects of treatment
The main AEs associated with icotinib were rash, elevated serum AST (aspartate aminotransferase), diarrhoea and leukopenia. In the chemotherapy arm, the main AEs were nausea, leukopenia and neutropenia.
3. Health‐related quality of life
The CONVINCE trial did not report HRQoL data.
4. Symptom palliation
The CONVINCE trial did not report symptom palliation data.
Toxicity and adverse effects of treatment ‐ general comments
The reporting of AEs differed across the 22 included trials. We described in Table 5 the trial‐defined reporting of AEs, and tabulated the three most frequently occurring grade 3 or 4 AEs for both the intervention and comparator arms of each trial. The data reported were for overall trial populations, and therefore included non‐EGFR M+ participants in trials where these were unselected. The trials were grouped according to the EGFR‐targeted treatment employed (erlotinib, gefitinib, afatinib, icotinib, cetuximab).
LUX‐Lung 3 and LUX‐Lung 6 reported three and two participants with interstitial lung disease, respectively (1%) in the afatinib arms.
The AEs associated with cytotoxic chemotherapy in all comparisons were neutropenia, fatigue, leukopenia, vomiting, anaemia, decreased appetite, diarrhoea, anorexia, thrombocytopenia, arthralgia, neuropathy, and dyspnoea.
Assessment of reporting biases
We have not included a funnel plot in the current review as we did not include a sufficient number of trials (n = 10) in any meta‐analysis. However, we devised and carried out a thorough search strategy to reduce the impact of publication bias.
Subgroup analyses
We did not include sufficient trials to allow subgroup analyses of smoking history, age, sex, ethnicity, type of mutation, or performance status.
Sensitivity analyses
We did not include sufficient trials in any one meta‐analysis to allow us to undertake the sensitivity analyses specified in the Methods section. However, where we detected moderate heterogeneity, we used a random‐effects model as a sensitivity analysis to compare results with the fixed‐effect model. We have reported these in the Effects of interventions section.
Network meta‐analysis
We considered that network meta‐analysis was not appropriate because of the different populations within the included trials. We identified other barriers to conducting network meta‐analysis: two trials reported adjusted analyses (IPASS; NEJSG), whereas all other trials reported unadjusted analyses; participants in all trials were allowed to switch treatment after progression, and we had no information regarding how this was handled in the analysis for OS; and finally, the Kaplan‐Meier plots shown in the trial reports crossed in four trials, indicating that using a Cox proportional hazards model may not be appropriate.
Summary of findings table
We have presented tables for pooled analyses for the outcomes of OS and PFS: Table 1; Table 2; Table 3; Table 4.
Discussion
Summary of main results
This review included 22 RCTs with a combined total of 3023 participants with EGFR M+ NSCLC. We identified five EGFR‐targeted treatments: afatinib (two trials); cetuximab (two trials); erlotinib (eight trials); gefitinib (nine trials); icotinib (one trial). We did not consider network meta‐analysis to be appropriate because of the different populations of included trials, the reporting of adjusted analyses versus unadjusted analyses, and the inappropriate use of the Cox proportional hazards model in some trials.
Our primary endpoints were:
1. overall survival (OS), and only two small trials reported an OS gain for participants treated with erlotinib or gefitinib plus cytotoxic chemotherapy compared to cytotoxic chemotherapy alone (FASTACT 2;Han 2017). None of the remaining 20 trials demonstrated any OS benefit of targeted therapy compared with cytotoxic chemotherapy. No OS effect was demonstrated in pooled analyses of erlotinib in ENSURE, EURTAC, and OPTIMAL. Pooled analysis of two gefitinib versus paclitaxed plus carboplatin trials, IPASS and NEJSG, two gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance trials, Han 2017 and Patil 2017, and the two afatinib trials, LUX‐Lung 3 and LUX‐Lung 6, also showed no OS benefit. It is important to note that the majority of the included trials of anti‐EGFR monotherapy allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis.
2. progression‐free survival (PFS). A pooled analysis of four trials (ENSURE; EURTAC; OPTIMAL; TORCH) of erlotinib (583 participants) demonstrated a clinical benefit compared with cytotoxic chemotherapy (HR 0.31, 95% CI 0.25 to 0.39; I2= 75%, high‐certainty evidence) . Of the non‐pooled trials, for erlotinib compared to cytotoxic chemotherapy, CHEN reported a non‐significant PFS effect of erlotinib (n = 24), and FASTACT 2 (n = 97) reported a significant PFS benefit for erlotinib plus cytotoxic chemotherapy (HR 0.25, 95% CI 0.16 to 0.39). The pooled analysis of the gefitinib trials IPASS and NEJSG (N = 491) demonstrated a significant benefit of gefitinib compared with paclitaxel with carboplatin (HR 0.39, 95% CI 0.32 to 0.48; I2=73%, high‐certainty evidence ). The pooled analysis of the gefitinib trials Han 2017 and Patil 2017 (N = 371) demonstrated a significant benefit of gefitinib compared with pemetrexed with carboplatin and pemetrexed maintenance (HR 0.59, 95% CI 0.46 to 0.74; I2= 77%, moderate‐certainty evidence). A single trial, WJTOG3405, also demonstrated a significant difference in PFS favouring gefitinib (HR 0.49, 95% CI 0.34 to 0.71). One other trial, First‐SIGNAL, demonstrated no clinical benefit of gefitinib compared with gemcitabine plus cisplatin (n = 42). For the comparison of gefitinib plus cytotoxic chemotherapy versus chemotherapy, Han 2017 and Yu 2014 both reported a significant benefit of the TKI plus chemotherapy (HR 0.16, 95% CI 0.09 to 0.29, HR 0.20, 95% CI 0.05 to 0.75). INTACT 1 and INTACT 2 reported no difference between a regimen of gefitinib plus cytotoxic chemotherapy compared with cytotoxic chemotherapy plus placebo (n = 32). Heterogeneity was high in the pooled analyses of both erlotinib and gefitinib. Five trials showed a significant improvement in PFS for the tyrosine‐kinase inhibitor (TKI) in tumours harbouring the Del19 mutation compared to chemotherapy (EURTAC; IPASS; LUX‐Lung 3; NEJSG; OPTIMAL). We have not performed meta‐analysis of this mutation site‐specific data.
In the analysis of tumour response, a pooled analysis of five trials of erlotinib including 593 participants favoured treatment with erlotinib (RR 2.26, 95% CI 1.85 to 2.7) (EURTAC; ENSURE; GTOWG; OPTIMAL; TORCH). One trial of erlotinib plus cytotoxic chemotherapy (n = 97) also favoured treatment with erlotinib (FASTACT 2), whilst one other small trial of erlotinib compared to cytotoxic chemotherapy reported no benefit from erlotinib (n = 24) (CHEN). For gefitinib, all six trials demonstrated a clinical benefit for gefitinib compared to cytotoxic chemotherapy: a pooled analysis of six trials including 996 participants yielded a RR of 1.74 (95% CI 1.53 to 1.97) (First‐SIGNAL;Han 2017; IPASS; NEJSG; Patil 2017; WJTOG3405). In Han 2017, the gefitinib plus cytotoxic chemotherapy versus chemotherapy alone comparison favoured the gefitinib arm (RR 2.54, 95% CI 1.59 to 4.06). Both afatinib trials (n = 709) reported a clinical benefit of afatinib compared with cytotoxic chemotherapy (LUX‐Lung 3; LUX‐Lung 6); the pooled analysis yielded a RR of 2.71 (95% CI 2.12 to 3.46). Heterogeneity was high for the erlotinib and gefitinib pooled comparisons and low for the two afatinib trials. No benefit for cetuximab was reported for either trial (BMSO99; FLEX).
The most commonly reported adverse effects (AEs) for people treated with TKI monotherapy were rash, diarrhoea, paronychia, stomatitis/mucositis (afatinib), and rash, diarrhoea, and fatigue (erlotinib and gefitinib). These AEs are consistent with those listed in the Summary of Product Characteristics for these products, which include diarrhoea, rash, interstitial lung disease, liver impairment, and ocular disorders. Participants treated with cytotoxic chemotherapy experienced the AEs usually associated with this treatment, for example, neutropenia, febrile neutropenia, leukopenia, and fatigue. However, it was difficult to accurately characterise and compare AEs across trials because of the different methods of reporting (definitions used and styles of reporting). This is particularly relevant to the rare but serious AE of interstitial lung disease. A meta‐analysis of erlotinib and gefitinib trials reported an incidence of 1.2% for interstitial lung disease with a mortality rate of 22.8% (Shi 2014). The data presented for afatinib suggest this complication occurs with equal frequency with all three TKIs, although no data on duration of therapy was provided. In addition, it should be noted that the AEs reported are relevant to an overall trial population and the 12 trials where EGFR M+ status was not an inclusion criterion were drawn from a much larger population. However, our comparisons highlight the differences in the AEs associated with TKIs and cytotoxic chemotherapy (Pilkington 2012).
Seven trials measured health‐related quality of life for participants with EGFR M+ tumours by a number of different methods (two comparing afatinib with cytotoxic chemotherapy, two comparing erlotinib with cytotoxic chemotherapy, and two comparing gefitinib with cytotoxic chemotherapy); all seven trials reported a beneficial effect of the TKI compared to cytotoxic chemotherapy. All three TKIs showed symptom palliation of cough, pain, and dyspnoea, although the methodology used was not standardised.
Any benefit in survival has to be weighed against increased toxicity. The median number of chemotherapy cycles given in the control arms was four out of a planned six three‐weekly cycles. The CONVINCE trial stated a median number of chemotherapy cycles of seven, but it was not clear if this included the maintenance phase of pemetrexed. The Han 2017 trial also included maintenance pemetrexed and provided limited information on adverse effects, and did not comment on discontinuations. The oral agents (TKIs) were generally given until progression and appeared to be better tolerated. The median duration of therapy was estimated to be around nine to 12 months. In the two gefitinib trials where data were presented, the number of participants discontinuing therapy was similar in the two groups, while in the EURTAC trial a higher proportion of participants on chemotherapy than on erlotinib discontinued due to toxicity.
Overall completeness and applicability of evidence
The median survival of people with advanced stages III or IV NSCLC is on the order of 12 months, and for adenocarcinomas 18 months. At present, there is no indication that increases in PFS fully translate into OS benefit, which is consistent with the evidence in the current literature base (Booth 2012). There was wide variation in the selection criteria for the included trials, including age, sex, smoking, and EGFR sequencing method. The later trials recruited participants only with proven EGFR mutations, and saw longer survival times. However, with the comparatively short survival in NSCLC, AEs and health‐related quality of life for either first‐line or second‐line treatments are important. The interpretation of OS was limited by cross‐over in most trials. From the limited data available on cross‐over at disease progression, the targeted agents and cytotoxics would appear to act on different cell populations.
This review did not include trials of either dacomitinib or osimertinib as both drugs were assessed against another TKI (gefitinib and erlotinib or gefitinib, respectively), and not versus cytotoxic chemotherapy.
Mutations in EGFR can be assessed by several methods including direct sequencing of the tumours, circulating tumour cells (Maheswaran 2008), or cell‐free DNA (Bai 2013) and these vary in specificity and sensitivity. Firstly, heterogeneity in the proportion of malignant and normal/stromal cells in the tissues sampled may contribute to variation in the classification of tumours as EGFR M+ or EGFR wild type based on the location of the sample, as in the majority of trials in this review (Tsiatis 2010), and there is preliminary evidence of heterogeneity of mutation analysis with multiple tissue sampling (Bai 2013). Secondly, methodological issues in the assessment of EGFR mutations may contribute to false‐negative results (Vogelstein 2013). We excluded immunohistochemical‐only categorisation of mutation from this review.
