Rational application of EGFR-TKI adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant NSCLC: a systematic review and meta-analysis of 11 randomized controlled trials

Abstract

Purpose: To determine the role and rational application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant non-small-cell lung cancer (NSCLC).

Method: Randomized controlled trials (RCTs) that compared the survival outcomes between adjuvant EGFR-TKIs and adjuvant chemotherapy or a placebo, or between different EGFR-TKI treatment durations for resected NSCLC, were eligible for inclusion. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated as effective measures using random-effect or fixed-effect models. Subgroup analysis was also performed.

Results: Eleven RCTs involving 2102 EGFR-mutant NSCLC patients with or without EGFR-TKI adjuvant therapy were included. For all stage IB-IIIA NSCLC patients, EGFR-TKIs adjuvant therapy could not only significantly improve DFS (HR 0.43, 95% CI 0.30-0.63, P < 0.001) and 2- and 3-year DFS rates, but also improve OS (HR 0.72, 95% CI, 0.54-0.96, P = 0.024), compared with chemotherapy or the placebo. Further subgroup analyses indicated prolonged OS from first-generation EGFR-TKI adjuvant therapy in stage III patients, compared with chemotherapy or the placebo (HR for OS, 0.34; 95% CI, 0.18-0.63; P = 0.001). Of note, osimertinib adjuvant therapy led to the OS benefit expanding from stage III to stage II-III patients, with significantly improved DFS and a lower risk of brain recurrence, compared with the placebo. A 2-year treatment duration with EGFR-TKI adjuvant therapy showed a significantly lower recurrence risk than a ≤ 1-year duration.

Conclusion: The DFS advantage from first-generation EGFR-TKI adjuvant therapy can translate into an OS benefit in stage III NSCLC patients. Osimertinib might be more suitable for adjuvant therapy than first-generation EGFR-TKIs, because of the lower recurrence rate and the potential OS benefit even in early-stage patients. The optimal treatment duration for EGFR-TKIs at different stages of disease needs to be validated.

Keywords: Adjuvant therapy; Epidermal growth factor receptor tyrosine kinase inhibitor; Meta-analysis; Mutation; Non-small-cell lung cancer.

Fig. 1

Overview of the study search and selection

Fig. 2

Effects of adjuvant EGFR-TKI on DFS. Forest plot of the HRs of DFS for adjuvant TKI vs. non-TKI therapy for resected patients with IB-III stage EGFR-mutant NSCLC (A), and for patients with different stages of disease (C); Forest plot of the RRs of the 2, 3, and 5-year DFS rates (B) and brain relapse rates (D) for adjuvant TKI vs. non-TKI therapy in these patients. EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; DFS, disease-free survival; HR, hazard ratio; RR, relative risk; NSCLC, non-small-cell lung cancer

Fig. 3

Effects of adjuvant EGFR-TKI on OS. Forest plot of the HRs of OS for adjuvant TKI vs. non-TKI therapy for resected patients with IB-III stage EGFR-mutant NSCLC (A), for all stage II-III patients (C) and for stage III patients (D); Forest plot of the RRs for the 5-year OS rates (B) between different groups. EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; OS, overall survival; HR, hazard ratio; RR, relative risk; NSCLC, non-small-cell lung cancer

Fig. 4

Forest plot of RRs for the rates of subsequent EGFR-TKI treatment (A) and HRs of DFS for different durations of adjuvant therapy (B) in resected patients with EGFR-mutant NSCLC. RR, relative risk; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; DFS, disease-free survival; HR, hazard ratio; EGFR, epidermal growth factor receptor

Fig. 5

Grade ≥ 3 AEs caused by different EGFR-TKI treatments

Fig. 6

Sensitivity analysis for DFS (A) and OS (B) and publication bias assessment for DFS (C) and OS (D). DFS, disease-free survival; OS, overall survival