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Meta-Analysis
. 2015 Mar;20(3):307-15.
doi: 10.1634/theoncologist.2014-0285. Epub 2015 Feb 5.

The role of smoking status on the progression-free survival of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor versus platinum doublet chemotherapy: a meta-analysis of prospective randomized trials

Yoshikazu Hasegawa  1 , Masahiko Ando  2 , Makoto Maemondo  1 , Satomi Yamamoto  1 , Shun-Ichi Isa  1 , Hideo Saka  1 , Akihito Kubo  1 , Tomoya Kawaguchi  1 , Minoru Takada  1 , Rafael Rosell  1 , Takayasu Kurata  1 , Sai-Hong Ignatius Ou  2
Affiliations
Meta-Analysis

The role of smoking status on the progression-free survival of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor versus platinum doublet chemotherapy: a meta-analysis of prospective randomized trials

Yoshikazu Hasegawa et al. Oncologist. 2015 Mar.

Abstract
in English, Chinese

Background: Univariate analyses from several randomized phase III trials seemed to suggest ever-smokers with advanced mutated epidermal growth factor receptor (EGFRm) non-small cell lung cancer (NSCLC) did not seem to benefit from EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment when compared with platinum-doublet chemotherapy as measured by progression-free survival (PFS).

Methods: A literature-based meta-analysis of PFS outcomes as measured by log-transformed pooled hazard ratio (HR) was performed using a random-effect model. Pooled HRs for smoking status, age, gender, ethnicity, type of EGFR mutation, and EGFR TKI were obtained. Comparison of the pooled HR was performed by metaregression analysis.

Results: Among the 1,649 EGFRm NSCLC patients analyzed from 7 prospective randomized trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, LUX Lung-3, LUX Lung-6, and ENSURE), 83.7% were Asians, and 30.0% were ever-smokers. An equal percentage of ever-smokers received doublet chemotherapy (30.2%) or EGFR TKI (30.0%). The pooled HR for PFS was 0.29 (95% confidence interval [CI]: 0.21-0.39) for never-smokers and 0.54 (95% CI: 0.38-0.76) for ever-smokers (p < .007 by metaregression). The pooled PFS HR for exon 19 deletion was 0.25 (95% CI: 0.19-0.31) and 0.44 for exon 21 substitution (95% CI: 0.34-0.57) (p < .001 by metaregression analysis). The pooled PFS HR was 0.33 (95% CI: 0.24-0.46) for Asians and 0.48 for non-Asians (95% CI: 0.28-0.84) (p = .261 by metaregression analysis).

Conclusion: EGFRm NSCLC patients derived significant PFS benefit from TKI over platinum-doublet chemotherapy as first-line treatment regardless of smoking status; however, PFS benefit is significantly better in never-smokers by metaregression analysis.

摘要

背景。来自几项 III 期随机试验的单变量分析似乎提示：通过无进展生存期 (PFS) 进行测量，与铂类双药化疗相比时，患有表皮生长因子受体突变 (EGFRm) 晚期非小细胞肺癌 (NSCLC) 的过去吸烟者似乎未从一线EGFR 酪氨酸激酶抑制剂 (TKI) 治疗中获益。

方法。使用随机效应模型，基于文献对通过对数转换汇总风险比 (HR) 所测量的 PFS 转归进行meta分析。获得了吸烟状态、年龄、性别、种族、EGFR 突变类型和 EGFR TKI 的汇总 HR。通过meta回归分析比较汇总的 HR。

结果。从 7 项前瞻性随机试验（WJTOG3405、NEJ002、EURTAC、OPTIMAL、LUX Lung-3、LUX Lung-6 和 ENSURE）分析的 1 649 名 EGFRm NSCLC 患者当中，83.7% 患者是亚裔，并且 30.0% 患者是过去吸烟者。相等百分数的过去吸烟者接受双药化疗 (30.2%) 或 EGFR TKI (30.0%)。对于从不吸烟者，PFS 的汇总 HR 是 0.29 [95% 置信区间（ CI）：0.21–0.39]，而对于过去吸烟者，是 0.54（95% CI：0.38-0.76）（通过meta回归分析，p < 0.007)。对于外显子 19 缺失，PFS 的汇总 HR 是 0.25（95% CI：0.19-0.31），而对于外显子 21 置换，是 0.44（95% CI：0.34-0.57）（通过meta回归分析，p < 0.001）。对于亚裔，PFS 的汇总 HR 是 0.33（95% CI：0.24-0.46），而对于非亚裔是 0.48 （95% CI：0.28-0.84）（通过meta回归分析，p = 0.261）。

结论。EGFRm NSCLC 患者无论吸烟状态如何，从一线 TKI 治疗的 PFS 获益优于铂类双药化疗；然而，meta 回归分析显示，PFS 获益在从不吸烟者中明显更好。The Oncologist 2015; 20:307–315

Keywords: Afatinib; EGFR TKIs; EGFR mutant non-small cell lung cancer; Erlotinib; Gefitinib; Meta-analysis; Smoking status.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
Trial selection process. Abbreviations: EGFR, epidermal growth factor receptor; EGFRm, mutated EGFR; TKI, tyrosine kinase inhibitor.
Figure 2.
Figure 2.
Pooled hazard ratios (HRs) and metaregression analysis of pooled HRs of EGFR TKI compared with platinum-doublet chemotherapy. (A): HRs and metaregression analysis according to smoking status. (B): HRs and metaregression analysis according to two common types of EGFR mutation. (C): HRs and metaregression analysis according to ethnicity. (D): HRs and metaregression analysis according to age. (E): HRs and metaregression analysis according to gender. (F): HRs and metaregression analysis according to type of EGFR TKI. Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
Figure 2.
Figure 2.
Pooled hazard ratios (HRs) and metaregression analysis of pooled HRs of EGFR TKI compared with platinum-doublet chemotherapy. (A): HRs and metaregression analysis according to smoking status. (B): HRs and metaregression analysis according to two common types of EGFR mutation. (C): HRs and metaregression analysis according to ethnicity. (D): HRs and metaregression analysis according to age. (E): HRs and metaregression analysis according to gender. (F): HRs and metaregression analysis according to type of EGFR TKI. Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
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