Data on the types of mutations in relation to their sensitivity to targeted therapy is limited (EURTAC). There is evidence that tumours with codon 20 mutations are resistant to EGFR TKI although this mutation commonly appears in acquired resistance to TKIs, while tumours with exon 19 or L858R codon 21 mutations are sensitive to EGFR TKI (Yasuda 2011). The improved survival of exon 19 deletion patients with afatinib compared to cytotoxic chemotherapy suggests that further data will evolve based on more detailed molecular characterisation of EGFR M+ NSCLC (Yang 2014). The cetuximab trials assessed K‐RAS and HER‐2 mutations and demonstrated no predictive effect of the biomarkers (Linardou 2008). Non‐randomised trials have shown that some mutations, principally T790M in codon 20, may contribute to the development of acquired resistance to these agents (Kosaka 2006; Rosell 2011; Su 2012). The majority of trials only included the common mutations in codons 19 and 21, although only four of the included trials excluded T790M mutations (FLEX; LUX‐Lung 3; LUX‐Lung 6; NEJSG).
With improving data on individualisation of treatment according to morphological and molecular criteria, patient choice may be a factor in the decision to accept significant toxicity (for example, from cytotoxic chemotherapy) at an earlier or later stage of NSCLC management. This review provides strong data supporting first‐line EGFR TKI in NSCLC patients whose EGFR mutation status is known to be positive. As mutation testing is not universally available, and the response time of reporting can be prolonged, chemotherapy may be an acceptable first‐line option when histological subtype and smoking history are known in patients with good performance status. Quality control of mutation profiling methodology and international agreement on standardisation would improve confidence in the use of EGFR TKIs in EGFR M+ patients. A more practical issue is the variation in turn‐round time for genetic testing which may lead to clinicians opting for empirical treatment (NCLA 2020).
There is some published evidence of ethnic differences in platinum‐based haematological toxicity, with Asian patients having a higher incidence of grade 3/4 neutropenia compared to non‐Asian patients, based on a pooled analysis of 11,271 participants in 50 phase II and III trials (Hasegawa 2011). It is less well established if there are ethnic differences in response to targeted therapies in the EGFR M+ subgroup, and there was wide variation in the ethnic composition of the reported trials. The majority of the data came from Asian patients, whose tumours may differ in genetic composition, both inherited and that acquired from carcinogen exposure, from non‐Asian patients.
Quality of the evidence
All the included trials were randomised, and the overall number of participants (n = 3023) in the 22 trials provides reasonable power to support the conclusions. The participants were spread across five different drug treatments (cetuximab, afatinib, erlotinib, gefitinib, icotinib), reducing the number providing data for each treatment.
We considered the quality of the evidence to be high for the comparisons of erlotinib versus control, gefitinib versus paclitaxel + carboplatin and afatinib versus chemotherapy (Table 1; Table 2; Table 4). We considered the quality of the evidence to be moderate for the comparison of gefitinib versus pemetrexed + carboplatin with pemetrexed maintenance. With the exception of FASTACT 2, all trials were of an open‐label design, however, all but three trials (Han 2017; IPASS; Patil 2017) reported independent review of radiographic outcomes.
The 'Risk of bias' table indicates a mixed risk of bias across the included trials for the majority of the assessment criteria, with most trials at unclear or high risk of bias (Figure 2; Figure 3). The two items considered to be at high risk of bias across the trials were related to blinding of treatment allocation for participants and personnel and blinding of outcome assessment. Blinding of participants and administrators is difficult to achieve in trials that compare oral therapy with intravenous chemotherapy treatments, and even if blinding procedures are implemented, the appearance of a rash (a common side effect of treatment with a TKI) would indicate the treatment regimen used. FASTACT 2 was blinded in both treatment allocation and imaging assessment. Blinding of outcome assessment is important when time‐to‐treatment‐failure outcomes, such as PFS, are the indicators of treatment efficacy, and blinded outcome assessment or blinded review of assessment should be part of the trial protocol. Of the large industry‐funded trials, OPTIMAL did not report blinding of outcome assessment for erlotinib, and neither did IPASS or WJTOG3405 for gefitinib. We acknowledge that some trials may have implemented such procedures but did not report them. Among the three new trials, CONVINCE was considered to be at high risk of bias for incomplete outcome data and selective reporting.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
The comparisons with cytotoxic chemotherapy were in general direct, but there was wide variation in the choice of cytotoxic chemotherapy in the comparator arm. This reflects variation in clinical practice, in particular, physician preference in relation to patient performance status and comorbidity in the NSCLC populations. For example, single‐agent vinorelbine, used as the comparator in two of the smaller erlotinib trials (CHEN; GTOWG), is associated with lower toxicity than the more widely given doublet chemotherapy combinations used in the other trials, and participants in both CHEN and GTOWG were selected on the basis of age (older than 70 years) and not primarily performance status. The trials also varied in the extent to which they included never‐smokers or former smokers, and in the male/female ratio. The remaining major factor contributing to heterogeneity was ethnicity, as the eight trials recruiting exclusively in Asia contributed 64% of the participants. All of these factors may contribute to variation in drug handling of both cytotoxic chemotherapy and targeted therapy. Heterogeneity was high for assessment of PFS for erlotinib, gefitinib, and afatinib comparisons in the pooled data. In keeping with emerging evidence from updated pemetrexed trials, CONVINCE, Han 2017 and Patil 2017 included maintenance pemetrexed in the chemotherapy and combined arms.
The results of this review should be interpreted cautiously. Just 10 of the included trials recruited only people with EGFR mutations (n = 2371). This means that the data extracted from the remaining 12 trials (n = 645) are derived from subgroups, with all the issues that the interpretation of subgroup data entails. However, it is worth noting that the subgroup of EGFR M+ patients in the IPASS trial, at 261, was larger than the total trial population of four of the EGFR M+ only trials (EURTAC; NEJSG; OPTIMAL; WJTOG3405) and Han 2017. It should be further noted that, in four trials. the tissue analyses were carried out retrospectively on a limited number of samples that were available at the end of the trial (BMSO99; FLEX; INTACT 1; INTACT 2). However, these four trials provided data from only 113 participants, and 80 of these participants were from the cetuximab trials. We do not believe this factor has an impact on the overall conclusions with respect to the three TKIs.
The confidence limits of the PFS and OS plots were narrow, with the exception of the small trial of erlotinib (CHEN), and suggest the data are precise. We saw wider confidence limits for response, which may reflect the subjective nature of the assessment, even with external review, and current concerns that PFS is the better endpoint for trial assessment where cross‐over is a factor (Booth 2012).
There is evidence that Asian patients with NSCLC have a higher proportion of EGFR M+ positivity which may imply there are differences in the biology of NSCLC between individuals of Asian and non‐Asian ethnicity. Of the 3023 participants reported on in this review, 2298 were recruited exclusively in trials conducted in Asian countries. We found no evidence that there was a different set of mutations in Asian and white patients, or differences in their toxicity profiles for the targeted or chemotherapy arms of the included trials.
Potential biases in the review process
We excluded trials that utilised EGFR‐targeted treatments but did not report any EGFR mutation testing of participants. However, inspection of review papers and reference lists indicated that in relation to four of these trials (BMSO99; FLEX; INTACT 1; INTACT 2), retrospective analyses of tissue samples from participants had taken place, the results of which were reported in papers separate to the original trial publication. It is possible that there are other retrospective analyses that we did not identify, however the patient population from any such analyses is likely to be small.
Agreements and disagreements with other studies or reviews
The results are in agreement with the meta‐analysis of Ku 2011, which compared gefitinib with first‐line chemotherapy. A more recent meta‐analysis of 14,570 participants given TKIs in first‐line, second‐line, and maintenance RCTs also reported improved PFS in EGFR M+ participants treated with erlotinib and gefitinib (Lee 2013). This analysis included data on subgroups of participants (n = 67) from TALENT, TOPICAL, and TRIBUTE that were not available to us at the time of analysis. The Lee review analysed no data on participant characteristics, toxicity, and health‐related quality of life (Lee 2013). Their analysis combined the data from 10 first‐line trials in a meta‐analysis of OS and PFS, and showed an overall HR of 0.43 (95% CI 0.38 to 0.49; P < 0.001) for PFS and no effect on OS. As described above, we considered this pooling to be inappropriate on statistical grounds, as adjusted and unadjusted data were combined. An updated meta‐analysis by the same group focused on seven trials (ENSURE; EURTAC; LUX‐Lung 3; LUX‐Lung 6; NEJSG; OPTIMAL; WJTOG3405), and concluded that never‐smokers, those with tumours with exon 19 deletions, and women had a greater benefit from erlotinib than chemotherapy (Lee 2015). Other reviews have combined data from seven phase III trials (in Hasegawa 2015) and eight phase lll trials (in Haaland 2014) for first‐line chemotherapy, and confirmed the benefit in PFS and response. The data on benefit in non‐smokers is difficult to interpret in these studies. One network meta‐analysis of 12 trials combined first‐ and second‐line treatments, and concluded that erlotinib, gefitinib, and afatinib showed similar effectiveness (Liang 2014). Our review of participants across 22 trials included additional trials and comparable data from the 3023 EGFR M+ participants on afatinib, erlotinib, and gefitinib. An individual patient meta‐analysis of four RCTs of cetuximab, Pujol 2014, (including BMSO99 and FLEX) in NSCLC reported improved PFS in squamous cell cancers (based on a subgroup analysis) but not in non‐squamous carcinomas, although these data were not analysed by mutation status.
The prespecified analysis of the Del19 subgroup across a pooled analysis of both of the afatinib trials showed an OS advantage for afatinib compared to chemotherapy in that subgroup, while the L858R subgroup (codon 21 mutation) showed no OS benefit (Yang 2014). Notably, cross‐over to afatinib in the control arm was not allowed, whilst in the majority of comparisons of erlotinib and gefitinib with cytotoxic chemotherapy, cross‐over to the corresponding TKI was permitted. Overall, there was a lack of data on the OS benefit of EGFR inhibitors, but with a low confidence in this, due to the inconsistency and imprecision of the results.
Authors' conclusions
Implications for practice.
Compared with cytotoxic chemotherapy, erlotinib, gefitinib, afatinib and icotinib are effective in prolonging PFS but not OS in EGFR M+ NSCLC patients, with acceptable toxicity. Health‐related quality of life and response are closely linked, and the available data would favour selection of TKIs over chemotherapy as first‐line treatment based on both these criteria, although only six trials reported on health‐related quality of life solely in the EGFR M+ population. The majority of trials included people with a performance status (PS) of 1 and 2, but the data on AEs suggest that some PS 3 as well as elderly patients might tolerate the agents better than cytotoxic chemotherapy (CHEN; GTOWG). TKIs may be an alternative to best supportive care in people with EGFR M+ NSCLC unsuitable for chemotherapy. Other reviews have concluded that the cytotoxic chemotherapy standard for non‐squamous NSCLC should now be cisplatin and pemetrexed (Brown 2013), at least in patients with a good PS. If mutation testing is not available, a decision about the selection of first‐line TKI therapy or chemotherapy may have to be made on the basis of histology, gender, smoking history, and ethnicity.
