Cardiovascular adverse events associated with epidermal growth factor receptor tyrosine kinase inhibitors in EGFR- mutated non-small cell lung cancer: systematic review and network meta-analysis

Abstract

Objective: To evaluate the risk of cardiovascular adverse events associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer (NSCLC).

Design: Systematic review and network meta-analysis.

Data sources: PubMed, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and three clinical trial registries, from inception to 20 November 2024.

Study selection: Randomised controlled trials comparing EGFR tyrosine kinase inhibitor monotherapy with placebo or other treatments in patients with EGFR-mutated NSCLC.

Data extraction and synthesis: Pairs of reviewers extracted data and assessed risk of bias. A random effects network meta-analysis using a frequentist approach compared adverse drug reactions across different treatments. Certainty of evidence was evaluated using the confidence in network meta-analysis approach. Pairwise meta-analyses were done to compare the three generations of EGFR tyrosine kinase inhibitors.

Results: The network meta-analysis comprised 89 randomised controlled trials involving 29 813 participants, mean follow-up 2.18 years. Compared with placebo, both first generation (odds ratio 1.51, 95% confidence interval 1.01 to 2.26; high certainty; pooled incidence 3.2%) and third generation EGFR tyrosine kinase inhibitors (2.18, 1.46 to 3.27; high certainty; 9.5%) were associated with increased risks of cardiac adverse events. Among third generation inhibitors, osimertinib (2.53, 1.53 to 4.19; high certainty; 8.9%) and lazertinib (2.84, 1.17 to 6.91; moderate certainty; 2.7%) were associated with cardiac adverse events. Combined therapies, such as antiangiogenesis with erlotinib or gefitinib, were associated with vascular adverse events (high certainty), whereas antiangiogenesis with osimertinib was associated with cardiovascular adverse events (moderate to high certainty). Also, the risk of arrhythmias was significantly higher with third generation inhibitors (3.26, 1.83 to 5.81; high certainty; 7.3%), such as osimertinib alone (3.35, 1.75 to 6.40; high certainty; 6.2%) and in combination with antiangiogenesis. Almonertinib was associated with vascular toxicity. In pairwise meta-analysis, third generation inhibitors were associated with higher risks of any grade and grade ≥3 cardiovascular adverse events compared with first generation inhibitors.

Conclusions: In patients with EGFR-mutated NSCLC, first and third generation EGFR tyrosine kinase inhibitors, as well as combination therapies with antiangiogenesis, were associated with increased risks of cardiovascular adverse events. Risks were significantly higher with third generation compared with first generation inhibitors.

Systematic review registration: PROSPERO CRD42023433003.

Fig 1

Flow chart of study identification, screening, and inclusion. ADRs=adverse drug reactions; EGFR TKI=epidermal growth factor receptor tyrosine kinase inhibitor

Fig 2

Network plots of epidermal growth factor receptor tyrosine kinase inhibitors compared with placebo for cardiovascular adverse drug reactions. Node sizes are proportional to the sample size of each intervention, and line thickness is proportional to the number of trials in the comparison (also indicated by numbers). Shading represents trials with more than two arms. One trial (befotertinib (D-0316) with icotinib (Lu 2023)) did not connect to the network and was not included. COX-2=cyclo-oxygenase-2; DHFR=dihydrofolate reductase; HER3=human epidermal growth factor receptor 3; HGF=hepatocyte growth factor; HMGCR=3-hydroxy-3-methylglutaryl-CoA reductase; IGF-1R=insulin-like growth factor 1 receptor; MET=mesenchymal-epithelial transition factor; MMP=matrix metalloproteinase; PARP=poly (ADP-ribose) polymerase; PD-L1=programmed death-ligand 1

Fig 3

EGFR TKIs compared with placebo for primary outcomes associated with treatments for non-small cell lung cancer. Certainty of evidence was assessed using confidence in network meta-analysis. Treatments that were inferior to standard therapy (ie, point estimates >1 and 95% CI not crossed) were considered inferior (in bold). ADRs=adverse drug reactions; CI=confidence interval; COX-2=cyclo-oxygenase-2; DHFR=dihydrofolate reductase; EGFR TKIs=epidermal growth factor receptor tyrosine kinase inhibitors; HER3=human epidermal growth factor receptor 3; HGF=hepatocyte growth factor; HMGCR=3-hydroxy-3-methylglutaryl-CoA reductase; IGF-1R=insulin-like growth factor 1 receptor; MET=mesenchymal-epithelial transition factor; MMP=matrix metalloproteinase; NA=not applicable; PARP=poly (ADP-ribose) polymerase; PD-L1=programmed death-ligand 1

Fig 4

EGFR TKIs compared with placebo for secondary outcomes associated with treatments for non-small cell lung cancer. Certainty of evidence was assessed using confidence in network meta-analysis. Bold numbers are treatments that were considered inferior to standard therapy (ie, point estimates >1 and 95% CI not crossed). For total hypertension, the result is based on the sensitivity analysis excluding high risk of bias studies, as it yielded more robust findings; results for all other outcomes are based on the main analysis. ADRs=adverse drug reactions; CI=confidence interval; COX-2=cyclo-oxygenase 2; DHFR=dihydrofolate reductase; EGFR TKIs=epidermal growth factor receptor tyrosine kinase inhibitors; HER3=human epidermal growth factor receptor 3; HGF=hepatocyte growth factor; HMGCR=3-hydroxy-3-methylglutaryl-CoA reductase; IGF-1R=insulin-like growth factor 1 receptor; MET=mesenchymal-epithelial transition factor; MMP=matrix metalloproteinase; NA=not applicable; PARP=poly (ADP-ribose) polymerase; PD-L1=programmed death-ligand 1

Fig 5

Forest plots showing cardiovascular ADRs associated with first to third generation EGFR TKIs. ADRs=adverse drug reactions; CI=confidence interval; EGFR TKIs=epidermal growth factor receptor tyrosine kinase inhibitors

Fig 6

Combined heatmaps showing cardiovascular ADRs associated with first to third generation EGFR TKIs. Dark red indicates a higher pooled incidence and dark blue a lower pooled incidence. ADRs=adverse drug reactions; EGFR TKIs=epidermal growth factor receptor tyrosine kinase inhibitors