Third generation vs first generation EGFR-TKIs in the first line treatment for EGFR-mutated locally advanced or
Wenjie Hu1, Yi Qin1, Taoming Dong1
1Department of Oncology, The Second People's Hospital of Jingdezhen, Jingdezhen, China.
Abstract:
Background: The prevailing belief is that third-generation tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) (TGET) outperform first-generation EGFR-TKIs (FGET) in managing advanced-stage EGFR-mutated non-small cell lung cancer (NSCLC). However, this standpoint lacks substantiation in evidence-based medicine. Therefore, this meta-analysis was conducted to compare the efficacy and adverse effects (AEs) of these two categories. Methods: We searched seven databases for relevant randomized controlled trials (RCTs), focusing on primary endpoints such as progression-free survival (PFS), overall survival (OS), and central nervous system PFS (CNS-PFS). Additional factors considered included treatment responses and AEs. Results: We analyzed 15 studies from 6 RCTs on six third-generation TKIs: Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Naquotinib, and Befotertinib. TGET showed better efficacy in PFS (hazard ratio [HR]: 0.55 [0.41, 0.75]), CNS-PFS (HR: 0.48 [0.35, 0.66]), CNS-objective response rate (CNS-ORR, risk ratio [RR]: 1.40 [1.19, 1.65]), and duration of response (DOR, HR: 0.52 [0.38, 0.72]). Most subgroups confirmed the PFS advantage. With longer survival time, the superiority in PFS, OS, and CNS-PFS of TGETs became more evident. Both groups had similar OS (HR: 0.86), ORR, CNS-DOR, total AEs, and grade 3-5 AEs. However, TGETs had more severe AEs (RR: 1.17 [1.02, 1.35]). Additionally, there were more grade 3-4 cases of diarrhea, decreased platelet count, pulmonary embolism, fatigue, decreased neutrophil count, and rash, and fewer grade 3-4 increases in alanine transaminase (ALT) and aspartate transaminase (AST) in the TGET group. The top 5 AEs in the TGET group were diarrhea (36.32%), rash (30.24%), decreased platelet count (29.15%), elevated serum creatinine (23.63%), and decreased white blood cell count (22.02%). Conclusions: Except for Naquotinib, TGETs demonstrate superiority over FGETs in treating EGFR-mutated locally advanced or metastatic NSCLC, showing improved survival and responses. However, the increased incidence of AEs necessitates careful consideration.
Insights
Third-generation EGFR-TKIs (TGET) show improved survival and response in advanced EGFR-mutated NSCLC compared to first-generation EGFR-TKIs (FGET). However, TGETs are associated with a higher incidence of severe adverse events, requiring careful patient management.
Area of Science:
- Oncology
- Pharmacology
- Clinical Medicine
Background:
- The prevailing belief suggests third-generation EGFR-TKIs (TGET) are superior to first-generation EGFR-TKIs (FGET) for advanced EGFR-mutated NSCLC.
- This belief lacks robust evidence-based substantiation.
- A meta-analysis was conducted to rigorously compare the efficacy and safety of TGET versus FGET.
Purpose of the Study:
- To compare the efficacy and adverse effects of third-generation EGFR-TKIs (TGET) against first-generation EGFR-TKIs (FGET).
- To evaluate endpoints including progression-free survival (PFS), overall survival (OS), and central nervous system PFS (CNS-PFS).
- To assess treatment responses and adverse events (AEs) associated with both TKI generations.
Main Methods:
- Systematic literature search across seven databases for relevant randomized controlled trials (RCTs).
- Analysis of 15 studies from 6 RCTs involving six third-generation TKIs (Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Naquotinib, Befotertinib).
- Primary endpoints included PFS, OS, CNS-PFS, objective response rates (ORR), and adverse events.
Main Results:
- TGET demonstrated superior efficacy in PFS (HR: 0.55), CNS-PFS (HR: 0.48), CNS-ORR (RR: 1.40), and DOR (HR: 0.52) compared to FGET.
- While OS, ORR, and total AEs were similar, TGETs showed a higher incidence of severe adverse events (RR: 1.17).
- Specific grade 3-4 AEs were more frequent with TGET, including diarrhea, rash, and decreased platelet count, but less frequent for ALT/AST elevation.
Conclusions:
- Third-generation EGFR-TKIs (TGET), excluding Naquotinib, are superior to FGET for advanced EGFR-mutated NSCLC, improving survival and response rates.
- The increased incidence of severe adverse events with TGET necessitates careful monitoring and management strategies.
- Further research may explore optimizing TGET use to mitigate adverse effects while maximizing therapeutic benefits.
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