In people with a good PS, the intercalated regimen of erlotinib or gefitinib and cytotoxic chemotherapy is another option in view of its preliminary OS benefit (FASTACT 2; Han 2017). The lack of overall OS benefit across the majority of trials is likely to be due in large part to treatment cross‐over and may prove difficult to resolve.
Our results for AEs underline the evidence for reduced toxicities experienced with TKI therapy versus cytotoxic chemotherapy. This will have implications for patient care and healthcare costs (Pilkington 2012).
Implications for research.
Future trials of these agents should only include participants with known EGFR mutations, and attempt to clarify the effectiveness in the common mutant subtypes (codons 19, and 21) as well as the estimated 12% with multiple and rare mutations (Kobayashi 2016). Biomarker trials may help to select patients in whom optimal activity will be demonstrated; for example, codon 19 to 21 mutations are more likely to be associated with receptor internal domain alterations which will not respond to the ligand‐binding action of cetuximab (Khambata‐Ford 2010) and, as the preliminary data presented here have shown, individual TKIs may prove more effective for specific codon alterations. The FLAURA trial has shown the value of the third generation TKI osimertinib in the treatment of patients with the T790M mutation, which contributes to intrinsic and acquired resistance to first and second generation agents, and efficacy in those with brain metastases. It follows that stratification of NSCLC patients by appropriate molecular profile will evolve progressively with the introduction of new agents.
The effectiveness of combining EGFR‐targeted therapy and cytotoxic chemotherapy and the associated toxicity remain to be established, but the data from the BMSO99, FLEX, INTACT 1, and INTACT 2 trials do not favour this approach, either in terms of effectiveness or toxicity. The FASTACT 2 trial demonstrated positive outcomes for the combination of erlotinib and cytotoxic chemotherapy given in an intercalated design, and another small trial Han 2017 showed a survival gain for a combination of gefitinib and chemotherapy. Further evaluation of the value of combinations of TKIs with chemotherapy in terms of effectiveness and toxicity is needed.
Evidence is accumulating that there may be different subgroups of non‐squamous NSCLC based on driver gene mutations such as KRAS (Kirsten ras sarcoma gene) and the ALK (anaplastic lymphoma kinase) gene rearrangement and these would appear to be mutually exclusive with the EGFR M+; only isolated case reports have shown multiple gene mutations in the same patient.
Further comparative trials with cytotoxic chemotherapy would seem unlikely to be of value in EGFR M+ patients; the focus should instead be on identifying the predictive value of specific mutations to optimise survival and minimise toxicity from inappropriate therapy (Lee 2015).
The majority of studies in this review used a range of molecular sequencing techniques from a primary tumour biopsy for stratification. Research is currently in progress to assess the utility of less invasive technologies such as cell‐free DNA (Murtaza 2013). Future trials should report in detail the degree and duration of symptom control as well as health‐related quality of life scores to improve patient selection.
The management of relapsed disease after first line TKI, in particular the high incidence of brain metastases, is an area requiring further study. Finally, there is a continuing concern about the emergence of new mutations, including to the third generation agents such as osimertinib.
What's new
| Date | Event | Description |
|---|---|---|
| 9 October 2020 | New search has been performed | Background updated. A new author joined the review team: Marty Chaplin. Two authors left the team: Pooja Jain and Kerry Dwan |
| 9 October 2020 | New citation required but conclusions have not changed | New literature search ran on 27th July 2020. Three new studies identified and fully included (CONVINCE; Han 2017; Patil 2017). 1 new SoF added (Table 3), Grade approach applied. Conclusion unchanged. |
History
Protocol first published: Issue 2, 2013 Review first published: Issue 5, 2016
Acknowledgements
We thank all authors who provided data: Chen, Di Maio (TORCH), Maemondo, Mitsudomi, Zhou (OPTIMAL), and Reck (GTOWG); Prabhash (Patil 2017), members of the Cochrane Lung Cancer Group and peer reviewers who provided helpful comments (Virginie Westeel, Mia Schmidt‐Hansen, Fergus Macbeth, Frederic Fiteni, Marta Roqué, Ivan Sola, and Ian Stubbin). Thanks to Corynne Marchal for all her review and procedural advice and the Cochrane Lung Cancer Group, who provided our searches. Many thanks to Kerry Dwan who provided statistical expertise for the previous two versions of this review. We also thank Gemma Cherry for her reviewing skills.
Appendices
Appendix 1. Cochrane Central Register of Controlled Trials
#1 MeSH descriptor: [Carcinoma, Non‐Small‐Cell Lung] explode all trees
#2 lung:ti,ab
#3 (cancer* or carcin* or neoplasm* or tumour* or tumor*):ti,ab
#4 (non‐small or nonsmall):ti,ab 4
#5 #2 and #3 and #4
#6 nsclc:ti,ab
#7 #1 or #5 or #6
#8 (tyrosine kinase inhibit* or monoclonal antibod* or EGFR or TKI*):ti,ab
#9 (erlotinib or tarceva):ti,ab
#10 (gefitinib or iressa):ti,ab
#11 (afatinib or gilotrif):ti,ab
#12 #8 or #9 or #10 or #11
#13 #7 and #12
Appendix 2. MEDLINE
1 exp Carcinoma, Non‐Small‐Cell Lung/
2 (lung and (cancer$ or carcin$ or neoplasm$ or tumour$ or tumor$) and ((non‐small or nonsmall) and cell)).ti,ab.
3 nsclc.ti,ab.
4 1 or 2 or 3
5 (tyrosine kinase inhibit$ or monoclonal antibod$ or EGFR or TKI$).tw.
6 (erlotinib or tarceva).af.
7 (gefitinib or iressa).af.
8 (afatinib or gilotrif).af.
9 5 or 6 or 7 or 8
10 4 and 9
11 randomized controlled trial.pt.
12 controlled clinical trial.pt.
13 randomized.ab.
14 placebo.ab.
15 drug therapy.fs.
16 randomly.ab.
17 trial.ab.
18 groups.ab.
19 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20 exp animals/
21 humans.sh.
22 20 not 21
23 19 not 22
24 10 and 23
Appendix 3. Embase
1 exp lung non small cell cancer/
2 (lung and (cancer$ or carcin$ or neoplasm$ or tumour$ or tumor$) and ((non‐small or nonsmall) and cell)).ti,ab.
3 nsclc.ti,ab.
4 1 or 2 or 3
5 (tyrosine kinase inhibit$ or monoclonal antibod$ or EGFR or TKI$).tw.
6 (erlotinib or tarceva).af.
7 (gefitinib or iressa).af.
8 (afatinib or gilotrif).af.
9 5 or 6 or 7 or 8
10 4 and 9
11 random.tw. or placebo.mp. or double‐blind.mp.
12 10 and 11
Appendix 4. ISI Web of Science
Topic=(non small cell lung) AND Topic=((erlotinib or tarceva or gefitinib or iressa or tyrosine kinase inhibit* or monoclonal antibod* or EGFR)) AND Topic=(random*)
Timespan=All Years. Databases= Science Citation Index Expanded (SCI‐ EXPANDED): 1899‐present; Conference Proceedings Citation Index‐ Science (CPCI‐S): 1990‐present. Refined by: Document Types=( Article Or Meeting Abstract Or Review Or Proceedings Paper)
Data and analyses
Comparison 1. Erlotinib versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Overall survival | 4 | Hazard Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.1.1 Erlotinib versus platinum‐based chemotherapy | 3 | Hazard Ratio (IV, Random, 95% CI) | 0.95 [0.75, 1.22] | |
| 1.1.2 Erlotinib versus vinorelbine | 1 | Hazard Ratio (IV, Random, 95% CI) | 2.16 [0.58, 8.10] | |
| 1.2 Progression‐free survival | 5 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Erlotinib versus CTX | 4 | Hazard Ratio (IV, Fixed, 95% CI) | 0.31 [0.25, 0.39] | |
| 1.2.2 Erlotinib versus vinorelbine | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.55 [0.21, 1.46] | |
| 1.3 Tumour response | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Erlotinib versus CTX | 5 | 593 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.26 [1.85, 2.76] |
| 1.3.2 Erlotinib versus vinorelbine | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.19, 3.67] |
Comparison 2. Erlotinib plus CTX versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2.1 Overall survival | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 Erlotinib plus gemcitabine plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin plus placebo | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.48 [0.27, 0.85] | |
| 2.2 Progression‐free survival | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 Erlotinib plus gemcitabine plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin plus placebo | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.25 [0.16, 0.39] | |
| 2.3 Tumour response | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.3.1 Erlotinib plus gemcitabine plus carboplatin or cisplatin versus gemcitabine plus carboplatin or cisplatin plus placebo | 1 | 97 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.74 [2.86, 11.50] |
Comparison 3. Gefitinib versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 3.1 Overall survival | 6 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1.1 Gefitinib versus gemcitabine plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 1.04 [0.50, 2.20] | |
| 3.1.2 Gefitinib versus paclitaxel plus carboplatin | 2 | Hazard Ratio (IV, Fixed, 95% CI) | 0.95 [0.77, 1.18] | |
| 3.1.3 Gefitinib versus docetaxel plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 1.25 [0.88, 1.77] | |
| 3.1.4 Gefitinib versus pemetrexed plus carboplatin | 2 | Hazard Ratio (IV, Fixed, 95% CI) | 0.84 [0.63, 1.11] | |
| 3.2 Progression‐free survival | 6 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 3.2.1 Gefitinib versus gemcitabine plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.54 [0.27, 1.10] | |
| 3.2.2 Gefitinib versus paclitaxel plus carboplatin | 2 | Hazard Ratio (IV, Fixed, 95% CI) | 0.39 [0.32, 0.48] | |
| 3.2.3 Gefitinib versus docetaxel plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.49 [0.34, 0.71] | |
| 3.2.4 Gefitinib versus pemetrexed plus carboplatin | 2 | Hazard Ratio (IV, Fixed, 95% CI) | 0.59 [0.46, 0.74] | |
| 3.3 Tumour response | 6 | 996 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.74 [1.53, 1.97] |
| 3.3.1 Gefitinib versus gemcitabine plus cisplatin | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.26 [1.17, 4.34] |
| 3.3.2 Gefitinib versus paclitaxel plus carboplatin | 2 | 489 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.83 [1.54, 2.18] |
| 3.3.3 Gefitinib versus docetaxel plus cisplatin | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.93 [1.26, 2.94] |
| 3.3.4 Gefitinib versus pemetrexed plus carboplatin | 2 | 348 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [1.23, 1.86] |
Comparison 4. Gefitinib plus CTX versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 4.1 Overall survival | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1.1 Gefitinib plus pemetrexed and carboplatin versus pemetrexed and carboplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 4.2 Progression‐free survival | 2 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 4.2.1 Gefitinib plus pemetrexed and cisplatin or carboplatin versus pemetrexed and cisplatin or carboplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.20 [0.05, 0.75] | |
| 4.2.2 Gefitinib plus pemetrexed and carboplatin versus pemetrexed and carboplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.16 [0.09, 0.29] | |
| 4.3 Tumour response | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.3.1 Gefitinib plus pemetrexed and carboplatin versus pemetrexed and carboplatin | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected |
Comparison 5. Afatinib versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 5.1 Overall survival | 2 | Hazard Ratio (IV, Fixed, 95% CI) | 0.91 [0.75, 1.10] | |
| 5.1.1 Afatinib versus pemetrexed plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.88 [0.66, 1.17] | |
| 5.1.2 Afatinib versus gemcitabine plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.93 [0.72, 1.22] | |
| 5.2 Progression‐free survival | 2 | Hazard Ratio (IV, Fixed, 95% CI) | 0.42 [0.34, 0.53] | |
| 5.2.1 Afatinib versus pemetrexed plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.58 [0.43, 0.78] | |
| 5.2.2 Afatinib versus gemcitabine plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.28 [0.20, 0.39] | |
| 5.3 Tumour response | 2 | 709 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [2.12, 3.46] |
| 5.3.1 Afatinib versus pemetrexed plus cisplatin | 1 | 345 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [1.74, 3.54] |
| 5.3.2 Afatinib versus gemcitabine plus cisplatin | 1 | 364 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.92 [2.08, 4.09] |
Comparison 6. Cetuximab plus CTX versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 6.1 Overall survival | 2 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 6.1.1 Cetuximab plus paclitaxel or docetaxel plus carboplatin versus paclitaxel or docetaxel plus carboplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 1.62 [0.54, 4.84] | |
| 6.1.2 Cetuximab plus vinorelbine plus cisplatin versus vinorelbine plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 1.48 [0.77, 2.82] | |
| 6.2 Progression‐free survival | 2 | Hazard Ratio (IV, Fixed, 95% CI) | Subtotals only | |
| 6.2.1 Cetuximab plus paclitaxel or docetaxel plus carboplatin versus paclitaxel or docetaxel plus carboplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 1.17 [0.36, 3.80] | |
| 6.2.2 Cetuximab plus vinorelbine plus cisplatin versus vinorelbine plus cisplatin | 1 | Hazard Ratio (IV, Fixed, 95% CI) | 0.92 [0.53, 1.60] | |
| 6.3 Tumour response | 2 | 81 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.83, 2.47] |
| 6.3.1 Cetuximab plus paclitaxel or docetaxel plus carboplatin versus paclitaxel or docetaxel plus carboplatin | 1 | 17 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.50 [0.63, 32.38] |
| 6.3.2 Cetuximab plus vinorelbine plus cisplatin versus vinorelbine plus cisplatin | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.67, 2.11] |
Comparison 7. Icotinib versus CTX.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 7.1 Overall survival | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 7.1.1 Icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 7.2 Progression‐free survival | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Totals not selected | |
| 7.2.1 Icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy | 1 | Hazard Ratio (IV, Fixed, 95% CI) | Totals not selected |
