A Meta-Analysis of First Generation EGFR TKIs vs. Chemotherapy in Patients with Wild Type EGFR Non-Small Cell Lung Cancer

Chemotherapy associated with improvement in progression-free survival

A meta-analysis of 11 clinical trials with 1605 included patients with advanced non-small cell lung cancer (NSCLC), harbouring wild type (WT) epidermal growth factor receptor (EGFR), shows that previous treatment with chemotherapy compared with first generation EGFR tyrosine kinase inhibitors (TKIs) is associated with improvement in progression-free survival (PFS), but not with improvement in overall survival. The results are published by researchers from Republic of Korea in the 9 April 2014 issue of JAMA.

Drug-sensitive mutations in EGFR are found in about 10% of Western patients and almost 50% of Asian patients with NSCLC. However, a majority of patients with advanced NSCLC worldwide do not have tumours with these mutations, a status known as wild type (WT).

Meta-analysis of first generation EGFR TKIs vs. chemotherapy

For their meta-analysis, the study team led by Dr June Koo-Lee of the Department of Internal Medicine, Seoul National University Hospital in Seoul searched PubMed, EMBASE, Cochrane database, and meeting abstracts presented at congresses of the American Society of Clinical Oncology and European Society of Medical Oncology until December 2013. They retrieved 1947 articles in total.

According to eligibility criteria, only reports from randomised controlled trials that compared erlotinib or gefitinib with conventional chemotherapy in patients with advanced NSCLC were taken into consideration. The primary outcome was PFS, measured as hazard ratios (HRs). The secondary outcomes were objective response rate and overall survival, expressed as relative risks and HRs. 

Among patients with WT EGFR tumours, chemotherapy was associated with improvement of PFS compared with TKIs (6.4 vs. 1.9 months). No statistically significant subgroup difference was identified in term of treatment line (first-line vs. second- or further-line), drug, ethnicity, or EGFR mutation analysis method. However, studies using more sensitive platforms than direct sequencing were associated with a significant PFS benefit with chemotherapy. 

The association of chemotherapy with improvement in PFS was also significant in trials of second- or further-line treatment. The objective response rate (defined as the proportion of complete response and partial responses among all evaluable patients) was higher with chemotherapy than for TKIs (16.8% vs. 7.2%); however, no statistically significant difference was observed in term of overall survival between the two groups.

The authors wrote "… this study suggests that, in patients with WT EGFR tumors, conventional chemotherapy could be a preferable treatment option over EGFR TKI, although this recommendation cannot be conclusive because the overall comparisons were not based on randomization. Furthermore, the toxicity outcome was not assessed".

This work was supported in part by National Research Foundation of Korea grants funded by the Korean government.

What ESMO guidelines recommend? 

The authors wrote in background information of theirJAMAarticle that it is not currently clear that EGFR TKIs are as effective as standard chemotherapy in patients without EGFR mutations, but both options are recommended in current guidelines for patients with WT EGFR, previously treated NSCLC.

The ESMO guideline for diagnosis, treatment and follow-up of patients with metastatic NSCLC states that in WT EGFR patients, EGFR TKIs are not recommended as first-line therapy, as being inferior to chemotherapy. In term of second- and third-line treatment, the ESMO guideline, based on studies published until 2012, states that erlotinib was shown to improve the overall survival in patients with all histologies, not eligible for further chemotherapy, including those with PS 3. Erlotinib was shown to be equivalent to pemetrexed or docetaxel in refractory patients in a randomised trial. Gefitinib was proved non-inferior to docetaxel in a large randomised trial with a better toxicity profile and QoL. In particular, any patient with a tumour bearing sensitising EGFR mutation should receive an EGFR TKI as second-line therapy, if not received previously. But, there is no mention on patients without driver mutations, and some of cited trials have been performed in pre-EGFR testing era.

In addition, a recently published report from the 2nd ESMO Consensus Conference on Lung Cancer that complements existing ESMO guidelines for NSCLC patients, in part of patients without driver mutations, states that platinum based chemotherapy should be offered to PS 2 patients and that combination treatment is preferred over single agent chemotherapy.

Furthermore, the expert consensus states that second- or third-line therapy should be offered to patients with PS 0-1 who present with signs of disease progression (radiological and/or clinical) after first- or second-line therapy. Regarding kind of treatment that should be offered in second-line, the report states that regardless of the WT status of the tumour, a choice between docetaxel, pemetrexed or erlotinib can be made. For fit patients, chemotherapy may be more effective than erlotinib. 

Before such conclusion, the consensus panel elaborate that the choice of therapy depends on the first-line treatment, co-morbidities and disease-free period. In third-line, only erlotinib is registered for those who are EGFR TKI naive. In fit patients, supportive care and inclusion in clinical studies should be offered.

References

Lee J-K, Hahn S, Kim D-W, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors vs. Conventional Chemotherapy in Non–Small Cell Lung Cancer Harboring Wild-Type Epidermal Growth Factor Receptor A Meta-analysis.JAMA2014; 311(14):1430-1437. doi:10.1001/jama.2014.3314.

Link

https://jama.jamanetwork.com/article.aspx?articleid=1857337 

S. Peters, A.A. Adjei, C. Gridelli, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012; 23 (Suppl. 7): vii56–vii64.

Link

http://annonc.oxfordjournals.org/content/23/suppl_7/vii56.full.pdf+html

B. Besse, A. Adjei, P. Baas, et al. 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines in advanced disease. Annals of Oncology 2014; Advance Access published March 25. doi:10.1093/annonc/mdu123.

Link

http://annonc.oxfordjournals.org/content/early/2014/03/25/annonc.mdu123