Efficacy and safety of distinct regimens for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: A systematic review and network meta-analysis.

Abstract

3075 Background: Targeted therapy with EGFR tyrosine-kinase inhibitors (TKIs) is the preferred first-line treatment for EGFR-mutated advanced non-small cell lung cancer (NSCLC), but acquired resistance inevitably occurs in almost all responding individuals. We aimed to comprehensively review the literature to investigate the efficacy and safety of distinct regimens in the subsequent-line setting, thereby identifying the optimal regimen for these TKI-resistant NSCLC patients. Methods: The PubMed, Embase, Cochrane Library databases, and abstracts of ASCO, ESMO, and WCLC were searched from database inception to 3 November 2024, to identify eligible randomized controlled trials (RCTs) that assessed distinct regimens for individuals with advanced EGFR-mutated NSCLC who progressed on TKIs. The outcomes of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events (≥3AEs) were compared and ranked in overall patients and various subgroups among 8 regimens by network meta-analysis and the surface under the cumulative ranking curve, respectively. The protocol is registered with PROSPERO, CRD42024601619. Results: 14 RCTs, involving 3177 participants and 8 treatment regimens (chemotherapy plus ivonescimab (PD-1/VEGF inhibitor) [CT+IVO]; CT+amivantamab+lazertinib [CT+AMI+LAZ], CT+immunotherapy+bevacizumab [CT+IO+BEV], CT+AMI, CT+BEV, CT+IO, CT, and IO), were included. In overall patients, the most pronounced PFS benefit was observed with the CT+IVO, followed by CT+AMI+LAZ, CT+IO+BEV, and CT+AMI, ranked second, third, and fourth, respectively. In terms of OS, the regimen of CT+AMI ranked the best, followed by CT+IVO. However, the comparisons of OS among different regimens did not reach statistical significance, possibly due to immature data. The results for ORR and DCR were similar to those for OS, with CT+AMI topping the rankings, followed by CT+AMI+LAZ. In terms of safety, the incidence of ≥3AEs was highest in CT+AMI+LAZ, followed by CT+AMI. In subgroup analysis, CT+IVO demonstrates stable PFS benefits across clinicopathological characteristics, ranking first in most subgroups. Due to the unavailability of OS subgroup data in most RCTs, many regimens were missing in the OS subgroup analysis. Conclusions: Integrating the results of different clinical outcomes and subgroup analyses, we conclude that CT+IVO is the optimal treatment option with an acceptable safety profile for patients with advanced EGFR-mutated NSCLC who have progressed on TKIs. CT+AMI+LAZ and CT+AMI are alternative subsequent line options as well, with superior efficacy compared to immunotherapy-based or chemotherapy regimens, yet elevated toxicity profiles requiring vigilant management.