7.1. Analysis.
Comparison 7: Icotinib versus CTX, Outcome 1: Overall survival
7.2. Analysis.
Comparison 7: Icotinib versus CTX, Outcome 2: Progression‐free survival
Characteristics of studies
Characteristics of included studies [ordered by study ID]
BMSO99.
| Study characteristics | ||
| Methods | Open‐label, randomised, multicentre phase III trial conducted in the USA Length of follow‐up: not reported The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 17) was retrospective and reported in a paper separate to the primary published paper. |
|
| Participants | 676 people with histologically or cytologically confirmed stage IV, stage IIIB (with malignant pleural effusion), or recurrent (after radiotherapy or surgery) NSCLC with bidimensionally measurable disease Inclusion criteria: > 18 years; ECOG PS < 2. People with previously treated CNS metastases accepted, but people with symptomatic, uncontrolled disease or requiring corticosteroids were not. Prior surgery (4 weeks) or chest radiation (12 weeks) but no prior chemotherapy for NSCLC or EGFR‐targeted therapy Exclusion criteria: previous infusion reactions to chimerised/murine MABs; pregnant/nursing women; history of acute myocardial infarction (3 months prior); grade 2 peripheral neuropathy; inadequate haematologic, hepatic, or renal function Median age: 64 years Male: 57% Ethnicity: 88% white |
|
| Interventions | Treatment arm (8/338 participants EGFR M+): cetuximab plus taxane/carboplatin Comparator arm (9/338 participants EGFR M+): taxane/carboplatin Cetuximab, the first dose was 400 mg/m2, 120‐minute IV, with subsequent doses of 250 mg/m2, 60‐minute IV, weekly until disease progression or intolerable toxicity, even after completion of chemotherapy Paclitaxel 225 mg/m2, 3‐hour IV, or docetaxel 75 mg/m2, 1‐hour IV with carboplatin (AUC = 6, 30‐minute IV) on day 1 every 3 weeks until disease progression or intolerable toxicity for 6 cycles |
|
| Outcomes | Primary outcome: PFS (based on modified WHO criteria) Secondary outcomes: ORR, OS, HRQoL, safety |
|
| Mutation Assessment Method | QIAamp | |
| Exons assessed | 18 to 21 | |
| Notes | The trial was originally designed as a randomised phase II trial to provide noncomparative data on the efficacy of cetuximab combined with standard chemotherapy (ORR as primary endpoint). 10 months after accrual initiation, the protocol was amended to be conducted as a phase III trial to evaluate the addition of cetuximab to taxane plus carboplatin, with a primary endpoint of PFS. Participant accrual was increased from 300 to 660. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No information provided on randomisation |
| Allocation concealment (selection bias) | Unclear risk | No information provided |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | This was an open‐label trial. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Independent radiological assessment was undertaken. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 13 participants in the cetuximab arm did not receive treatment; 18 participants in the taxane‐only arm did not receive treatment. Reasons not given. However, ITT analysis was carried out. |
| Selective reporting (reporting bias) | Low risk | All stated outcomes reported |
| Other bias | Unclear risk | Trial support from drug manufacturers |
CHEN.
| Study characteristics | ||
| Methods | Open‐label, randomised phase II trial conducted in Taiwan Length of follow‐up: not reported The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 24) was presented as subgroup analysis in the primary published paper. |
|
| Participants | 113 participants aged 70 years or older with histologic or cytologic diagnosis of inoperable NSCLC who had never received chemotherapy, targeted therapy, or hormonal therapy were entered into the trial after giving informed consent. Inclusion criteria: ECOG PS of 0 to 3; measurable lesion(s); no previous radiotherapy on measurable lesion(s); adequate bone marrow reserve with granulocyte count more than or equal to 1500/mm3, platelets more than or equal to 100,000/mm3, and haemoglobin more than or equal to 10 g/dL Exclusion criteria: Previous therapy, symptomatic or unstable brain metastases, inadequate liver or renal function, or uncontrolled systemic disease Median age: 77 years Male: 81% Ethnicity: 100% East Asian |
|
| Interventions | Treatment arm (9/57 participants EGFR M+): erlotinib 150 mg/daily Comparator arm (15/56 participants EGFR M+): vinorelbine 60 mg/m2 days 1 and 8 of every 3‐weekly cycle Responding participants and those with stable disease continued treatment until disease progression or completion of 6 cycles. Participants could continue treatment beyond 6 cycles provided their disease was controlled. |
|
| Outcomes | Primary outcome: ORR Secondary outcomes: OS, PFS (RECIST version 1 criteria), disease control rate, tolerability, HRQoL (FACT‐L) |
|
| Mutation Assessment Method | VarientSEQr | |
| Exons assessed | 18 to 21 | |
| Notes | All participants were aged 70 years or older. Vinorelbine dose increased to 80 mg/m2 beginning from cycle 2 if no toxicity of grade 2 or higher. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Paper stated that participants were randomised with stratification. No other information given |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No evidence of independent assessment of PFS |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants were accounted for. |
| Selective reporting (reporting bias) | High risk | The protocol stated that time to progression was a secondary outcome. This was not mentioned or reported in the published paper. |
| Other bias | Unclear risk | Trial partially sponsored by pharmaceutical company |
CONVINCE.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial conducted across 18 sites in China Length of follow‐up (median): 18 months (icotinib) 15.7 months (cytotoxic chemotherapy) |
|
| Participants | 296 patients were randomised. 285 patients were treated. Inclusion criteria: histologically confirmed stage IIIB or IV lung adenocarcinoma (AJCC TNM version 7) with activating EGFR mutations (exon 19 deletion or L858R mutation in exon 21) assessed by the central laboratory, older than 18 years, no history of chemotherapy for metastatic disease, measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, and adequate organ function Exclusion criteria; non‐adenocarcinoma or negative EGFR mutation, uncontrolled brain metastases, and serious lung or cardiac disease, or had received previous systemic anticancer therapy for advanced disease Male: 29% Median age: 56 years Ethnicity: not reported, but all patients recruited from centres in China |
|
| Interventions | Treatment arm (148/148 participants EGFR M+): icotinib 375 mg daily until disease progression, toxicity, or withdrawal of consent Comparator arm (137/137 participants EGFR M+): 3 week cycles of intravenous chemotherapy (75 mg/m2cisplatin plus 500 mg/m2 pemetrexed on day 1. Patients with non‐progressive disease after 4 cycles of chemotherapy were maintained with pemetrexed, until progressive disease or withdrawal of consent. |
|
| Outcomes | Primary PFS (IRC) Secondary OS AEs |
|
| Mutation Assessment Method | Amplification refractory mutation system (ARMS; Therascreen EGFR Mutation Test kit, Qiagen Manchester Ltd, Manchester, UK) | |
| Exons assessed | 19 and 21 | |
| Notes | EGFR mutation analysis defined as inclusion criteria, therefore all enrolled participants were EGFR positive. 11/148 patients randomised to chemotherapy were not treated. Dose reductions were allowed in the chemotherapy arm if necessary. Dose reductions of icotinib were not recommended, but treatment was allowed to be interrupted for up to 14 days if Grade 3 or 4 adverse events were observed. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation was done centrally by Department of Medical Statistics of the Fourth Military Medical University of Chinese PLA using an interactive web‐based randomisation system |
| Allocation concealment (selection bias) | Low risk | Centralised allocation system used |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Neither physicians nor patients were masked to treatment assignment. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | PFS was assessed by independent response evaluation committee. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 11 participants did not receive treatment in the chemotherapy arm, but reasons not reported. A per protocol analysis was conducted. |
| Selective reporting (reporting bias) | High risk | Trial protocol was not available. Outcomes listed at NCT01719536 were PFS (primary), OS and objective response rate. No data were presented for objective response rate. |
| Other bias | Unclear risk | The trial received funding from a pharmaceutical company and from China's National Key Special Program for Innovative Drugs. Two investigators were employees and shareholders of the sponsoring pharmaceutical company. |
ENSURE.
