Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non–Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials

Zhang, Yaxiong; Zhang, Zhonghan; Huang, Xiao-Dan; Kang, Shiyang; Chen, Gang; Wu, Mei‐Mei; Miao, Siyu; Huang, Yan; Zhao, Hongyun; Zhang, Li

doi:10.1016/j.cllc.2016.09.006

Cited by 17 publications

(13 citation statements)

References 34 publications

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“…To our knowledge, this is the first study that performed an NMA to compare the results between five first-line EGFR-TKIs. Previous NMA studies failed to show significant differences between EGFR-TKIs 22–26. By including additional evidence from new RCTs19,20,40 and updating results in the network, new results were produced, namely significant efficacy differences between the TKIs.…”

Section: Discussionmentioning

confidence: 99%

“…The NMA method enables judicious estimation of the relative treatment effect for comparative effectiveness purposes 21. Previously published NMAs did not show significant differences between EGFR-TKIs 22–26. New data for several (new) TKIs are available (ARCHER1050 and FLAURA trials),19,20 which may lead to new insights into the relative efficacy and toxicity of the EGFR-TKIs.…”

Section: Introductionmentioning

confidence: 99%

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First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis

Holleman¹,

Tinteren²,

Groen³

et al. 2019

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Background EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib have proven efficacy in terms of progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, an overall view for comparing efficacy and toxicity on a meta-level is lacking. This study compared efficacy and toxicity of first-line treatment with five different EGFR-TKIs by conducting a network meta-analysis (NMA). Methods A systematic review was performed, aiming to find eligible literature. Data of PFS, overall survival (OS), objective response rate (ORR), and adverse events were extracted. An NMA based on Bayesian statistics was established to synthesize the efficacy and toxicity of all treatments. Results Thirteen randomized controlled trials, including data from 3,539 patients with EGFR-mutated NSCLC, were analyzed. Rank probabilities showed that osimertinib had a potentially better efficacy in terms of PFS and OS compared to all other TKIs. For ORR, afatinib and osimertinib showed a trend of superiority compared to the other four TKIs. Furthermore, there was a high risk of diarrhea and rash for patients treated with afatinib or dacomitinib as well as a moderate risk for treatment with erlotinib, gefitinib, and osimertinib. Conclusion Our study showed a favorable efficacy of osimertinib in terms of PFS and OS compared to all other EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations. Furthermore, gefitinib, erlotinib, and osimertinib were associated with fewer toxicities compared to the other TKIs. Therefore, osimertinib is indicated as a preferable first-line TKI in patients with activating EGFR-mutated NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis

Holleman¹,

Tinteren²,

Groen³

et al. 2019

OTT

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“…A network meta-analysis compared erlotinib, gefitinib, icotinib, afatinib, and dacomitinib using data from six head-to-head Phase III studies in patients with advanced EGFR mutation-positive NSCLC 60. While the five TKIs were found to have similar therapeutic efficacy in terms of all outcome measures (ORR, disease control rate, 1-year PFS, 1-year OS, and 2-year OS), rank probabilities indicated a preferable therapeutic efficacy for the second-generation TKIs relative to the first-generation TKIs.…”

Section: Clinical Efficacy In Egfr Mutation-positive Advanced Nsclc Pmentioning

confidence: 99%

Second-generation EGFR and ErbB tyrosine kinase inhibitors as first-line treatments for non-small cell lung cancer

Wang¹,

Li²

2019

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The discovery that mutations in the EGFR gene are present in up to 50% of patients with lung adenocarcinoma, and the development of highly efficacious EGFR tyrosine kinase inhibitors (TKIs), has revolutionized the way this common malignancy is treated. Three generations of EGFR TKIs are now approved for use in EGFR mutation-positive non-small cell lung cancer (NSCLC); the first-generation agents erlotinib, gefitinib, and icotinib; the second-generation ErbB family blockers afatinib and dacomitinib; and most recently, osimertinib, a third-generation EGFR TKI. The second-generation agents have demonstrated impressive efficacy relative to both standard platinum-based chemotherapy and first-generation EGFR TKIs, significantly improving response and progression-free and overall survival. Data from real-world studies suggest that afatinib is as effective and well tolerated in routine clinical practice as it is in clinical studies and is effective in patients with certain uncommon EGFR mutations, patients with brain metastases, and older patients. Few real-world data are available for dacomitinib in the first-line setting. Afatinib and dacomitinib have similar safety profiles, with acne/skin dryzness, diarrhea, stomatitis, and paronychia the most common adverse events (AEs) reported in clinical and real-world studies. Numerous studies have shown that tolerability-guided dose reductions can help manage afatinib-related AEs without reducing efficacy. As the number of therapeutic options for advanced NSCLC increases, the optimal choice for first-line treatment will be determined by considering patient factors such as the presence of brain metastases, the type of EGFR mutation, tolerability, and subsequent therapy options for long-term treatment.

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“…Network meta-analysis, which synthesises evidence from direct and indirect comparisons, is therefore needed to determine the best available treatments 14. Previous network meta-analyses have only partly compared treatments for patients with advanced EGFR mutated NSCLC but they have not incorporated recent alternative treatments or available trials and have not been specific enough in regards to accurate treatment profiles for tumours with different subtype mutations 1516 17 18 With a well designed and comparative synthesis, we performed this network meta-analysis of randomised controlled trials to investigate the relative efficacy and safety of all first line treatments in patients with advanced EGFR mutated NSCLC, and then a subgroup analysis by EGFR mutation type (exon 19 deletion and Leu858Arg mutations) to identify the best clinical choice.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis

Zhao

Liu

Cai

et al. 2019

BMJ

131

114

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ObjectiveTo compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).DesignSystematic review and network meta-analysis.Data sourcesPubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019.Eligibility criteria for selecting studiesPublished and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher.Results18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation.ConclusionsThese results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively.Systematic review registrationPROSPERO CRD42018111954.

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Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non–Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials

Cited by 17 publications

References 34 publications

<p>First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis</p>

<p>First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis</p>

<p>Second-generation EGFR and ErbB tyrosine kinase inhibitors as first-line treatments for non-small cell lung cancer</p>

Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis

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