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Original Investigation |

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

June-Koo Lee, MD1; Seokyung Hahn, PhD2,3; Dong-Wan Kim, MD, PhD1,4; Koung Jin Suh, MD1; Bhumsuk Keam, MD1,4; Tae Min Kim, MD, PhD1,4; Se-Hoon Lee, MD, PhD1,4; Dae Seog Heo, MD, PhD1,4
[+] Author Affiliations
1Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
2Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Republic of Korea
3Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
4Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
JAMA. 2014;311(14):1430-1437. doi:10.1001/jama.2014.3314.
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Importance  Current guidelines recommend both epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic chemotherapy drugs as standard treatment options for patients with wild-type (WT) EGFR who were previously treated for non–small cell lung cancer (NSCLC). However, it is not clear that EGFR TKIs are as efficacious as chemotherapy in patients with WT EGFR.

Objective  To determine the association between first-generation EGFR TKI vs chemotherapy and survival in advanced NSCLC patients with WT EGFR.

Data Sources  PubMed, EMBASE, Cochrane database, and meeting abstracts of the American Society of Clinical Oncology and European Society of Medical Oncology through December 2013.

Study Selection  Eligible studies were randomized controlled trials comparing EGFR TKI with conventional chemotherapy in patients with advanced NSCLC. Out of 1947 retrieved articles, 11 trials incorporating 1605 patients with WT EGFR were included.

Data Extraction and Synthesis  Two reviewers extracted trial characteristics and outcomes. The risk of bias was evaluated using the Cochrane tool. All measures were pooled using random-effects models and 95% CIs were calculated.

Main Outcomes and Measures  The primary outcome was progression-free survival (PFS), measured as hazard ratios (HRs). The secondary outcomes were objective response rate and overall survival, expressed as relative risks and HRs, respectively.

Results  Among patients with WT EGFR tumors, chemotherapy was associated with improvement of PFS, compared with TKI (HR for TKI, 1.41; 95% CI, 1.10-1.81). No statistically significant subgroup difference was identified in terms of line of treatment (first-line vs second- or later-line), experimental drug, dominant ethnicity, or EGFR mutation analysis method. Trials using more sensitive platforms than direct sequencing were associated with a significant PFS benefit with chemotherapy (HR for TKI, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy with improvement in PFS was also significant in second- or later-line trials (HR, 1.34; 95% CI, 1.09-1.65). The objective response rate was higher with chemotherapy (92/549, 16.8%, vs 39/540, 7.2%, for TKI; relative risk for TKI, 1.11; 95% CI, 1.02-1.21); however, no statistically significant difference was observed with respect to overall survival (HR for TKI, 1.08; 95% CI, 0.96-1.22).

Conclusions and Relevance  Among patients with advanced NSCLC harboring WT EGFR, conventional chemotherapy, compared with first-generation EGFR TKI, was associated with improvement in PFS but not overall survival.

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Figure 1.
Trial Selection Process

EGFR indicates epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

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Figure 2.
Progression-Free Survival From the 10 Randomized Controlled Trials Comparing EGFR TKI With Chemotherapy

The size of the data markers (squares) corresponds to the weight of the study in the meta-analysis. The treatment effects were calculated with a random-effects model. (Numbers of events when reported are shown in eTable 1 in the Supplement.) EGFR indicates epidermal growth factor receptor; HR, hazard ratio; TKI, tyrosine kinase inhibitor.

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Figure 3.
Relative Risks for Objective Response Rate and Hazard Ratios for Overall Survival From the Trials With Available Data

The size of the data markers (squares) corresponds to the weight of the study in the meta-analysis. The treatment effects were calculated with a random-effects model. (Numbers of events for all groups when reported are shown in eTable 1 in the Supplement.) HR indicates hazard ratio; RR, relative risks; TKI, tyrosine kinase inhibitor.aThe RR was calculated from the nonresponse events of the 2 treatment groups.

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Figure 4.
Subgroup Analyses for Progression-Free Survival According to the Line of Treatment (First vs Second or Later), EGFR TKI Agents, Ethnicity, and EGFR Mutation Analysis Methods for Patients With WT EGFR

The treatment effects were calculated with a random-effects model. EGFR indicates epidermal growth factor receptor; HR, hazard ratio; TKI, tyrosine kinase inhibitor.

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