| Study characteristics | ||
| Methods | Open‐label phase III RCT conducted in Asia Length of follow‐up: 28.9 months (erlotinib), 27.1 months (cytotoxic chemotherapy) |
|
| Participants | 217 people with stage IIIB/IV non‐small cell lung cancer with EGFR mutations in their tumours Median age erlotinub = 57.5 (33–79) Median age cytotoxic chemotherapy = 56.0 (30–78) |
|
| Interventions | Erlotinib (n = 110) 150 mg once daily until progression/unacceptable toxicity Gemcitabine plus cisplatin (n = 117) gemcitabine 1250 mg/m2 IV days 1 and 8 plus cisplatin 75 mg/m2 IV day 1, every 3 weeks, for up to 4 cycles |
|
| Outcomes | Primary PFS (RECIST) Secondary ORR, DCR, OS, AEs, HRQoL |
|
| Mutation Assessment Method | cobas EGFR Mutation Test (Roche Molecular Systems) | |
| Exons assessed | 19, 21 | |
| Notes | Estimated primary completion date: December 2015. ClinicalTrials.gov identifier: NCT01342965 Trial ended early after interim analysis (73% of PFS events). PFS data cutoff July 2012 and OS data cutoff April 2014 |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No description given |
| Allocation concealment (selection bias) | Unclear risk | No description given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Independent radiological assessment used as a sensitivity analysis |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for in the analyses |
| Selective reporting (reporting bias) | Low risk | All outcomes measured were reported. |
| Other bias | Unclear risk | Trial stopped after interim analysis Trial sponsored by pharmaceutical company |
EURTAC.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial conducted in Spain, France, and Italy Length of follow‐up (months): 41 (erlotinib) and 35 (cytotoxic chemotherapy) |
|
| Participants | 173 people with NSCLC and EGFR mutations Inclusion criteria: Histological diagnosis of stage IIIB (with pleural effusion) or stage IV NSCLC (based on the 6th TNM staging system), measurable or evaluable disease. Activating EGFR mutations (exon 19 deletion or L858R mutation in exon 21), age older than 18 years, and no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy was allowed if it ended ≥ 6 months before entry to trial) Exclusion criteria: Non‐EGFR mutated patients, previous chemotherapy for metastatic disease Median age: 65 years Male: 28% Ethnicity: 92% white |
|
| Interventions | Treatment arm (86/86 participants EGFR M+): erlotinib 150 mg/daily until disease progression, toxicity, or withdrawal of consent Comparator arm (87/87 participants EGFR M+): cisplatin 75 mg/m2 on day 1, docetaxel 75 mg/m2 on day 1, or gemcitabine 1250 mg/m2 on day 1 and 8. Cycle of 3 weeks for up to 4 cycles People who were ineligible for cisplatin treatment received IV carboplatin chemotherapy instead (3‐week cycles of AUC 6 on day 1 with 75 mg/m2 docetaxel on day 1, or AUC 5 on day 1 with 1000 mg/m2 gemcitabine on days 1 and 8) |
|
| Outcomes | Primary outcome: PFS (RECIST version 1 criteria) Secondary outcomes: OS, ORR |
|
| Mutation Assessment Method | ABI Prism 3130 Genetic Analyzer | |
| Exons assessed | 19, 21 | |
| Notes | EGFR mutation analysis defined as inclusion criteria, therefore all enrolled participants were EGFR positive. Trial enrolment was stopped at interim data analysis as trial had met primary endpoint. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation, stratified by EGFR mutation type and ECOG performance status |
| Allocation concealment (selection bias) | Low risk | Centralised allocation system used |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | PFS and treatment responses were confirmed by an external review of CT scans by a central review board. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants were accounted for. |
| Selective reporting (reporting bias) | Low risk | All outcomes reported (trial protocol available via NICE STA process) |
| Other bias | Unclear risk | Trial sponsored in part by pharmaceutical company. Trial enrolment was stopped at interim data analysis as trial had met primary endpoint. |
FASTACT 2.
| Study characteristics | ||
| Methods | Double‐blind, placebo‐controlled, randomised phase III trial conducted in Asia Length of follow‐up (months): erlotinib = 28; cytotoxic chemotherapy = 28 The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 97) is presented as a subgroup analysis in the primary published paper. |
|
| Participants | 451 people with stage IIIB/IV NSCLC Inclusion criteria: ECOG PS 0 or 1; measurable disease according to RECIST version 3.0. Exclusion criteria: Previous treatment with agents targeting the HER axis; previous systemic antitumour treatment; adjuvant or neoadjuvant treatment for non‐metastatic disease within 6 months; surgery less than 4 weeks before the trial; localised radiotherapy; brain metastasis; any unstable illness; people known to be HIV positive Median age: 58 years Male: 60% Ethnicity: 100% Southeast Asian |
|
| Interventions | Treatment arm (49/226 participants EGFR M+): erlotinib 150 mg per day plus gemcitabine (1250 mg/m2 on days 1 and 8 of a 4‐week cycle, intravenously) plus platinum (carboplatin 5 × AUC or cisplatin 75 mg/m2 on day 1 of a 4‐week cycle) Comparator arm (48/225 participants EGFR M+): placebo plus gemcitabine (1250 mg/m2 on days 1 and 8 of a 4‐week cycle, intravenously) plus platinum (carboplatin 5 × AUC or cisplatin 75 mg/m2 on day 1 of a 4‐week cycle) plus placebo |
|
| Outcomes | Primary outcome: PFS Secondary outcomes: OS, ORR, duration of response, TTP, safety |
|
| Mutation Assessment Method | cobas 4800 system | |
| Exons assessed | 19, G719X, L858R, or L861Q | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were randomly assigned in a 1:1 ratio by use of a central randomisation programme with a minimisation algorithm. |
| Allocation concealment (selection bias) | Low risk | Central randomisation and drug‐pack allocation were assigned by use of an interactive internet response system. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Everyone outside the company responsible for the interactive internet response system was masked to treatment allocation with the exception of a small independent group that was responsible for monitoring data and safety early in the trial. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | An independent review committee masked to treatment assignment reviewed all tumour images and determined tumour response and progression status. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for in final analysis. ITT analysis conducted. Equal numbers (n = 4) in each arm did not receive allocated treatment. |
| Selective reporting (reporting bias) | Low risk | All outcomes reported in protocol were assessed and presented in published paper. |
| Other bias | Unclear risk | Trial sponsored in part by pharmaceutical company |
First‐SIGNAL.
| Study characteristics | ||
| Methods | Open‐label, randomised, multicentre phase III trial conducted in Korea Length of follow‐up (months): 35 The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 42) is presented as a subgroup analysis in the primary published paper. |
|
| Participants | 313 Korean never‐smoker patients with stage IIIB or IV lung adenocarcinoma Inclusion criteria: Chemotherapy‐naive never‐smokers older than 18 years with stage IIIB (ineligible for curative radiotherapy) or IV adenocarcinoma of the lung with measurable or non‐measurable disease, PS of 0 to 2, and adequate bone marrow, liver, and renal function Exclusion criteria: Severe hypersensitivity to gefitinib or any constituents of this product; any evidence of clinically active interstitial lung disease; severe or uncontrolled systemic disease; concomitant use of phenytoin, carbamazepine, rifampin, barbiturate, or St John’s Wort; and non‐stable brain metastasis Median age: 57 years Male: 11% Ethnicity: 100% East Asian |
|
| Interventions | Treatment arm (26/159 participants): gefitinib 250 mg/daily until disease progression Comparator arm (16/154 participants): cisplatin 75 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8. Cycle of 3 weeks for up to 9 cycles |
|
| Outcomes | Primary outcome: OS Secondary outcomes: PFS (WHO criteria), HRQoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer–specific module LC13), ORR |
|
| Mutation Assessment Method | QIAamp | |
| Exons assessed | 19 to 21 | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Participants were recruited to the trial by 1:1 random assignment and stratified by sex, PS, and disease stage. No details of randomisation procedures reported |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Independent blinded assessment of PFS was reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for (4 withdrew consent in gemcitabine arm prior to treatment) |
| Selective reporting (reporting bias) | Low risk | No protocol available, but all outcomes stated in the paper as measured were reported. |
| Other bias | Unclear risk | Trial sponsored in part by a pharmaceutical company |
FLEX.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial conducted internationally Length of follow‐up (months): cetuximab = 24; cytotoxic chemotherapy = 24 The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 64) was retrospective and reported in a paper published separately from the main analyses. |
|
| Participants | 1125 chemotherapy‐naive patients with histologically or cytologically proven stage IIIB or IV NSCLC and IHC evidence of EGFR expression in at least 1 positively stained tumour cell Inclusion criteria: > 18 years, ECOG PS 0 to 2, adequate organ function, at least 1 bi‐dimensionally measurable tumour lesion Exclusion criteria: Brain metastases, previous treatment with EGFR‐targeted drugs or MABs, major surgery within previous 4 weeks, chest irradiation 12 weeks prior to trial entry, active infection, pregnancy, symptomatic peripheral neuropathy Median age: 59 years Male: 70% Ethnicity: 85% white |
|
| Interventions | Treatment arm (28/557 participants EGFR M+): cetuximab plus cisplatin and vinorelbine. Cetuximab starting dose of 400 mg/m2 intravenous infusion over 2 hrs on day 1, and from day 8 onwards at 250 mg/m2 over 1 hr per week. Cisplatin 80 mg/m2 intravenous infusion on day 1, and vinorelbine 25 mg/m2 intravenous infusion on days 1 and 8 of every 3‐week cycle for up to 6 cycles Comparator arm (36/568 participants EGFR M+): cisplatin plus vinorelbine Cetuximab was continued after the end of chemotherapy until disease progression or unacceptable toxicity occurred. |
|
| Outcomes | Primary outcome: OS Secondary outcomes: PFS (modified WHO criteria), TTP, ORR, HRQoL, AEs |
|
| Mutation Assessment Method | DxS EGFR 29 Mutation Test Kit | |
| Exons assessed | 19 | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation schedule |
| Allocation concealment (selection bias) | Low risk | Centralised IVRS used |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label. No evidence of independent assessment of radiological outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for. ITT analysis |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported except disease control rate |
| Other bias | Unclear risk | Trial supported by pharmaceutical company |
GTOWG.
| Study characteristics | ||
| Methods | A randomised phase II trial conducted in Germany Length of follow‐up (months): not reported The trial included a mixed patient population. The analysis of data for participants with EGFR M+ tumours (n = 10) was retrospective in the primary publication |
|
| Participants | 284 people aged 70 years or older with stage IIIB or IV NSCLC | |
| Interventions | Treatment arm (144 participants): erlotinib 150 mg/daily Comparator arm (140 participants): carboplatin AUC 5 d 1 and vinorelbine 25 mg/m2 day 1, 8 every 21 days for up to 6 cycles |
|
| Outcomes | Primary outcome: PFS (RECIST criteria) Secondary outcomes: OS, response, tolerability, HRQoL |
|
| Mutation Assessment Method | Direct | |
| Exons assessed | Not reported | |
| Notes | The patient population was over 70 years old. Only exons 17 and 19 were screened using the ABI 3500 Genetic Analyzer. Health‐related quality of life was not reported, nor was OS or PFS for EGFR M+ participants. Trial information taken from poster provided by trial authors |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised. No information provided. Trial information taken from conference abstract |
| Allocation concealment (selection bias) | Unclear risk | No information. Trial information taken from conference abstract |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No information provided. Trial information taken from conference abstract |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No information |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 9 participants did not receive treatment, but reasons not reported |
| Selective reporting (reporting bias) | Unclear risk | Health‐related quality of life not reported |
| Other bias | Unclear risk | Pharmaceutical company support unclear |
Han 2017.
