Efficacy and safety of adjuvant EGFR TKI alone and in combination with chemotherapy for resected EGFR mutation-positive non-small cell lung cancer: A Bayesian network meta-analysis

Lung cancer is the primary cause of cancer mortality worldwide, accounting for 11.4% of all cancers diagnosed in 2020 and 18.0% of all cancer deaths (Sung et al., 2021), with non-small cell lung cancer (NSCLC) being the most common type. Surgical resection is the primary management for early-stage NSCLC, but occult metastasis and local and/or systemic relapse have been observed in many patients. Even in patients with stage I NSCLC, the recurrence rate is as high as 90% after surgery (Vansteenkiste et al., 2013), and the 5-year survival rate is approximately 80% (Chansky et al., 2017). A significant improvement in patient survival with adjuvant chemotherapy for stage II and IIIA NSCLC was demonstrated by a meta-analysis demonstrating an improvement in the 5-year overall survival (OS) rate from 4% to 5.4% (Pignon et al., 2008, Burdett et al., 2015). The effectiveness of multimodal treatments, including targeted therapy such as tyrosine kinase inhibitor (TKI), immunotherapy such as programmed death-ligand 1 or programmed cell death protein 1 blockade, and antiangiogenic agents, have been explored (Isaacs and Stinchcombe, 2022).

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family, which is composed of EGFR, HER2 (ERBB2), HER3, and HER4 (Pao and Chmielecki, 2010, Baselga and Arteaga, 2005), and is involved in lung cancer growth and proliferation. Mutations in the EGFR gene contribute to the growth and proliferation of lung cancer and are present in 15% of patients with NSCLC in the United States (Poels et al., 2021) and 51.4% of patients in Asia (Shi et al., 2014). EGFR-TKIs improve survival with a high response rate, but many patients eventually acquire resistance to these drugs. Theoretically, adding chemotherapy could postpone resistance; however, the current evidence is conflicting. In advanced NSCLC, evidence has shown that adding chemotherapy to first-generation EGFR-TKIs results in the maximum elongation of patient survival (Noronha et al., 2020, Wu et al., 2021). However, the third-generation EGFR-TKI, osimertinib, combined with chemotherapy, did not perform well. The overall response rate and progression-free survival (PFS) were 53.6% and 14.6 months in the combination group versus 71.4% and 15.8 months in the osimertinib monotherapy group (Tanaka et al., 2021). The combination of chemotherapy and EGFR-TKI also significantly increases the possibility and severity of side effects compared with chemotherapy or EGFR-TKI alone (Noronha et al., 2020, Yu et al., 2014). In stage IB-IIIA EGFR-mutated NSCLC, the European Society for Medical Oncology expert consensus recommends the use of adjuvant osimertinib for a duration of 3 years and the National Comprehensive Cancer Network (NCCN) guidelines recommends adjuvant cytotoxic chemotherapy prior to the application of osimertinib (Passaro et al., 2022, National Comprehensive Cancer Network, 2022). It remains unclear whether EGFR-TKI combined with chemotherapy, compared to EGFR-TKI alone, could improve the survival of patients with EGFR-mutated NSCLC after complete resection.

Here, we performed a literature search and network meta-analysis (NMA) using data from randomised controlled trials (RCTs) and retrospective comparative studies (RCSs) in adjuvant settings to generate comparative efficacy and safety data between EGFR-TKI plus chemotherapy and single-agent EGFR-TKI.

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