Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis

Abstract

Antiangiogenic agents plus epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are a potentially effective treatment but with some controversy. Our meta-analysis suggests that the combination might yield better progression-free survival outcomes in treatment-naïve EGFR-mutant nonesmall-cell lung cancer but with a greater risk of serious adverse events. No significant benefits in overall survival or overall response rate were found between the 2 treatments. Background: Antiangiogenic agents combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered potentially effective biologically synergistic drug combinations for EGFR-mutant advanced nonesmall-cell lung cancer (NSCLC), although some controversy remains. The European Commission has approved the use of bevacizumab plus erlotinib as first-line treatment of EGFR-mutated NSCLC; however, it has not yet been approved by the U.S. Food and Drug Administration. Recently, several phase III, randomized controlled trials of combinations of antiangiogenic agents and EGFR-TKIs have been reported. These studies have not yet been included in any previous meta-analysis. Materials and Methods: We performed a meta-analysis to compare antiangiogenic agents plus EGFR-TKIs versus EGFR-TKIs alone for treatment of EGFR-mutant NSCLC. The main outcomes were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), and adverse events (AEs). Results: We identified 9 previous reports of 6 randomized controlled trials and 1 prospective cohort study, involving 1295 patients. Compared with EGFR-TKIs alone, antiangiogenic agents plus EGFR-TKIs resulted in a higher PFS (hazard ratio, 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001). However, no significant differences in OS (hazard ratio, 0.79; 95% CI, 0.53-1.18; P ¼ .26) and ORR (risk ratio, 1.03; 95% CI, 0.97-1.10; P ¼ .30) were found between the 2 groups. An increased risk of serious AEs (risk ratio, 1.41; 95% CI, 1.11-1.79; P ¼ .005) was found in the combination drug therapy group. Conclusions: Antiangiogenic agents plus EGFR-TKIs enhanced PFS for patients with EGFR-mutant NSCLC but with a greater risk of serious AEs. No significant benefits for OS and ORR were found between the 2 groups.

RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non–Small Cell Lung Cancer

“…Interestingly, a consistent PFS benefit between ex19del and ex21L858R groups has also been reported in patients receiving erlotinib and bevacizumab ( Table 1 ; refs. 16–18 ), and meta-analyses of EGFR-TKI and antiangiogenic agent combinations ( 26, 27 ), suggesting that addition of an antiangiogenic agent appears to abrogate the differential efficacy observed in ex21L858R compared with ex19del patients when treated with EGFR-TKI monotherapy. Unfortunately, a comprehensive understanding of the underlying biological mechanisms that could support the clinical observations with ex19del and ex21L858R mutations is currently lacking, and so it is unknown if this is related to dual EGFR/VEGF pathway inhibition.…”

Comparison of the profiles of first-line PD-1/PD-L1 inhibitors for advanced NSCLC lacking driver gene mutations: a systematic review and Bayesian network meta-analysis

“…47 Further clinical researches confirmed the PFS, OS, and ORR benefits of bevacizumab in combination with chemotherapy or targeted therapy. [48][49][50][51] Apart from the well-known angiogenesis effect, VEGF was demonstrated to play an immunomodulatory role in several steps of cancer immunity circle. [52][53][54] First, by inhibiting the maturation from dendritic cells into antigen-presenting cells, tumor-derived VEGF interfered with the identification and capture of tumor neoantigens, which is the critical first step of cell immunity.…”

The benefit of anti-angiogenic therapy in EGFR exon 21 L858R mutant non-small cell lung cancer patients: a retrospective study

“…No survival data by mutation subtype was revealed in the follow-up of the trial. Several meta-analyses had been done to confirm the rationale of this A + T combination 22 – 24 , however, there has not been a study that succeeded in showing an OS benefit for the A + T combo. The lack of an OS benefit might be explained by the prolonged survival of EGFR mutant patients.…”