| Study characteristics | ||
| Methods | Open‐label, randomised phase II trial conducted in a single centre in China Length of follow‐up not reported |
|
| Participants | 121 participants Inclusion: 18 years of age or older with a histologic or cytologic diagnosis of locally advanced or metastatic adenocarcinoma (Stage IIIB or IV) with a confirmed activating mutation of EGFR (an exon 19 deletion or an exon 21 L858R point mutation). The staging was performed according to the 7th edition of the TNM classification. Patients required at least one measurable lesion meeting Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1. Exclusion: any systemic anticancer therapy for advanced disease, symptomatic or untreated brain metastases or unstable systemic disease, including active infection, uncontrolled hypertension or unstable angina Median age: not reported Male: 41% Ethnicity: not reported, but all patients recruited from a single centre in China |
|
| Interventions | Treatment arm A (n = 40): pemetrexed (500 mg/m2 on day 1) plus carboplatin (AUC 5 on day 1) combined with gefitinib (250 mg/day on days 5–21) and repeated every four weeks for up to six cycles and then continued to receive pemetrexed combined with gefitinib every four weeks Treatment arm B (n = 40): pemetrexed (500 mg/m2 on day 1) plus carboplatin (AUC 5 on day 1) repeated every four weeks for up to six cycles and then received pemetrexed alone every four weeks Treatment arm C (n = 41): gefitinib alone (250 mg/day) |
|
| Outcomes | Primary outcome: PFS Secondary outcomes: OS, response rate and AEs |
|
| Mutation Assessment Method | Amplification Refractory Mutation System(ARMS) according to the manufacturer’s protocol of the DxS EGFR mutation test kit (DxS) | |
| Exons assessed | 19 and 21 | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Patients were allocated in a 1:1:1 ratio using minimisation software. |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Clinicians and study participants were not masked to the identity of the study treatment. |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | PFS was assessed according to RECIST criteria. However, no independent verification of assessments was reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants were accounted for. ITT analysis was conducted. |
| Selective reporting (reporting bias) | Unclear risk | No protocol available, but all outcomes stated in paper and at NCT02148380 were reported. |
| Other bias | Unclear risk | One trial author had received fees from a number of pharmaceutical companies. |
INTACT 1.
| Study characteristics | ||
| Methods | Double‐blind, randomised, placebo‐controlled phase III trial conducted internationally Length of follow‐up (months): 15.9 Combined retrospective molecular analysis of INTACT 1 and 2 participants (combined total of 32) was reported in a publication separate to the main trial publication. |
|
| Participants | 1093 people histologically/cytologically confirmed NSCLC, locally advanced stage III disease not curable with surgery or radiotherapy or stage IV disease Inclusion criteria: Aged 18 years or older and WHO PS of 0 to 2 Exclusion criteria (main): Previous chemotherapy (prior surgery or localised radiation were allowed); hypersensitivity to mannitol, corticosteroids, H2‐antagonists, antihistamines, or agents formulated with polyoxyethylated castor oil; radiotherapy within the last 2 weeks; unresolved toxicity from previous radiation therapy or incomplete healing from previous surgery; pre‐existing motor or sensory neurotoxicity; severe or uncontrolled systemic disease; recent conditions requiring medication or uncontrolled significant active infections; pregnant or breastfeeding; coexisting malignancies or malignancies diagnosed within the last 5 years with the exception of basal‐cell carcinoma or cervical cancer in situ; mixed NSCLC plus small‐cell lung cancer Median age: 60 years Male: 74% Ethnicity: 90% white |
|
| Interventions | Treatment arm A (365 participants): gefitinib 500 mg/daily plus gemcitabine 1250 mg/m2 IV 30 minutes on days 1 and 8 and cisplatin 80 mg/m2 after gemcitabine administration on day 1 only Treatment arm B (365 participants): gefitinib 250 mg/daily plus gemcitabine and cisplatin Comparator arm (363 participants): placebo plus gemcitabine and cisplatin Chemotherapy was administered in 3‐week cycles for a total of 6 cycles; subsequently, participants continued on gefitinib or placebo until disease progression. |
|
| Outcomes | Primary outcome: OS Secondary outcomes: TTP (RECIST), response rate, and safety |
|
| Mutation Assessment Method | BigDye Terminator | |
| Exons assessed | 18 to 21 | |
| Notes | Number of EGFR M+ participants unclear | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomly assigned. No information given |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information given |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind, placebo‐controlled design |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | No independent review, but outcome assessors were blinded. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No information |
| Selective reporting (reporting bias) | Low risk | No protocol available, but all outcomes stated in paper as measured were reported. |
| Other bias | Unclear risk | Supported by a grant from AstraZeneca, Wilmington, DE |
INTACT 2.
| Study characteristics | ||
| Methods | Double‐blind, randomised, placebo‐controlled phase III trial conducted mainly in the USA Length of follow‐up (months): not reported Combined retrospective molecular analysis of INTACT 1 and 2 participants (combined total of 32) was reported in a publication separate to the main trial publication. |
|
| Participants | 1037 people with histologically confirmed NSCLC, unresectable stage III or IV disease Inclusion criteria: No prior chemotherapy, aged 18 years or older, and WHO PS 0 to 2 Exclusion criteria (main): Mixed NSCLC or small‐cell lung cancer, brain metastases that were newly diagnosed or had not been treated with surgery or radiation, previously treated CNS metastases or spinal‐cord compression in the absence of clinically stable disease, less than 2 weeks since radiotherapy, unresolved toxicity from prior radiotherapy or incomplete healing from surgery, severe systemic disease, pregnancy or breastfeeding, and hypersensitivity to mannitol, corticosteroids, H2‐antagonists, antihistamines, or agents formulated with polyoxyethylated castor oil Median age: 62 years Male: 59% Ethnicity: 90% white |
|
| Interventions | Treatment arm A (347 participants): gefitinib 500 mg/daily plus intravenous paclitaxel 225 mg/m2 over 3 hours on day 1 of a 3‐week cycle immediately followed by intravenous carboplatin area under concentration/time curve of 6 mg/min/mL over 15 to 30 minutes on day 1 Treatment arm B (345 participants): gefitinib 250 mg/daily plus intravenous paclitaxel 225 mg/m2 over 3 hours on day 1 of a 3‐week cycle immediately followed by intravenous carboplatin area under concentration/time curve of 6 mg/min/mL over 15 to 30 minutes on day 1 Comparator arm (345 participants): placebo plus intravenous paclitaxel 225 mg/m2 over 3 hours on day 1 of a 3‐week cycle immediately followed by intravenous carboplatin area under concentration/time curve of 6 mg/min/mL over 15 to 30 minutes on day 1 Chemotherapy was continued for 6 cycles in the absence of disease progression. Thereafter, participants were maintained on gefitinib or placebo (control arm) until disease progression or drug intolerance. |
|
| Outcomes | Primary outcome: OS Secondary outcomes: TTP (RECIST criteria), ORR, symptom control, HRQoL, AEs |
|
| Mutation Assessment Method | BigDye Terminator | |
| Exons assessed | 18 to 21 | |
| Notes | Number of EGFR M+ participants unclear | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomised |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information given |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind, placebo‐controlled design |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | No independent review, but outcome assessors were blinded |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No information |
| Selective reporting (reporting bias) | Low risk | No protocol available, but all outcomes stated in paper as measured were reported |
| Other bias | Unclear risk | Supported by a grant from AstraZeneca, Wilmington, DE |
IPASS.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial conducted in East Asia Length of follow‐up (months): 17 The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 261) was retrospective and reported in a paper published separately from the main analyses. |
|
| Participants | 1217 people who had advanced pulmonary adenocarcinoma and who were non‐smokers or former light smokers Inclusion criteria: 18 years of age or older, histologically or cytologically confirmed stage IIIB or IV NSCLC with histologic features of adenocarcinoma (including bronchoalveolar carcinoma), were non‐smokers (people who had smoked < 100 cigarettes in their lifetime) or former light smokers (those who had stopped smoking at least 15 years previously and had a total of ≤ 10 pack‐years of smoking), and who had had no previous chemotherapy or biologic or immunologic therapy Median age: 57 years Male: 20% Ethnicity: 99% East Asian |
|
| Interventions | Treatment arm (132/609 participants EGFR M+): gefitinib 250 mg/daily Comparator arm (129/608 participants EGFR M+): carboplatin at a dose calculated to produce an area under the concentration–time curve of 5.0 or 6.0 mg per millilitre per minute, administered intravenously over a period of 15 to 60 minutes in cycles of once every 3 weeks for up to 6 cycles and paclitaxel (200 mg/m2), administered intravenously over a 3‐hour period on the first day of the cycle in cycles of once every 3 weeks for up to 6 cycles |
|
| Outcomes | Primary outcome: PFS (RECIST criteria) Secondary outcomes: OS, ORR, HRQoL (FACT–L questionnaire, Trial Outcome Index, and reduction in symptoms, assessed with LCSS score), safety, and adverse event profile |
|
| Mutation Assessment Method | DxS EGFR 29 Mutation Test Kit | |
| Exons assessed | 18 to 21 | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Use of dynamic balancing randomisation procedure. Assumed computer program used |
| Allocation concealment (selection bias) | Low risk | Although not reported in paper, interactive voice response system was used (source AstraZeneca evidence submission to NICE). |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | PFS was assessed according to RECIST criteria. However, no independent verification of assessments was reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Low risk | No selective reporting occurred |
| Other bias | Unclear risk | Trial sponsored by pharmaceutical company |
LUX‐Lung 3.
| Study characteristics | ||
| Methods | Open‐label, international phase III trial Length of follow‐up (months): 16.4 |
|
| Participants | 345 participants with adenocarcinoma, stage IIIB or IV, EGFR M+, and ECOG PS of 0 to 1 Inclusion criteria: Activating mutation in EGFR treatment‐naive advanced lung adenocarcinoma; good performance status (ECOG 0 or 1); adequate end‐organ function; and measurable disease using RECIST version 1.1 Median age: 61 years Male: 34.5% Ethnicity: 71% East Asian |
|
| Interventions | Treatment arm (230/345 participants EGFR M+): afatinib 40 mg/day, escalated to 50 mg if limited adverse events observed in cycle 1 until progression Comparator arm (115/115 participants EGFR M+): cisplatin 75 mg/m2 and pemetrexed every 21 days for up to 6 cycles |
|
| Outcomes | Primary outcome: PFS Secondary outcomes: OS, ORR, DCR, tumour shrinkage, HRQoL (EORTC QLQ‐C30 and QLQ‐LC13), AEs |
|
| Mutation Assessment Method | therascreen EGFR 29 | |
| Exons assessed | 18 to 21 | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Company's standard validated random number‐generating system was used to generate the randomisation schedules, verified by a trial‐independent statistician. |
| Allocation concealment (selection bias) | Low risk | Randomisation was performed centrally using IVRS/IWRS |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label trial |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Open‐label trial but with independent review |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Unclear risk | Protocol not available. Outcomes measured unclear from slides |
| Other bias | Unclear risk | Trial sponsored in part by pharmaceutical company |
LUX‐Lung 6.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial Length of follow‐up (months): 16.6 |
|
| Participants | 364 Asian patients all with therascreen positive EGFR M+ NSCLC Inclusion criteria: Pathologically confirmed and previously untreated stage IIIB or IV lung adenocarcinoma ECOG PS 0 or 1; measurable disease according to RECIST version 1.1; adequate organ function. Tumour tissue had to be EGFR M+ at the screening stage. Median age: 58 years Male: 34% Ethnicity: 90% Chinese |
|
| Interventions | Treatment arm (242/242 participants EGFR M+) afatinib 40 mg/day Comparator arm (122/122 participants EGFR M+) gemcitabine 1000 mg/m2 d 1 and 8 and cisplatin 75 mg/m2 for up to 6 cycles |
|
| Outcomes | Primary outcome: PFS by central independent review Secondary outcomes: overall response rate, disease control rate, OS, safety, HRQoL |
|
| Mutation Assessment Method | Therascreen EGFR 29 | |
| Exons assessed | 19 to 21 | |
| Notes | HR 0.26 P < 0.0001 in favour of afatinib. Participant‐reported outcomes pain, cough, and dyspnoea all significantly improved | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation was done centrally with a random number‐generating system and an interactive internet and voice response system. |
| Allocation concealment (selection bias) | Low risk | As above |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label trial. Clinicians and participants were not masked to treatment assignment. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | The trial investigators who performed assessments of participant‐reported outcomes and safety, along with supportive assessments of tumour response (used for sensitivity analyses), were not masked to treatment assignment, but the independent central imaging review group were. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for. ITT analysis conducted |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
| Other bias | Unclear risk | Trial sponsored in part by pharmaceutical company |
NEJSG.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial conducted in Asia Length of follow‐up (months): 24 |
|
| Participants | 230 people with metastatic NSCLC and EGFR mutations Inclusion criteria: NSCLC with EGFR mutations, chemo‐naive, aged < 75 years Exclusion criteria: Previous chemotherapy/targeted therapy, presence of resistant EGFR mutation T790M Mean age: 62 years Male: 36% Ethnicity: 100% Chinese |
|
| Interventions | Treatment arm (114/114 participants EGFR M+): gefitinib 250 mg/daily until disease progression, toxicity, or withdrawal of consent Comparator arm (114/114 participants EGFR M+): carboplatin, dose equivalent to an area under the concentration–time curve of 6, given intravenously over a 1‐hour period on day 1 every 3 weeks and paclitaxel 200 mg/m2, given intravenously over a 3‐hour period every 3 weeks. Treatment was given for at least 3 cycles until unacceptable toxicity or withdrawal of consent. |
|
| Outcomes | Primary outcome: PFS (RECIST version 1 criteria) Secondary outcomes: OS, ORR, time to the deterioration of performance status, AEs |
|
| Mutation Assessment Method | PNA‐LNA | |
| Exons assessed | 19 to 21 (excluding T90M) | |
| Notes | EGFR mutation analysis defined as inclusion criteria, therefore all enrolled participants were EGFR positive | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomisation with block size of 2. Stratification factors of mutation type, histology and smoking status (source: company submission to NICE erlotinib 1st line). Assumed computer program used |
| Allocation concealment (selection bias) | Low risk | Centralised allocation |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Independent radiological review conducted |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Low risk | All outcomes were reported. |
| Other bias | Low risk | None identified |
OPTIMAL.
