Early stereotactic body radiation therapy improves progression-free survival of first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated lung cancer: an observational cohort study

Abstract

Background: Stereotactic body radiation therapy (SBRT) in treating non-small-cell lung cancer (NSCLC) exhibits a remarkable therapeutic efficacy. However, its effectiveness in overcoming resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced EGFR mutations (EGFRm) NSCLC remains uncertain.

Objective: We aimed to analyze the effect of SBRT on patients with first-line EGFR-TKIs.

Design and methods: Eligible patients with advanced NSCLC initially diagnosed with EGFRm were enrolled. Patients in the EGFR-TKIs group received only the first-generation EGFR-TKIs until disease progression or death, while the others in the EGFR-TKIs + SBRT group received EGFR-TKIs and early SBRT (dose of 40-60 Gy/5-8 F) targeting the primary lung tumor at 1 month after EGFR-TKIs. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were treatment-related adverse effects, overall survival (OS), and sites of initial failure.

Results: A total of 184 advanced NSCLC patients with EGFRm were enrolled, including 39 patients in the EGFR-TKIs + SBRT group and 145 patients in the EGFR-TKIs group. The median PFS was 15.50 months in the EGFR-TKIs + SBRT group compared to 9.33 months in the EGFR-TKIs group (p = 0.0020). However, the median OS was 29.10 months in the EGFR-TKIs + SBRT group and 26.33 months in the EGFR-TKIs group, with no significant difference observed (p = 0.22). SBRT is an independent positive prognostic factor for PFS in advanced EGFRm NSCLC. EGFR exon 19 deletion mutation (16.33 vs 11.55 months, p = 0.0087) and fewer metastases (0-5) (31.94 vs 9.59 months, p = 0.0059) were associated with improved PFS in EGFR-TKIs + SBRT versus EGFR-TKIs. Combination therapy increased radiation pneumonitis mainly in Grades 1-2 (89.74% vs 0.0%). The EGFR-TKIs + SBRT group mainly had new site failure (57.10% vs 32.10%) rather than the original site failure.

Conclusion: Early SBRT for primary lung tumors may overcome targeted resistance in advanced EGFRm NSCLC patients combined with EGFR-TKIs without serious toxicities, especially for EGFR exon 19-del.

Trial registration: ChiCTR-OIN-17013920.

Keywords: epidermal growth factor receptor; non-small-cell lung cancer; stereotactic body radiation therapy.

Figure 1.

Flow chart of patient enrollment. EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; SBRT, stereotactic body radiation therapy; TKI, tyrosine kinase inhibitor.

Figure 2.

Overall PFS (a) and OS (b) were compared by the Kaplan–Meier methods between patients who underwent SBRT or not. CI, confidence interval; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; SBRT, stereotactic body radiation therapy.

Figure 3.

Subtype analysis of PFS and OS was compared by the Kaplan–Meier methods between patients who underwent SBRT or not. SBRT. (a) PFS of patients with L858R mutation in EGFR-TKIs + SBRT group and EGFR-TKIs group. (b) OS of patients with L858R mutation in EGFR-TKIs + SBRT group and EGFR-TKIs group. (c) PFS of patients with a 19-del mutation in EGFR-TKIs + SBRT group and EGFR-TKIs group. (d) OS of patients with a 19-del mutation in EGFR-TKIs + SBRT group and EGFR-TKIs group. (e) PFS of patients with fewer metastasis (0–5) in EGFR-TKIs + SBRT group and EGFR-TKIs group. (f) OS of patients with fewer metastasis (0–5) in EGFR-TKIs + SBRT group and EGFR-TKIs group. (g) PFS of patients with multi-metastasis (>5) in EGFR-TKIs + SBRT group and EGFR-TKIs group. (h) OS of patients with multi-metastasis (>5) in EGFR-TKIs + SBRT group and EGFR-TKIs group. CI, confidence interval; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; OS, overall survival; PFS, progression-free survival; SBRT, stereotactic body radiation therapy.

Figure A1.

Comparison of patients who underwent secondary gene testing or not (a) and detected T790M mutation positive or negative (b) after the initial progression between EGFR-TKIs + SBRT group and EGFR-TKIs group. EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; SBRT, stereotactic body radiation therapy.