Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: The use of combination epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) and immune checkpoint inhibitor (ICI) in EGFR-mutant, advanced non-small cell lung cancer (NSCLC) has raised concerns over the risk of overlapping toxicities. Although a higher proportion of interstitial lung diseases was reported with the combination of osimertinib and durvalumab, the current evidence on the treatment-related adverse events (trAEs) of EGFR-TKI and ICI remains limited to pneumonitis and the use of osimertinib. This systematic review and meta-analysis investigates whether combination EGFR-TKI and ICI increases the incidence of overall and organ-specific trAEs compared to TKI monotherapy. A higher proportion of high-grade organ-specific trAEs was observed in combination TKI and ICI including skin, gastrointestinal adverse events, and interstitial lung diseases. Further prospective studies are warranted to determine the optimal drug of choice of ICI and the best timing of initiation of ICI after failure to prior EGFR-TKI. ABSTRACT: (1) Background: We performed a meta-analysis to examine whether combined epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) and immune checkpoint inhibitor (ICI) increases treatment-related adverse events (trAEs) in advanced non-small cell lung cancer (NSCLC). (2) Methods: Articles from MEDLINE, EMBASE, and Cochrane databases were searched. Proportions and odds ratios (ORs) of the pooled incidence of overall and organ-specific trAEs in combination EGFR-TKI and ICI were compared to TKI monotherapy. (3) Results: Eight studies fulfilled our selection criteria. Any-grade organ-specific trAEs were more common in combination EGFR-TKI and ICI than TKI monotherapy (skin: OR = 1.19, p = 0.012; gastrointestinal tract: OR = 1.04, p = 0.790; ILD: OR = 1.28, p = 0.001). Grade ≥ 3 trAEs were also more frequent in combination treatment (skin: OR = 1.13, p = 0.082; gastrointestinal tract: OR = 1.13, p = 0.076; ILD: OR = 1.16, p = 0.003). (4) Conclusions: A higher proportion of grade ≥3 skin and gastrointestinal trAEs and ILDs was observed in combination TKI and ICI compared to TKI alone. Caution has to be taken when interpreting the results owing to the small number of studies included in this meta-analysis.