| Study characteristics | ||
| Methods | Open‐label, randomised, multicentre phase III trial conducted in China Length of follow‐up (months): not reported |
|
| Participants | 165 people with NSCLC Inclusion criteria: Confirmed EGFR mutations in exon 19 or 21; more than 18 years of age; histologically confirmed advanced or recurrent stage IIIB or IV NSCLC measurable disease ECOG PS 0–2; adequate haematological, biochemical, and organ function Exclusion criteria: Uncontrolled brain metastases or had received previous systemic anticancer therapy for advanced disease Median age: 58 years Male: 40.5% Ethnicity: 100% Chinese |
|
| Interventions | Treatment arm (83/83 participants EGFR M+): erlotinib 150 mg/daily until disease progression Comparator arm (82/82 participants EGFR M+): carboplatin (area under the curve = 5) on day 1 of a 3‐week cycle and gemcitabine 1000 mg/m2 on days 1 and 8 for up to 4 cycles |
|
| Outcomes | Primary outcome: PFS (RECIST version 1 criteria) Secondary outcomes: OS, ORR, TTP, duration of response, safety, HRQoL (FACT‐L questionnaire and Lung Cancer Subscale) |
|
| Mutation Assessment Method | Direct | |
| Exons assessed | 19 to 21 | |
| Notes | EGFR mutation analysis defined as inclusion criteria, therefore all enrolled participants were EGFR M+ | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were assigned (1:1) to either erlotinib or chemotherapy by dynamic minimisation procedure with Mini randomisation software. Central randomisation was done by a clinical research organisation. |
| Allocation concealment (selection bias) | Low risk | Centralised allocation by email and telephone |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No independent review of radiological outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
| Other bias | Unclear risk | Trial sponsored by pharmaceutical company |
Patil 2017.
| Study characteristics | ||
| Methods | Open‐label, randomised, single‐centre phase III trial conducted in India Length of follow‐up (months): 14.2 |
|
| Participants | 290 people with NSCLC Inclusion criteria: Confirmed adenocarcinoma of the lung, EGFR mutations in exon 18, 19 or 21; 18 years and above; locally advanced stage IIIB not amenable to local therapy or stage IV disease; measurable disease according to RECIST V.1.1; adequate organ function; ECOG PS 0–2 Exclusion criteria: uncontrolled medical comorbidities; concurrent use of any other investigational agent; pregnancy; previously received palliative chemotherapy, biological therapy or immunotherapy; known severe hypersensitivity to carboplatin or pemetrexed; pre‐existing idiopathic pulmonary fibrosis; life expectancy of less than 12 weeks Mean age: 54 years Male: 56% Ethnicity: Indian |
|
| Interventions | Treatment arm (145/145 participants EGFR M+): gefitinib 250 mg/daily until disease progression Comparator arm (145/145 participants EGFR M+): pemetrexed 500 mg/m2 immediately followedbycarboplatin (area under the curve = 5) on day 1 of a 3‐week cycle. Patients who had non‐progressive disease following the completion of 6 cycles were offered maintenance pemetrexed 500 mg/m2 intravenously every 3 weeks until disease progression, intolerable toxicity or other prespecified criteria for discontinuation were met. |
|
| Outcomes | Primary outcome: PFS (RECIST version 1.1 criteria) Secondary outcomes: OS, ORR, HRQoL (EORTC) and AEs |
|
| Mutation Assessment Method | DNA was extracted from the formalin‐fixed paraffin‐embedded tumour blocks and amplified for exons 18, 19, 20 and 21 using a nested‐PCR method with Taqman probes | |
| Exons assessed | 18, 19 and 21 | |
| Notes | EGFR mutation analysis defined as inclusion criteria, therefore all enrolled participants were EGFR M+ | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomisation was done centrally by a neutral person who was not a part of the study team and was based in the clinical research secretariat in the hospital campus. |
| Allocation concealment (selection bias) | Low risk | Block randomisation was done centrally by a neutral person who was not a part of the study team and was based in the clinical research secretariat in the hospital campus. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding procedures were reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for. ITT analysis conducted |
| Selective reporting (reporting bias) | Unclear risk | The publication stated that HRQoL was measured using the EORTC General and Lung Cancer specific questionnaires. The results of the HRQoL data collection were not reported. |
| Other bias | Low risk | None identified |
TOPICAL.
| Study characteristics | ||
| Methods | Double‐blind, placebo‐controlled, randomised, multicentre phase III trial conducted in the UK Length of follow‐up (months): not reported The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 28) was reported in the main paper. |
|
| Participants | 670 people with newly diagnosed, pathologically confirmed NSCLC; stage IIIB or IV disease; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor ECOG PS (PS ≥ 2) or presence of several comorbidities Inclusion criteria: Newly diagnosed, pathologically confirmed NSCLC; stage IIIB or IV disease; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor ECOG PS (≥ 2) or presence of several comorbidities (including impaired renal function with creatinine clearance < 60 mL/min), or both; estimated life expectancy of at least 8 weeks; older than 18 years Exclusion criteria: Previous treatment with any biological anticancer therapy; previous palliative radiotherapy (except to bone metastases, within the previous 2 weeks); pregnant or lactating women; evidence of significant laboratory finding or concurrent uncontrolled medical illness judged to potentially interfere with the trial treatment; present treatment with a COX‐2 inhibitor Median age: 77 years Male: 61% Ethnicity: 97% white |
|
| Interventions | Treatment arm (17/350 participants EGFR M+): erlotinib 150 mg/daily Comparator arm (11/320 participants EGFR M+): placebo |
|
| Outcomes | Primary: OS Secondary: PFS, HRQoL, AEs |
|
| Mutation Assessment Method | Sequenom OncoCarta Panel v1.0 | |
| Exons assessed | 19, 21 | |
| Notes | The trial set out to assess the benefits of erlotinib in a population of patients with NSCLC who were considered unsuitable for chemotherapy. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were randomised with a computer‐generated sequence with a block size of 10. |
| Allocation concealment (selection bias) | Low risk | Randomisation was done by site staff telephoning the Cancer Research UK and University College London Cancer Trials Centre. All investigators, clinicians, and participants were masked to assignment. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | All investigators, clinicians, and participants were masked to assignment. Use of placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | All investigators, clinicians, and participants were masked to assignment. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for. ITT analysis conducted |
| Selective reporting (reporting bias) | Low risk | All specified outcomes reported |
| Other bias | Unclear risk | Risk of participants in erlotinib arm developing rash, thereby disclosing treatment allocation. Partial funding from pharmaceutical company |
TORCH.
| Study characteristics | ||
| Methods | Open‐label, randomised phase III trial conducted in Italy and Canada Length of follow‐up (months): 24.3 The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 39) was presented as subgroup analysis in the primary publication. |
|
| Participants | 760 people with NSCLC Inclusion criteria: Histologically or cytologically confirmed NSCLC stage IIIB (with malignant pleural effusion or supraclavicular nodes) or IV, at least 1 target or non‐target lesion, age younger than 70 years (no age limits for Canadian centres), ECOG PS 0 to 1. People at first diagnosis and those with recurrence after surgery were eligible. Exclusion criteria: Prior treatment with anti‐EGFR agents; history of prior invasive malignancy or inadequate bone marrow; any unstable systemic disease, including active infections and significant cardiovascular, hepatic, renal, or metabolic disease; inflammatory eye surface changes; inability to take or absorb oral medications. Median age: 62.5 years Male: 66% Ethnicity: 96% white |
|
| Interventions | Treatment arm (19/380 participants EGFR M+): erlotinib 150 mg/daily until disease progression Comparator arm (20/380 participants EGFR M+): cisplatin 80 mg/m2 intravenously on day 1 and gemcitabine 1200 mg/m2 intravenously per day on days 1 and 8 every 3 weeks until progression |
|
| Outcomes | Primary outcome: OS Secondary outcomes: Total PFS, time from random assignment to progression after second‐line treatment or death if it occurred before second progression, or last follow‐up visit for participants not included in the previous 2 categories. PFS after first‐line therapy (first PFS), defined as the time from random assignment to progression after first‐line treatment, or death if it occurred before first progression, or last follow‐up visit for participants not included in the previous 2 categories ORR, defined as the number of participants with complete or partial response at any time divided by the total number of participants enrolled onto each arm (All based on RECIST criteria) Toxicity |
|
| Mutation Assessment Method | Direct | |
| Exons assessed | 19 | |
| Notes | The trial was terminated early because non‐inferiority of the experimental arm was demonstrated. This was a 2‐stage trial with erlotinib given as first‐line treatment and cisplatin plus gemcitabine as second‐line treatment. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were centrally randomly assigned to the 2 treatment arms (1:1 ratio) through a centralised automated minimisation procedure by using histology (adenocarcinoma vs other), smoking status (never‐ vs ever‐smoker), sex, age (< 70 vs ≥ 70years), centre, and PS (0 vs 1) as strata. |
| Allocation concealment (selection bias) | Low risk | Centralised admin system used |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | The trial was open‐label. |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No evidence of independent assessment |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Unclear risk | Paper stated that further secondary endpoints, including health‐related quality of life, comparisons of resource use, and studies of exploratory biomarkers in tumour and blood samples, were not reported in this article. |
| Other bias | High risk | The trial was stopped early because non‐inferiority of the experimental arm was demonstrated. The trial was funded by a pharmaceutical company. |
WJTOG3405.
