The overall objective of this project is to summarise the evidence on the clinical- and cost-effectiveness of EGFR-TK mutation tests (commercial or in-house) to identify those previously un-treated adults with locally advanced, or metastatic NSCLC who may benefit from first-line treatment with EGFR-TK inhibitors (gefitinib or erlotinib). We therefore defined the following research questions to address the review objectives:

What is the technical performance of the different EGFR-TK mutation tests (e.g. proportion tumour cells needed, failures, costs, turnaround time)?

What is the accuracy (clinical validity) of EGFR-TK mutation testing, using any test, for predicting response to treatment with tyrosine kinase inhibitors? If individual patient data (IPD) are available, we will investigate the association between individual mutations detected and patient outcome?

How do clinical outcomes from treatment with EGFR-TK receptor inhibitors vary according to which test is used to select patients for treatment?

What is the cost-effectiveness of the use of the different EGFR-TK mutation tests to decide between standard chemotherapy or anti-EGFR TKIs?

Search strategies will be based on target condition and intervention, as recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Additional supplementary searches will be carried out as necessary. Searches for studies for cost and quality of life will be developed separately.

Candidate search terms will be identified from target references, browsing database thesauri (e.g. Medline MeSH and Embase Emtree), existing reviews identified during the rapid appraisal process and initial scoping searches. These scoping searches will be used to generate test sets of target references, which will inform text mining analysis of high-frequency subject indexing terms using Endnote reference management software. Strategy development will involve an iterative approach testing candidate text and indexing terms across a sample of bibliographic databases, aiming to reach a satisfactory balance of sensitivity and specificity.

The following databases will be searched for relevant studies from 2000 to the present:

• MEDLINE (OvidSP)

• MEDLINE In-Process Citations and Daily Update (OvidSP)

• EMBASE (OvidSP)

• Cochrane Database of Systematic Reviews (CDSR ) (Internet)

• Cochrane Central Register of Controlled Trials (CENTRAL) (Internet)

• Database of Abstracts of Reviews of Effects (DARE) (Internet)

• Health Technology Assessment Database (HTA) (Internet)

• Science Citation Index (SCI) (Web of Science)

• LILACS (Latin American and Caribbean Health Sciences Literature) (Internet)

http://regional.bvsalud.org/php/index.php?lang=en

• Biosis

• NIHR Health Technology Assessment Programme (Internet)

• PROSPERO (International Prospective Register of Systematic Reviews) (Internet)

http://www.crd.york.ac.uk/prospero/

Completed and ongoing trials will be identified by searches of the following resources (2000-present):

• NIH ClinicalTrials.gov (http://www.clinicaltrials.gov/)

• Current Controlled Trials (http://www.controlled-trials.com/)

• WHO International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/)

Key conference proceedings, to be identified in consultation with clinical experts, will be screened for the last five years. References in retrieved articles and relevant systematic reviews will be checked. Search strategies will be developed specifically for each database and the keywords associated with non-small cell lung cancer will be adapted according to the configuration of each database.

No restrictions on language or publication status will be applied. Limits will be applied to remove animal. Searches will take into account generic and other product names for the intervention. The search strategies used will be adapted as necessary following consultation with clinical experts. All searching undertaken at Kleijnen Systematic Reviews Ltd is independently peer reviewed by a second Information Specialist, using the PRESS-EBC checklist.

Inclusion:

Question 1 - to be addressed by survey of UK laboratories.

Questions 2 & 3 - RCTs (CCTs and cohort studies will be considered if no RCTs are identified).

Exclusion: None specified

Locally advanced or metastatic non-small-cell lung cancer (NSCLC) in previously untreated adults, who are undergoing EGFR-TK mutation testing to inform selection of the most appropriate course of treatment.

Inclusion:

All research questions - Adult patients (<=18 years) with treatment naive, locally and regionally advanced or metastatic (stage IIIb or IV) non-small-cell lung cancer (NSCLC).

Exclusion: None specified

Inclusion:

Questions 1,2 &4 - Any commercial or in-house EGFR-TK mutation test.

Questions 3 - EGFR-TK receptor inhibitors.

Exclusion: None specified.

Inclusion:

Questions 1 & 2 - not applicable.

Qestion 3 - standard care.

Exclusion: None specified

UK laboratories who are registered for EGFR-TK mutation testing with national quality assurance schemes.

