A comprehensive comparison of third generation epidermal growth factor receptor tyrosine kinase inhibitors in the treatment efficacy and adverse events: A Bayesian meta-analysis

Abstract

Background: It is a challenge for clinicians to choose the optimal third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment for individual patients. In this meta-analysis we compare the efficacy of five third-generation EGFR-TKIs, as first-line and second-line therapies for non-small cell lung cancer (NSCLC) patients, and their adverse events (AEs).

Methods: A Bayesian hierarchical network meta-analysis was conducted to evaluate the hazard ratios (HR) of first-line therapeutic effects and AEs for these third-generation EGFR-TKIs comparing with first-generation EGFR-TKIs. Additionally, a simple comparison analysis was conducted to evaluate second-line therapeutic effects.

Results: All third-generation TKIs exhibited superior efficacy compared to Gefitinib in first-line treatment. Furmonertinib achieved the lowest HR in the exon 19 deletions subgroup (HR: 0.35; 95 % CI: 0.23-0.54), while Lazertinib showed the most favorable HR in the exon 21 L858R subgroup (HR: 0.44; 95 % CI: 0.28-0.70) and among patients with brain metastases (HR: 0.33; 95 % CI 0.18-0.59). In the second-line setting, Furmonertinib achieved the highest numerically objective response rate across the overall population (74.0 %; 95 % CI: 68.0-80.0 %) and all evaluated subgroups. Adverse event analysis showed that Furmonertinib had the lowest overall AE incidence, and Lazertinib had the lowest rate of high-grade (≥ grade 3) AEs.

Conclusions: All third-generation EGFR-TKIs exhibited favorable efficacy in both first- and second-line settings. Differences in AE profiles were also noted.

Keywords: Adverse events; EGFR mutations; Efficacy; Non-small cell lung cancer; Third-generation TKIs.

Graphical abstract

Fig. 1

Study selection and flowchart of the included clinical trials.

Fig. 2

Network meta-analysis results of first-line therapeutic effect of third generation EGFR-TKIs using fixed-effect models on (a) whole patients (or total population), (b) patients with EGFR exon 19 deletion, (c) patients with EGFR exon 21 L858R, and (d) patients with brain metastasis, and using the random-effect model for four subgroups (e∼h).

Fig. 3

Results of simple comparison analysis for second-line therapeutic effecs of third-generation TKIs. (A) Line plot of reported ORR (%) in total patients and three different subgroups. (B) Forest plot of reported PFS (months) with 95 % confidence interval and line plot of the negative logarithm of p-values by t-test (red line) for each drug compared with pemetrexed/platin chemotherapy. The p-values were transformed by -log₁₀₀₀(·)to fit the scale.

Fig. 4

Result of analysis of adverse events. (A) Radar plots of the incidence rates of all 27 adverse effects of interest. The six plots in the first row represent all-grade adverse effects (AE), and those in the second row are the corresponding plots for ≥ 3 AEs. (B) Radar plots for five SAEs of interest. Oral mucosal AEs includes mouth ulceration and stomatitis. SAE: serious adverse effect. 1st-G TKI: first-generation EGFR-TKIs.