Rational Application of First-Line EGFR-TKIs Combined with Antiangiogenic Inhibitors in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Abstract

Purpose. A meta-analysis of randomized controlled trials (RCTs) was conducted to compare the difference in efficacy and safety between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with antiangiogenic inhibitors ( A + T ) and EGFR-TKI monotherapy in patients with treatment-naïve advanced EGFR-mutant non-small-cell lung cancer (NSCLC). Methods. PubMed, Embase, Web of Science, and Cochrane electronic databases were searched for relevant RCTs. Meeting abstracts were also reviewed to identify appropriate studies. The endpoints included progression-free survival (PFS), overall survival (OS), 1- and 2-year OS rates, objective response rate (ORR), and grade ≥ 3 adverse events. All pooled outcomes were expressed using hazard ratios (HRs) or relative risk ratios (RRs). Results. Data were collected from six eligible RCTs, which included 1,244 participants (619 in the A + T group and 625 in the TKI alone group). PFS was significantly improved with A + T compared to TKI alone ( HR = 0.60 ; P < 0.01 ) regardless of EGFR mutation types (exon 19 deletion or L858R) and brain metastasis status (with or without brain metastases). There was no significant difference in median OS between the A + T and TKI alone groups ( HR = 0.933 ; P = 0.551 ) regardless of EGFR mutation type. The ORR for A + T combination therapy was significantly increased compared to TKI monotherapy in exon 19 deletion subgroups ( RR = 0.774 ; P = 0.008 ). There was no difference in the positive rates of acquired T790M mutation between the two groups ( RR = 0.967 ; P = 0.846 ). More patients in the TKI alone group received a variety of subsequent systemic treatments than those in the A + T group ( RR = 0.881 ; P = 0.002 ). Conclusion. Addition of antiangiogenic inhibitors to first-line EGFR-TKI therapy significantly reduced the risk of disease progression for patients with advanced EGFR-mutant NSCLC regardless of EGFR mutation type and brain metastasis status. The lack of OS benefit may be explained by differences in subsequent treatments rather than drug resistance mechanisms.

Efficacy and safety of bevacizumab biosimilar compared with reference bevacizumab in locally advanced and advanced non-small cell lung cancer patients: A retrospective study

“…Among these treatments, approximately 80% of other targeted therapies are EGFR–TKI. Preclinical studies have shown that VEGF and EGFR share a common downstream signaling pathway ( 25 – 28 ), but the clinical trial data of EGFR–TKI combined with bevacizumab are still immature and have many uncertainties ( 29 ). Our study confirmed the benefits of bevacizumab (or bevacizumab biosimilar) combined with EGFR–TKI in ORR and PFS but failed to obtain OS results for all patients because of the short follow-up period.…”

Effectiveness and safety of the bevacizumab and erlotinib combination versus erlotinib alone in EGFR mutant metastatic non-small-cell lung cancer: systematic review and meta-analysis

“…Another statistically significant result was ORR which was higher with the bevacizumab-erlotinib combination (RR = 0.79; 95% CI, 0.64-0.97, p = 0.03). However, higher ORR has not been replicated in all meta-analysis, probably because of heterogeneity (31,(35)(36)(37)(38)(39)(40) . Our analysis only included clinical trials where the combination of bevacizumab and erlotinib was used to maintain a homogeneous population (I 2 = 0%, p = 0.66).…”

Comparison of the Efficacy of EGFR-TKIs Combined with Antiangiogenic Agents between Patients with Exon 19 Deletion and Patients with Exon 21 Leu858 Arg Mutation: A Systematic Review and Meta-Analysis

“…To improve PFS, TKIs combined with antiangiogenic agents have been investigated. Several trials have suggested that the addition of antiangiogenic agents to TKIs signi cantly reduces the risk of disease progression [11][12][13][14][15][16][17][18][19][20][21].…”