Primary outcomes

Question 1 - Proportion tumour cells needed, failures, turnaround time, costs, expertise/logistics of test.

Question 2 - Overall survival or progression free survival in EGFR-TK positive versus EGFR-TK negative patients. Test accuracy – the number of true positive, false negative, false positive and true negative. IPD if available.

Question 3 - Overall survival or progression free survival.

Secondary outcomes

None

Two reviewers will independently screen titles and abstracts of all reports identified by searches and discrepancies will be discussed. Full copies of all studies deemed potentially relevant, after discussion, will be obtained and two reviewers will independently assess these for inclusion; any disagreements will be resolved by consensus or discussion with a third reviewer.

Where available, data will be extracted on the following: study design/details, participants, EGFR-TK mutation test(s), clinical outcomes, and test performance outcome measures (against treatment response as reference standard), test failure rates, limit of detection. For RCTs that assess the clinical validity of one or more EGFR-TK mutation tests, we will contact the authors directly in order to request IPD linking specific mutation with individual patient outcome. Data will be extracted by one reviewer, using a piloted, standard data extraction form. A second reviewer will check data extraction and any disagreements will be resolved by consensus or discussion with a third reviewer.

The methodological quality of included RCTs will be assessed using the Cochrane Risk of Bias Tool. Diagnostic accuracy studies will be assessed using QUADAS-2. The results of the quality assessment will be used for descriptive purposes to provide an evaluation of the overall quality of the included studies and to provide a transparent method of recommendation for design of any future studies. Quality assessment will be undertaken by one reviewer and checked by a second reviewer, any disagreements will be resolved by consensus or discussion with a third reviewer.

If sufficient data are available summary estimates of the sensitivity and specificity together with 95% confidence intervals (CIs) and prediction regions of each mutation test for the prediction of response to treatment will be calculated. We will use the bivariate/hierarchical summary receiver operating characteristic (HSROC) random effects model to generate summary estimates and an SROC curve. If more than one RCT evaluates treatment effect in patients who were tested with the same EGFR-TK mutation test, then data will be pooled on treatment effect (e.g. hazard ratios, odds ratio, relative risks) within the test positive and, where available test negative arms. The DerSimonian and Laird random effects model will be used to generate summary estimates together with 95% CIs.

If IPD is obtained then we will evaluate which specific mutations, and where possible the level of mutation, associated with a response to treatment. For each mutation reported we will calculate measures of treatment effectiveness (e.g. hazard ratio (HR) together with 95% CI for progression free survival in those treated with tyrosine kinase inhibitors compared to those treated with conventional chemotherapy).

Where meta-analysis is considered unsuitable for some or all of the data identified (e.g. due to the heterogeneity and/or small numbers of studies), we will employ a narrative synthesis. Typically, this will involve the use of text and tables to summarise data. These will allow the reader to consider any outcomes in the light of differences in study designs and potential sources of bias for each of the studies being reviewed. Studies will be organised by EGFR-TK mutation test and by research question addressed. A detailed commentary on the major methodological problems or biases that affected the studies will also be included, together with a description of how this may have affected the individual study results. Recommendations for further research will be made based on any gaps in the evidence or methodological flaws.

None planned

Topic Guidance will be isued by NICE and the full report will be published in Health Technology Assessment. Additional papers and conference abstracts may be submitted as the team considers appropriate.

Marie Westwood

Kleijnen Systematic Reviews Ltd

Unit 6, Escrick Business park

Riccall Rd

Escrick

York

YO19 6FD

marie@systematic-reviews.com

Kleijnen Systematic Reviews Ltd

www.systematic-reviews.com

Dr Marie Westwood, KSR Ltd
Dr Penny Whiting, KSR Ltd
Dr Manuela Joore, Maastricht University
Dr Thea van Asselt, Maastricht University
Dr Nigel Armstrong, KSR Ltd
Ms Kelly Lee, KSR Ltd
Ms Kate Misso, KSR Ltd
Professor Jos Kleijnen, KSR Ltd
Professor Hans Severens, Erasmus university Rotterdam

01 August 2012

06 February 2013

National Institute for Health Research, Health Technology Assessment programme, project number 12/34

None known

English

England, Netherlands

Subject indexing assigned by CRD

Adults; Carcinoma, Non-Small-Cell Lung; Genetic testing; Humans; Protein-Tyrosine Kinases; Receptor, Epidermal Growth Factor

21 August 2012

21 August 2012