| Study characteristics | ||
| Methods | Open‐label, randomised, multicentre phase III trial conducted in Japan Length of follow‐up: 59.1 months |
|
| Participants | 177 chemotherapy‐naive patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harbouring EGFR mutations (5 people were excluded after randomisation) Inclusion criteria: Histologically or cytologically confirmed NSCLC, harbouring activating EGFR mutations (either exon 19 deletion or L858R in exon 21), aged 75 years or younger, WHO PS 0 to 1, measurable or non‐measurable disease, and adequate organ function Exclusion criteria: Previous drug therapy targeting EGFR, history of interstitial lung disease, severe drug allergy, active infection or other serious disease condition, symptomatic brain metastases, poorly controlled pleural effusion, pericardial effusion or ascites necessitating drainage, active double cancer, or severe hypersensitivity to drugs containing polysolvate 80 Median age: 64 years Male: 36% Ethnicity: 100% Japanese |
|
| Interventions | Treatment arm (86/86 participants EGFR M+): gefitinib 250 mg/daily Comparator arm (86/86 participants EGFR M+): cisplatin 80 mg/m2, IV over 90 min once every 3‐week cycle and docetaxel 60 mg/m2, administered IV over 1 hr once every 3‐week cycle Treatment continued until progression of the disease, development of unacceptable toxic effects, a request by the participant to discontinue treatment, serious noncompliance with the protocol, or completion of 3 to 6 chemotherapy cycles. Further therapy after progression of the disease was at the physician’s discretion. |
|
| Outcomes | Primary outcome: PFS (RECIST criteria) Secondary outcomes: OS, ORR, disease control rate, safety |
|
| Mutation Assessment Method | PNA‐LNA | |
| Exons assessed | 19, 21 | |
| Notes | All participants were EGFR M+. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Participants were allocated to each treatment group at the data centre using a desktop computer programmed for the minimisation method. |
| Allocation concealment (selection bias) | Low risk | Centralised allocation (see above) |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No independent verification of PFS |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All participants accounted for |
| Selective reporting (reporting bias) | Low risk | No concern over selective reporting |
| Other bias | Unclear risk | 7 authors had received remuneration from pharmaceutical companies, including AstraZeneca. The trial group was non‐profit‐making, but received unrestricted funding from several pharmaceutical companies. |
Yu 2014.
| Study characteristics | ||
| Methods | Open‐label, single‐centre phase II trial Length of follow‐up (months): 35 The trial included a mixed patient population. The analysis of EGFR M+ data only (n = 31) was presented as subgroup analysis in the primary publication. |
|
| Participants | 117 chemo‐naive patients with advanced (stage IIIB or IV) non‐squamous NSCLC. ECOG 0 or 1 Mean age: 55 years Male: 50% Ethnicity: 100% Chinese |
|
| Interventions | Treatment arm (13/58 participants EGFR M+): gefitinib 250 mg days 3 to 16 + pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 or carboplatin AUC = 5 every 3 weeks up to 6 cycles Comparator arm (18/59 participants EGFR M+): pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 or carboplatin AUC = 5 every 3 weeks up to 6 cycles |
|
| Outcomes | Primary outcome: non‐progression rate (RECIST 1.0) Secondary outcomes: ORR, PFS, OS, AE |
|
| Mutation Assessment Method | Direct sequencing | |
| Exons assessed | 18 to 21 | |
| Notes | Treatment in both arms was administered for a maximum of 6 cycles. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No details given |
| Allocation concealment (selection bias) | Unclear risk | No details given |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label trial |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No evidence of independent radiological assessment |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | All participants accounted for |
| Selective reporting (reporting bias) | Unclear risk | Protocol not available, but all stated outcomes were reported on |
| Other bias | Unclear risk | No other bias identified |
AE: adverse event AFA: afatinib AJCC: American Joint Committee on Cancer Classification AUC: area under the curve CET: cetuximab CNS: central nervous system CT: computed tomography DCR: disease control rate DNA: Deoxyribonucleic acid ECOG PS: Eastern Cooperative Oncology Group Performance Status EGFR M+: epidermal growth factor receptor mutation positive EORTC QLQ‐LC13: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire ‐ lung cancer‐specific module EORTC QLQ‐C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire ‐ Core 30 ERL: erlotinib FACT‐L: Functional Assessment of Cancer Therapy ‐ Lung GEF: gefitinib HER: human epidermal growth factor receptor HIV: human immunodeficiency virus HR: hazard ratio HRQoL: health‐related quality of life IHC: immunohistochemistry IRC: independent review committee ITT: intention to treat IV: intravenous IVRS: interactive voice response system IWRS: interactive web response system LCSS: Lung Cancer Symptom Scale MAB: monoclonal antibody NICE: National Institute for Health and Care Excellence NSCLC: non‐small cell lung cancer ORR: overall response rate OS: overall survival PCR: Polymerase chain reaction PFS: progression‐free survival PLA: placebo PS: performance status RCT: randomised controlled trial RECIST: Response Evaluation Criteria in Solid Tumors STA: single technology appraisal TNM: tumour‐node‐metastasis TTP: time to progression TTR: time to treatment response vs: versus WHO: World Health Organization
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Boutsikou 2013 | Only people surviving at 1 year were tested for EGFR mutation status. |
| Crino 2008 | EGFR expression tested only |
| ECOG 4508 | Insufficient robust EGFR M+ samples available in trial |
| FASTACT | Data for the 7 EGFR participants not in usable format |
| Gatzemeier 2003 | EGFR expression tested only |
| Goss 2009 | EGFR expression tested only |
| Heigener 2014 | The number of EGFR M+ participants was considered to be too small for analysis. |
| Hirsh 2011 | TKI used in both trial arms |
| Janne 2012 | TKI used in both trial arms |
| JO25567 | TKI used in both trial arms |
| Lilenbaum 2008 | EGFR expression tested only |
| Massuti 2014 | TKI used in both trial arms |
| NEJ005 2014 | TKI used in both trial arms |
| NEJ009 | TKI used in both trial arms |
| Rosell 2004 | EGFR expression tested only |
| Rosell 2008 | EGFR expression tested only |
| Thatcher 2014 | EGFR testing by IHC |
| White | Due to small sample size, survival analyses for participants with EGFR mutations were not determined. |
| Xie 2015 | TKI used in both trial arms |
| Yang 2015 | TKI used in both trial arms |
EGFR M+: epidermal growth factor receptor mutation positive IHC: immunohistochemistry TKI: tyrosine‐kinase inhibitor
Characteristics of studies awaiting classification [ordered by study ID]
TALENT.
| Methods | Placebo‐controlled, randomised, international phase III trial |
| Participants | 1159 people with histologically documented, unresectable, locally advanced, recurrent, or metastatic (stage IIIB/IV) NSCLC; age 18 years or over; ECOG PS 0 or 1 |
| Interventions | Treatment arm (580 participants): erlotinib 150 mg/daily + cisplatin and gemcitabine Comparator arm (579 participants): placebo + cisplatin and gemcitabine Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of each cycle Treatment up to 6 cycles |
| Outcomes | Primary outcome: OS Secondary outcomes: TTP (RECIST criteria), ORR, duration of response, HRQoL, AEs |
| Notes |
TRIBUTE.
| Methods | Placebo‐controlled, randomised, multicentre phase III trial conducted in the USA |
| Participants | 1079 people with histologically documented stage IIIB/IV NSCLC; age 18 years or over; and ECOG PS 0 or 1 |
| Interventions | Treatment arm (539 participants): erlotinib 150 mg/daily + paclitaxel and carboplatin Comparator arm (540 participants): placebo + paclitaxel and carboplatin Paclitaxel 200 mg/m2 and carboplatin AUC 6 every 3 weeks until disease progression |
| Outcomes | Primary outcome: OS Secondary outcomes: TTP, ORR, AEs |
| Notes |
AE: adverse event AUC: area under the curve ECOG PS: Eastern Cooperative Oncology Group Performance Status HRQoL: health‐related quality of life NSCLC: non‐small cell lung cancer ORR: overall response rate OS: overall survival PS: Performance status RECIST: Response Evaluation Criteria in Solid Tumors TTP: time to progression
Differences between protocol and review
In this update, we have updated our background. We have added one new 'Summary of findings' table reporting results for the outcomes overall survival and progression‐free survival for the comparison of ongefitinib versus pemetrexed + carboplatin with pemetrexed maintenance (Table 3).
We have added three new studies (CONVINCE; Han 2017; Patil 2017) and removed two trials we previously classified as awaiting classification, INSPIRE and ARCHER. Neither of these trials met our inclusion criteria as they included an EGFR treatment in both arms.
Progression‐free survival has now become a primary outcome.
Contributions of authors
All review authors listed below contributed to the text or data sections, or both, and analysis. All review authors took part in the editing and production of the review.
J Greenhalgh: project co‐ordination, data extraction, report writing
M Chaplin: statistical advisor
A Boland: project management
V Bates: data extraction, entry, and analysis
F Vecchio: searching, data extraction, entry, and analysis
Y Dundar: searching, article screening
JA Green: input into all aspects of the review
Sources of support
Internal sources
None, Other
External sources
None, Other
Declarations of interest
Janette Greenhalgh: none known
Angela Boland: none known
Victoria Bates: none known
Fabio Vecchio: none known
Yenal Dundar: none known
Marty Chaplin: none known
John A Green: none known
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
BMSO99 {published data only}
- Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu L-A, Horak CE, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. Journal of Clinical Oncology 2010;28(6):918-27. [DOI] [PubMed] [Google Scholar]
- Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small cell lung cancer: results of the randomized multicenter phase III trial BMS099. Journal of Clinical Oncology 2010;28(6):911-7. [DOI] [PubMed] [Google Scholar]
CHEN {published data only}
- Chen YM, Tsai CM, Fan WC, Shih JF, Liu SH, Wu CH, et al. Phase II randomized trial of erlotinib or vinorelbine in chemonaive, advanced, non-small cell lung cancer patients aged 70 years or older. Journal of Thoracic Oncology 2012;7(2):412-8. [DOI] [PubMed] [Google Scholar]
CONVINCE {published data only}
- Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Annals of Oncology 2017;28(10):2443-50. [DOI] [PubMed] [Google Scholar]
ENSURE {published data only}
- Wu Y-L, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Annals of Oncology 2015;26(9):1883-9. [DOI] [PubMed] [Google Scholar]
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EURTAC {published and unpublished data}
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FASTACT 2 {published data only}
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First‐SIGNAL {published data only}
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FLEX {published data only}
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GTOWG {published data only}
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Han 2017 {published data only}
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INTACT 1 {published data only}
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INTACT 2 {published data only}
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IPASS {published data only (unpublished sought but not used)}
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LUX‐Lung 3 {published data only}
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LUX‐Lung 6 {published data only}
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NEJSG {published and unpublished data}
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OPTIMAL {published and unpublished data}
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Patil 2017 {published data only}
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TOPICAL {published data only}
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TORCH {published data only}
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WJTOG3405 {published data only}
- Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, et al. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR). Journal of Clinical Oncology 2012;30(15 (S1)):7521. [Google Scholar]
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References to studies excluded from this review
Boutsikou 2013 {published data only}
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ECOG 4508 {published data only}
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FASTACT {published data only}
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Janne 2012 {published data only}
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JO25567 {published data only}
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NEJ009 {published data only}
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Rosell 2004 {published data only}
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Rosell 2008 {published data only}
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