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. As it shows few symptoms, it has often spread by the time it is diagnosed. Consequently surgery is usually not possible, and drug treatment, typically chemotherapy, is required.

The most common 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 specific changes to the cancer cells in 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 quality of life than those having standard chemotherapy.

Trial characteristics

We found 19 trials that looked at four different EGFR-targeted drugs: erlotinib, gefitinib, afatinib, and the antibody cetuximab. We included trials reporting results up to June 2015.

Results

Our results showed that people given erlotinib, gefitinib, or afatinib have a longer time before the cancer progresses and experience fewer side effects than those people given standard chemotherapy, which is most commonly cisplatin plus one other drug. However, the people given erlotinib, gefitinib, or afatinib did not live any longer than those given standard chemotherapy. Treatment with cetuximab combined with chemotherapy did not delay further lung cancer spread and did not extend life compared with chemotherapy alone.

Conclusion

Erlotinib, gefitinib, and afatinib delay further spread of EGFR M+ lung cancer and improve quality of life, but do not extend life. Giving cetuximab with chemotherapy is no better at controlling this type of cancer or extending life than chemotherapy alone.

Authors' conclusions: 

Erlotinib, gefitinib, and afatinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged progression-free survival compared to cytotoxic chemotherapy. We also found a beneficial effect of the TKI compared to cytotoxic chemotherapy. However, we found no increase in overall survival for the TKI when compared with standard chemotherapy. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, or afatinib and is associated with greater toxicity. There were no data supporting the use of monoclonal antibody therapy.

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Background: 

Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is emerging as an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men and is less associated with smoking.

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 outcome was overall survival. Secondary outcomes included progression-free survival, response rate, toxicity, and quality of life.

Search strategy: 

We conducted electronic searches of the the Cochrane Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to 1 June 2015), EMBASE (1980 to 1 June 2015), and ISI Web of Science (1899 to 1 June 2015). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (1 June 2015); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles.

Selection criteria: 

Parallel 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: 

Nineteen trials met the inclusion criteria. Seven 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 2317, of whom 1700 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 the intervention treatment used in eight trials, gefitinib in seven trials, afatinib in two trials, and cetuximab in two trials. The findings of one trial (FASTACT 2) did report a statistically significant OS gain for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, but this result was based on a small number of participants (n = 97). For progression-free survival (PFS), a pooled analysis of 3 trials (n = 378) demonstrated a statistically significant benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24 to 0.38).

In a pooled analysis with 491 participants administered gefitinib, 2 trials (IPASS and NEJSG) demonstrated a statistically significant PFS benefit of gefitinib compared with cytotoxic chemotherapy (HR 0.39; 95% CI 0.32 to 0.48).

Afatinib (n = 709) showed a statistically significant PFS benefit when compared with chemotherapy in a pooled analysis of 2 trials (HR 0.42; 95% CI 0.34 to 0.53).

Commonly reported grade 3/4 adverse events for afatinib, erlotinib, and gefitinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms, fatigue and anorexia were also associated with some chemotherapies.

No statistically significant PFS or OS benefit for cetuximab plus cytotoxic chemotherapy (n = 81) compared to chemotherapy alone was reported in either of the two trials.

Six trials reported on quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, 2 trials showed improvement in one or more indices for the tyrosine-kinase inhibitor (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.

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