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Meta-Analysis
. 2021 Mar 18;3(3):CD010383.
doi: 10.1002/14651858.CD010383.pub3.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer

Janette Greenhalgh  1 , Angela Boland  1 , Victoria Bates  1 , Fabio Vecchio  1 , Yenal Dundar  1   2 , Marty Chaplin  3 , John A Green  4
Affiliations
Meta-Analysis

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer

Janette Greenhalgh et al. Cochrane Database Syst Rev. .

Abstract

Background: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours.

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 outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life.

Search methods: We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles.

Selection criteria: Parallel-group 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: Twenty-two trials met the inclusion criteria. Ten 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 3023, of whom approximately 2563 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 used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the 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.

Authors' conclusions: Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.

PubMed Disclaimer

Conflict of interest statement

Janette Greenhalgh: none known

Angela Boland: none known

Victoria Bates: none known

Fabio Vecchio: none known

Yenal Dundar: none known

Marty Chaplin: none known

John A Green: none known

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
1.1
1.1. Analysis
Comparison 1: Erlotinib versus CTX, Outcome 1: Overall survival
1.2
1.2. Analysis
Comparison 1: Erlotinib versus CTX, Outcome 2: Progression‐free survival
1.3
1.3. Analysis
Comparison 1: Erlotinib versus CTX, Outcome 3: Tumour response
2.1
2.1. Analysis
Comparison 2: Erlotinib plus CTX versus CTX, Outcome 1: Overall survival
2.2
2.2. Analysis
Comparison 2: Erlotinib plus CTX versus CTX, Outcome 2: Progression‐free survival
2.3
2.3. Analysis
Comparison 2: Erlotinib plus CTX versus CTX, Outcome 3: Tumour response
3.1
3.1. Analysis
Comparison 3: Gefitinib versus CTX, Outcome 1: Overall survival
3.2
3.2. Analysis
Comparison 3: Gefitinib versus CTX, Outcome 2: Progression‐free survival
3.3
3.3. Analysis
Comparison 3: Gefitinib versus CTX, Outcome 3: Tumour response
4.1
4.1. Analysis
Comparison 4: Gefitinib plus CTX versus CTX, Outcome 1: Overall survival
4.2
4.2. Analysis
Comparison 4: Gefitinib plus CTX versus CTX, Outcome 2: Progression‐free survival
4.3
4.3. Analysis
Comparison 4: Gefitinib plus CTX versus CTX, Outcome 3: Tumour response
5.1
5.1. Analysis
Comparison 5: Afatinib versus CTX, Outcome 1: Overall survival
5.2
5.2. Analysis
Comparison 5: Afatinib versus CTX, Outcome 2: Progression‐free survival
5.3
5.3. Analysis
Comparison 5: Afatinib versus CTX, Outcome 3: Tumour response
6.1
6.1. Analysis
Comparison 6: Cetuximab plus CTX versus CTX, Outcome 1: Overall survival
6.2
6.2. Analysis
Comparison 6: Cetuximab plus CTX versus CTX, Outcome 2: Progression‐free survival
6.3
6.3. Analysis
Comparison 6: Cetuximab plus CTX versus CTX, Outcome 3: Tumour response
7.1
7.1. Analysis
Comparison 7: Icotinib versus CTX, Outcome 1: Overall survival
7.2
7.2. Analysis
Comparison 7: Icotinib versus CTX, Outcome 2: Progression‐free survival
See this image and copyright information in PMC

