Risk of treatment-related toxicity from EGFR tyrosine kinase inhibitors: a systematic review and network meta-analysis of randomized clinical trials in EGFR -mutant non-small cell lung cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with -mutation, while their toxicity profiles are non-negligible and inconsistent. This study aimed to assess the toxicity intensity and profiles of different EGFR-TKIs in NSCLC patients with -mutation. This random-effect Bayesian framed network meta-analysis (NMA) only included exclusively randomized clinical trials with demonstrated evidence on safety of EGFR-TKIs in NSCLC patients with EGFR-mutation. Pooled odds ratios and surface under the cumulative ranking curve (SUCRA) were calculated to depict the toxicity map of EGFR-TKIs. This review included 23 randomized clinical trials incorporating 7,006 patients and 11 treatments: erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, furmonertinib, aumolertinib, pemetrexed-free chemotherapy (PfCT), pemetrexed-based chemotherapy (PbCT) and placebo. Overall, chemotherapy and second-generation EGFR-TKIs exhibited higher toxicity. A toxicity sequence according to the likelihood of causing grade ≥3 adverse events (AEs) was identified as follows: PfCT > PbCT > afatinib > dacomitinib > erlotinib > aumolertinib > gefitinib > furmonertinib > osimertinib > placebo > icotinib. For discontinuation due to AEs, among EGFR-TKIs, icotinib and afatinib demonstrated best and second-best safety profiles according to pooled odds ratios and SUCRA. Regarding specific toxicity, EGFR-TKIs demonstrated variable toxicity intensity and different predominate toxicity spectrums. This is the first study to depict the difference in toxicity of EGFR-TKIs in a population with EGFR-mutant NSCLC. In general, osimertinib and icotinib were associated with favorable safety compared with other EGFR-TKIs. Difference in safety between the third-generation EGFR-TKIs was also first investigated comprehensively. Furthermore, this review elaborated the varied predominate spectrum and ranked the toxicity of EGFR-TKIs for providing toxicity rationale for treatment decisions.