Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Combination Therapy as First-Line Treatment for Patients with Advanced EGFR-Mutated, Non-Small Cell Lung Cancer: A Systematic Review and Bayesian Network Meta-Analysis

SIMPLE SUMMARY: As clinical practice lacks direct data for head-to-head comparisons across targeted combination approaches, we performed a Bayesian network meta-analysis to indirectly analyze the efficacy and safety of various combination therapies. A total of 12 modes of combination TKI therapy are compared. We find that radiation combined with EGFR-Tyrosine Kinase Inhibitor (TKI), is superior to other combination treatments in progression free survival (PFS) and overall survival (OS). TKI combined with chemotherapy may improve objective response rate (ORR), PFS, and OS, but may increase grade 3 or higher hematological side events. Combining efficacy and safety, we show that macro-monoclonal antibody antiangiogenic drugs, such as bevacizumab or ramucirumab, may be the ideal combination treatment choice, while the efficacy of small molecule inhibitors, such as apatinib, needs more investigation. Our findings have significant implications for the clinical management of non-small cell lung cancer patients, providing new ideas and evidence for doctors’ decision making, as well as pointing to future research options. ABSTRACT: (1) Background: Several randomized controlled trials (RCTs) have been conducted in combination with Efficacy and Safety of Epidermal Growth Factor Receptor(EGFR)-Tyrosine Kinase Inhibitor (TKI) for the first-line treatment of patients with advanced non-small cell lung cancer; however, head-to-head comparisons of combination therapies are still lacking. Therefore, this study aims to compare the efficacy and safety of various combination treatments. (2) Methods: We conducted a systematic review and Bayesian network meta-analysis by searching MEDLINE, EMBASE, and COCHRANE for relevant RCTs. (3) Results: TKI combined with antiangiogenic therapy, chemotherapy, or radiation achieved a significant benefit compared with TKI alone for progression free survival (PFS). A combination with radiation yielded better benefits in PFS than any other treatment. In terms of overall survival (OS), only the combination with pemetrexed and carboplatin (HR = 0.63, 95% credible interval 0.43–0.86)/radiation (0.44, 0.23–0.83) was superior to TKI alone. All of the combination therapies may increase the incidence of ≥Grade 3 AEs, as the pooled RRs are over 1; different toxicity spectrums were revealed for individual treatments. (4) Conclusions: The TKI combination of radiation/pemetrexed and carboplatin could provide the best antitumor effects among the first generation TKI-based treatments. Considering safety, ramucirumab and bevacizumab may be the ideal additions to TKIs (systematic review registration: PROSPERO CRD42022350474).