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Review
. 2024 Mar 18;16(6):1188.
doi: 10.3390/cancers16061188.

Investigating the Efficacy of EGFR-TKIs and Anti-VEGFR Combination in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Prashant Sakharkar  1 , Sonali Kurup  2 , Subrata Deb  1 , Kaitlin Assaad  2 , Dayna Gesinski  2 , Erysa J Gayle  3
Affiliations
Review

Investigating the Efficacy of EGFR-TKIs and Anti-VEGFR Combination in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Prashant Sakharkar et al. Cancers (Basel). .

Abstract

Introduction: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with anti-vascular endothelial growth factor receptor (VEGFR) agents have shown improved survival outcomes in recent studies. However, its efficacy related to survival outcomes as a first- or second-line agent and based on generations remains to be explored. This study estimated the survival outcomes of EGFR-TKIs plus anti-VEGFR in combination in defined populations of advanced non-small cell lung cancer (NSCLC) patients overall, as a first- or second line of treatment, with different generations of EGFR-TKIs and EGFR-TKIs plus bevacizumab combination as a subgroup.

Methods: A literature search was conducted using PubMed, SCOPUS, Cochrane Library, and ClinicalTrials.gov databases through June 2023 to identify primary research reporting the survival outcomes of EGFR-TKIs in combination with anti-VEGFR agents in patients with advanced NSCLC. Studies that were single-arm, published in non-English languages, and had missing data on survival outcomes were excluded. A meta-analysis was conducted to generate pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS). Methodological quality and risk of bias in studies were assessed using the Cochrane Handbook for Systematic Reviews of Interventions risk of bias tool.

Results: A total of 20 randomized controlled trials were included in the qualitative synthesis, and 11 (2182 participants) were included in the meta-analysis. Patients' median age ranged from 58 to 68 years; 36% to 70% of patients were female; most of them had IIIa/b to IV stage cancer. In meta-analyses, the EGFR-TKIs plus anti-VEGFR combination resulted in improved PFS (HR, 0.73; 95% CI: 0.61, 0.86; p < 0.00001) in patients with advanced NSCLC but had no impact on OS (HR, 0.93; 95% CI: 0.79, 1.10; p = 0.41). The first line of treatment and first-generation EGFR-TKIs with the combination also improved the PFS (HR, 0.64; 95% CI: 0.57, 0.71; p < 0.00001; HR, 0.63; 95% CI: 0.56, 0.71; p < 0.00001) respectively, however, had no impact on OS.

Conclusions: Our meta-analysis indicated EGFR-TKIs with anti-VEGFR in combination not only improved overall PFS but also showed similar results to a first line and first-generation agent compared to EGFR-TKI alone.

Keywords: EGFR-TKIs; NSCLC; anti-VEGFR; bevacizumab; epidermal growth factor receptor; epidermal growth factor receptor tyrosine kinase inhibitors; erlotinib; non-small cell lung cancer; tyrosine kinase inhibitors; vascular endothelial epidermal growth factor receptor.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart of search and the eligible studies included in this meta-analysis.
Figure 2
Figure 2
(a) Graphical representation of the risk of bias assessment [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]. (b) Summary of the risk of bias assessment.
Figure 3
Figure 3
Meta-analysis showing the change in PFS between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: random-effects model [19,20,21,23,24,27,29,32,33,34,38]. PFS: Progression Free survival; EGFR-TKIs = Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
Figure 4
Figure 4
(A) Meta-analysis of subgroups showing change in PFS as a first line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,21,23,24,29,32,33,34]. (B) Meta-analysis of subgroups showing the change in PFS as a second line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: random-effects model [27,38]. (C) Meta-analysis of subgroups showing the change in PFS as a first generation (erlotinib and gefitinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,21,23,24,29,32,34]. (D) Meta-analysis of subgroups showing the change in PFS as a third generation (osimertinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [27,33,38]. PFS: Progression Free survival; EGFR-TKIs = Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
Figure 4
Figure 4
(A) Meta-analysis of subgroups showing change in PFS as a first line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,21,23,24,29,32,33,34]. (B) Meta-analysis of subgroups showing the change in PFS as a second line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: random-effects model [27,38]. (C) Meta-analysis of subgroups showing the change in PFS as a first generation (erlotinib and gefitinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,21,23,24,29,32,34]. (D) Meta-analysis of subgroups showing the change in PFS as a third generation (osimertinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [27,33,38]. PFS: Progression Free survival; EGFR-TKIs = Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
Figure 5
Figure 5
Meta-analysis showing the change in OS between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,23,24,27,29,35,38]. PFS: Progression Free survival; EGFR-TKIs = Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
Figure 6
Figure 6
(A) Meta-analysis of subgroups showing the change in OS as a first line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,23,24,29,35]. (B) Meta-analysis of subgroups showing the change in OS as a second line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [27,38]. (C) Meta-analysis of subgroups showing the change in OS as a first generation (erlotinib and gefitinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,23,24,29,35]. (D) Meta-analysis of subgroups showing the change in OS as a third generation (Osimertinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [27,38]. OS: Overall survival; EGFR-TKIs= Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
Figure 7
Figure 7
Meta-analysis showing the change in ORR between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,21,22,24,27,29,32,33,34,38]. PFS: Progression Free survival; EGFR-TKIs = Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
Figure 8
Figure 8
(A). Meta-analysis of subgroups showing the change in ORR as a first line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effect model [19,20,21,22,24,29,32,33,34]. (B) Meta-analysis of subgroups showing the change in ORR as a second line of treatment between EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [27,38]. (C) Meta-analysis of subgroups showing the change in ORR as a first generation (erlotinib and gefitinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [19,20,21,22,24,29,32,34]. (D) Meta-analysis of subgroups showing the change in ORR as a third generation (Osimertinib) of EGFR-TKIs + Anti-VEGFR and EGFR-TKIs: fixed-effects model [27,33,38]. ORR: Objective Response Ratel; EGFR-TKIs = Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors; Anti-VEGFR: Anti-Vascular Endothelial Growth Factor Receptor; SE: Standard Error; df: degrees of freedom; CI: Confidence Interval.
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