Update of

References

References to studies included in this review

BMSO99 {published data only}
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CHEN {published data only}
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CONVINCE {published data only}
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ENSURE {published data only}
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EURTAC {published and unpublished data}
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FASTACT 2 {published data only}
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First‐SIGNAL {published data only}
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FLEX {published data only}
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GTOWG {published data only}
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Han 2017 {published data only}
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INTACT 1 {published data only}
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INTACT 2 {published data only}
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IPASS {published data only (unpublished sought but not used)}
    1. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia (IPASS). Journal of Clinical Oncology 2011;29(21):2866-74. - PubMed
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LUX‐Lung 3 {published data only}
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LUX‐Lung 6 {published data only}
    1. Geater SL, Xu C-R, Zhou C, Hu C-P, Feng J, Lu S, et al. Symptom and quality of life improvement in LUX-Lung 6: an open-label phase III study of afatinib versus cisplatin/gemcitabine in Asian patients with EGFR mutation-positive advanced non–small-cell lung cancer. Journal of Thoracic Oncology 2015;10(6):883-9. - PubMed
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NEJSG {published and unpublished data}
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OPTIMAL {published and unpublished data}
    1. Chen G, Feng JF, Zhou C, Wu Y-L, Liu XQ, Wang C, et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Annals Oncology 2013;24(6):1615-22. - PubMed
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Patil 2017 {published data only}
    1. Patil VM, Noronha V, Joshi A, Choughule AB, Bhattacharjee A, Kumar R, et al. Phase III study of gefitinib or pemetrexed with carboplatin in EGFR mutated advanced lung adenocarcinoma. European Society for Medical Oncology Open 2017;2:e000168. - PMC - PubMed
TOPICAL {published data only}
    1. Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al. First-line erlotinib in patients with advanced non-small cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled phase III trial. Lancet Oncology 2012;13(11):1161-70. - PMC - PubMed
TORCH {published data only}
    1. Di Maio M, Leighl NB, Gallo C, Feld R, Ciardiello F, Butts C, et al. Quality of life analysis of TORCH, a randomized trial testing first-line erlotinib followed by second-line cisplatin/gemcitabine chemotherapy in advanced non–small cell lung cancer. Journal of Thoracic Oncology 2012;7(12):1830-44. - PubMed
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WJTOG3405 {published data only}
    1. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, et al. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR). Journal of Clinical Oncology 2012;30(15 (S1)):7521.
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Yu 2014 {published data only}
    1. Yu H, Zhang J, Wu X, Luo Z, Wang H, Sun S, et al. A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer. Cancer Biology & Therapy 2014;15(7):832-9. - PMC - PubMed

References to studies excluded from this review

Boutsikou 2013 {published data only}
    1. Boutsikou E, Kontakiotis T, Zarogoulidis P, Darwiche K, Eleptheriadou E, Porpodis K, et al. Docetaxel-carboplatin in combination with erlotinib and/or bevacizumab in patients with non-small cell lung cancer. OncoTargets and Therapy 2013;6:125-34. - PMC - PubMed
Crino 2008 {published data only}
    1. Crinò L, Cappuzzo F, Zatloukal P, Reck M, Pesek M, Thompson JC, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study. Journal of Clinical Oncology 2008;26(26):4253-60. - PubMed
ECOG 4508 {published data only}
    1. Aggarwal C, Dahlberg S, Hanna E, Kolesar N, Hirsch FR, Duresh S, et al. Exploratory biomarker analyses from ECOG 4508: three-arm randomized phase II study of carboplatin (C) and paclitaxel (P) in combination with cetuximab (CET), IMC-A12, or both for advanced non-small cell lung cancer (NSCLC) patients (pts). Journal of Clinical Oncology 2013;31(15 (S1)):8106.
FASTACT {published data only}
    1. Mok TSK, Wu Y-L, Yu C-J, Zhou C, Chen YM, Zhang L, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non–small-cell lung cancer. Journal of Clinical Oncology 2009;27(30):5080-7. - PubMed
Gatzemeier 2003 {published data only}
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Goss 2009 {published data only}
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JO25567 {published data only}
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NEJ005 2014 {published data only}
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Rosell 2004 {published data only}
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Rosell 2008 {published data only}
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White {published data only}
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References to studies awaiting assessment

TALENT {published data only (unpublished sought but not used)}
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TRIBUTE {published data only}
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References to other published versions of this review

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MeSH terms