The impact of adjuvant EGFR-TKIs and 14-gene molecular assay on stage I non-small cell lung cancer with sensitive EGFR mutations

Abstract

Background: Currently, the role of EGFR-TKIs as adjuvant therapy for stage I, especially IA NSCLC, after surgical resection remains unclear. We aimed to compare the effect of adjuvant EGFR-TKIs with observation in such patients by incorporating an established 14-gene molecular assay for risk stratification.

Methods: This retrospective cohort study was conducted at the First Affiliated Hospital of Guangzhou Medical University (Study ID: ChNCRCRD-2022-GZ01). From March 2013 to February 2019, completely resected stage I NSCLC (8th TNM staging) patients with sensitive EGFR mutation were included. Patients with eligible samples for molecular risk stratification were subjected to the 14-gene prognostic assay. Inverse probability of treatment weighting (IPTW) was employed to minimize imbalances in baseline characteristics.

Findings: A total of 227 stage I NSCLC patients were enrolled, with 55 in EGFR-TKI group and 172 in the observation group. The median duration of follow-up was 78.4 months. After IPTW, the 5-year DFS (HR = 0.30, 95% CI, 0.14-0.67; P = 0.003) and OS (HR = 0.26, 95% CI, 0.07-0.96; P = 0.044) of the EGFR-TKI group were significantly better than the observation group. For subgroup analyses, adjuvant EGFR-TKIs were associated with favorable 5-year DFS rates in both IA (100.0% vs. 84.5%; P = 0.007), and IB group (98.8% vs. 75.3%; P = 0.008). The 14-gene assay was performed in 180 patients. Among intermediate-high-risk patients, EGFR-TKIs were associated with a significant improvement in 5-year DFS rates compared to observation (96.0% vs. 70.5%; P = 0.012), while no difference was found in low-risk patients (100.0% vs. 94.9%; P = 0.360).

Interpretation: Our study suggested that adjuvant EGFR-TKI might improve DFS and OS of stage IA and IB EGFR-mutated NSCLC, and the 14-gene molecular assay could help patients that would benefit the most from treatment.

Funding: This work was supported by China National Science Foundation (82022048, 82373121).

Keywords: Adjuvant therapy; EGFR-TKI; Non–small-cell lung cancer; Risk stratification; Stage I.

Fig. 1

Study profile. Data cutoff on February 28, 2019. Abbreviations: EGFR, epidermal growth factor receptor; IPTW, inverse probability of treatment weighting; N, number; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Fig. 2

Love plots for standardized mean differences comparing covariate values before and after IPTW. Abbreviations: EGFR, epidermal growth factor receptor; ELN, examined lymph node; GGO, ground glass opacity; IPTW, inverse probability of treatment weighting; LVI, lympho-vascular invasion; MPLC, multiple primary lung cancer; VPI, visceral pleural invasion.

Fig. 3

Kaplan–Meier survival analysis for stage I NSCLC patients according to treatment. (A) DFS in stage I NSCLC patients. (B) OS in stage I NSCLC patients. (C) DFS in stage IA NSCLC patients. (D) OS in stage IA NSCLC patients. (E) DFS in stage IB NSCLC patients. (F) OS in stage IB NSCLC patients. The shaded area represents the 95% CI. Abbreviations: CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Fig. 4

Kaplan–Meier survival analysis of the observational cohorts, stratified by the 14-gene assay. (A) DFS in high-, intermediate-, and low-risk stage I NSCLC patients. (B) OS in high-, intermediate-, and low-risk stage I NSCLC patients. (C) DFS in intermediate-high- and low-risk stage I NSCLC patients. (D) OS in intermediate-high- and low-risk stage I NSCLC patients. The shaded area represents the 95% CI. Abbreviations: CI, confidence interval; DFS, disease-free survival; OS, overall survival.

Fig. 5

Association of adjuvant EGFR-TKIs with DFS and OS in stage I NSCLC patients, stratified by the 14-gene assay. (A) DFS in stage I NSCLC patients. (B) OS in stage I NSCLC patients. The shaded area represents the 95% CI. Abbreviations: CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Figure S1

Subgroup analysis for stage I NSCLC, stratified by clinicopathological variables. Each square represents the HR, and the corresponding horizontal line is the 95% CI. Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; ELN, examined lymph node; GGO, ground glass opacity; HR, hazard ratio; MIP, micropapillary; MPLC, multiple primary lung cancer; NA, not applicable; TKI, tyrosine kinase inhibitor.

Figure S2

Proportion and survival outcomes of stage I NSCLC patients with molecular high-, intermediate-, and low-risk. Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Figure S3

Proportion and survival outcomes of stage IA NSCLC patients with molecular high-, intermediate-, and low-risk. Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Figure S4

Proportion and survival outcomes of stage IB NSCLC patients with molecular high-, intermediate-, and low-risk. Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

Figure S5

Adjuvant EGFR-TKIs benefits in stage IA and IB NSCLC patients, stratified by the 14-gene assay. (A) DFS in stage IA NSCLC patients. (B) OS in stage IA NSCLC patients. (C) DFS in stage IB NSCLC patients. (D) OS in stage IB NSCLC patients. The shaded area represents the 95% CI. Abbreviations: CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.