The role of adjuvant EGFR-TKIs for completely resected EGFR-mutant non-small cell lung cancer in an era of chemotherapy: An updated systematic review and meta-analysis.
Authors: Qarqash Aref Ayman , Araiqat Bashar , Awad Baha , Aloqaily Ammar , Bani Mostafa Ayah Amjad , Husenat Maram , Atallah Micheal , Al-Horani Sami 
Published: June 2022

e20501 Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Previous meta-analyses explored the possible benefit of adjuvant EGFR-TKIs compared to chemotherapy for patients with completely resected non-small-cell lung cancer (NSCLC). In this meta-analysis, we present the most up-to-date efficacy and safety comparison of adjuvant tyrosine kinase inhibitors (TKIs) and adjuvant chemotherapy for those patients. Methods: We conducted a systematic review using PubMed, Scopus, and Cochrane CENTRAL databases up to January 2022. All randomized clinical trials (RCTs) comparing TKIs as a monotherapy or as a combination with chemotherapy against placebo or chemotherapy in a completely resected EGFR-mutant NSCLC adjuvant setting were included. Studies with ten or fewer patients in either arms were excluded. The primary outcomes were disease-free survival (DFS) and overall survival (OS) with a reported hazard ratio (HR), while adverse events (AEs) were the secondary outcome. Random or fixed-effects meta-analyses were performed based on heterogeneity. Results: A total of eight eligible RCTs of 1752 EGFR-mutant completely resected NSCLC patients were included in this meta-analysis. Six studies involved EGFR-TKIs as monotherapy (n = 1653) whereas two studies involved a combination of EGFR-TKIs with chemotherapy (n = 99). The DFS in the TKIs monotherapy group was significantly improved when compared to chemotherapy (HR = 0.48, 95% CI: 0.29-0.80; p = 0.005), but insignificantly when compared to placebo (HR = 0.34, 95% CI: 0.12-1.02; p = 0.06), with an overall HR of 0.42 (95% CI: 0.25-0.71; p = 0.001), while the OS difference was not of statistical significance (HR = 0.91, 95% CI: 0.70-1.17; p = 0.44). No difference in DFS was found when comparing between the Exon-19 deletion and L858R mutation types (p = 0.37). No subgroup difference in DFS was found as well between TKIs monotherapy and combination therapy when both were compared to chemotherapy (p = 0.45). Grade ≥ 3 AEs were significantly less common in the TKIs group compared to chemotherapy (OR = 0.12, 95% CI:0.06-0.24; p < 0.001). Grade 3/4 rash, diarrhea, and infections were more common in the TKIs group (3.6% vs 0.0%, 2.1% vs 0.7%, and 1.7% vs 0.0%, respectively), while chemotherapy had a higher hematological involvement in terms of grade 3/4 neutropenia, leukopenia, and anemia (44.9% vs 0.2%, 25.2% vs 0.0%, and 5.8% vs 0.1%, respectively). Conclusions: The use of TKIs as adjuvant therapy in completely resected EGFR-mutant NSCLC significantly improves the DFS compared to chemotherapy, regardless of the mutation type, and with a better AEs profile as well, but does not affect the OS. Furthermore, The combination of TKIs and chemotherapy did not demonstrate a difference in DFS when compared to TKIs alone, however, prospective trials comparing both arms are needed to confirm this finding.