EGFR-TKIs or EGFR-TKIs combination treatments for untreated advanced EGFR-mutated NSCLC: a network meta-analysis

Abstract

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and EGFR-TKI combination treatments have become the standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, the best option has yet to be determined. This study compares the efficacy and safety of various first-line EGFR-TKI monotherapies and combination treatments for advanced EGFR-mutated NSCLC.

Methods: We searched PubMed, Embase, the Cochrane Central Register of Controlled Clinical Trials databases, and several international conferences to identify randomized controlled trials reporting on first-line EGFR-TKI treatments for patients with advanced EGFR-mutated NSCLC. The study quality was assessed using the revised tool for risk of bias in randomized trials. The efficacy and safety outcomes of the included treatments were compared by network meta-analysis based on a frequentist approach.

Results: We identified 26 trials (8,359 patients) investigating 14 treatment groups, including first, second, and third-generation EGFR-TKIs and their combination treatments. Osimertinib plus chemotherapy and lazertinib plus amivantamab showed the highest efficacy in improving progression-free survival. New third-generation EGFR-TKIs demonstrated comparable efficacy to osimertinib alone but did not surpass it. Subgroup analyses revealed slight variation in treatment efficacy based on mutation types and patient demographics. Combination treatments were associated with a higher incidence of adverse events.

Conclusion: These results reveal that osimertinib plus chemotherapy and lazertinib plus amivantamab are superior first-line options for patients with advanced EGFR-mutated NSCLC. However, these combinations are associated with higher adverse event rates.

Keywords: Amivantamab; EGFR-TKI; Lazertinib; Non-small cell lung cancer; Osimertinib.

Fig. 1

PRISMA flowchart

Fig. 2

Network diagrams of the network meta-analysis. A-D: progression-free survival, overall survival, objective response rate and grade ≥ 3 adverse events in patients with advanced EGFR mutated NSCLC. FGTKI = first-generation EGFR-TKIs; Afa = afatinib; Dac = dacomitinib; Osi = osimertinib; Bef = befotertinib; Fur = furmonertinib; Laz = lazertinib; Aum = aumolertinib; Ami = amivantamab; Cet = cetuximab; Chem = chemotherapy; AntV = antiangiogenic agents

Fig. 3

Pooled estimates of the network meta-analysis. A: Pooled hazard ratios (95% confidence intervals) for progression-free survival (lower triangle) and overall survival (upper triangle) in patients with advanced EGFR-mutated NSCLC. B: Pooled risk ratios (95% confidence intervals) for objective response rate (lower triangle) and grade ≥ 3 adverse events (upper triangle) in patients with advanced EGFR-mutated NSCLC. The data in each cell represent hazard or risk ratios (95% confidence intervals) comparing the treatment defined in the column with the treatment defined in the row. Significant results are indicated in bold

Fig. 4

Pooled estimates for progression-free survival of subgroup analyses for patients with exon 19 deletion (lower triangle) and exon 21 L858R subgroups (upper triangle). The data in each cell represent hazard ratios (95% confidence intervals) comparing the treatment defined in the column with the treatment defined in the row. Significant results are indicated in bold

Fig. 5

Pooled estimates for progression-free survival of subgroup analyses based on various clinicopathological characteristics. A-F: age < 65 (lower triangle) and age ≥ 65 years (upper triangle), female (lower triangle) and male (upper triangle), ECOG PS of 0 (lower triangle) and ECOG PS of 1(upper triangle), smoker (lower triangle) and non-smoker (upper triangle), Asian (lower triangle) and Non-Asian (upper triangle), no brain metastasis (lower triangle) and brain metastasis (upper triangle). The data in each cell represent hazard or risk ratios (95% confidence intervals) comparing the treatment defined in the column with the treatment defined in the row. Significant results are in bold