e20728 Background: After progression on EGFR tyrosine kinase inhibitors (EGFR-TKIs), multiple second-line options exist for targeting all-comers. However, their comparative efficacy, safety, and subgroup-specific characteristics of these therapies remain incompletely defined, complicating individualized treatment selection. Methods: We performed a PRISMA-compliant network meta-analysis of 16 randomized controlled trials (RCTs) (n = 4909) evaluating second-line systemic therapies for EGFRm advanced NSCLC after EGFR-TKI failure. Treatments were categorized as platinum–pemetrexed chemotherapy (Chemo), immunotherapy +Chemo (IC), anti-VEGF+Chemo (VC), IO+anti-VEGF+Chemo (IVC), Amivantamab+Chemo (AC), Amivantamab+Lazertinib+Chemo (ALC), HER3-directed antibody–drug conjugate (HER3-ADC), TROP2-directed ADC (TROP2-ADC), docetaxel and ICI monotherapy. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoint was grade ≥3 treatment-related adverse events (TRAEs). Results: Compared with Chemo, most intensified strategies improved PFS. The largest PFS benefits were observed with ALC (HR 0.44, 95% CI 0.35–0.56), AC (HR 0.48, 95% CI 0.36–0.64), IVC (HR 0.52, 95% CI 0.45–0.60), and TROP2-ADC (HR 0.49, 95% CI 0.39–0.62). HER3-ADC and IC yielded more modest PFS gains (both HR 0.77), whereas ICI monotherapy was inferior (HR 1.92, 95% CI 1.27–2.90). OS effects were generally modest and homogeneous; TROP2-ADC was the only biomarker-agnostic regimen with a clear OS advantage versus Chemo (HR 0.60, 95% CI 0.44–0.82), while HER3-ADC remained OS-neutral despite PFS/ORR improvements. Rank analyses consistently placed IVC, Amivantamab-based regimens, and TROP2-ADC in the top efficacy tier. An efficacy–toxicity gradient was evident: grade ≥3 TRAEs were lowest with Chemo/ICI monotherapy, intermediate with VC and ADCs, and highest with Amivantamab-based and IO+anti-VEGF-based regimens. In prespecified PFS subgroup analyses, IVC showed particularly strong and stable efficacy in metastatic populations (brain and liver): brain metastases HR 0.38 (95% CI 0.29–0.52; I² = 0) and liver metastases HR 0.63 (95% CI 0.49–0.81; I² = 0). Across molecular subgroups, Amivantamab-based regimens and IVC remained consistently favorable in 19Del/L858R and post–3-generation TKI settings, while TROP2-ADC preserved benefit in T790M-positive disease. Conclusions: After EGFR-TKI failure, IVC demonstrates particularly strong and stable PFS benefit in patients with brain or liver metastases, supporting phenotype-guided selection. TROP2-ADC provides a biomarker-agnostic therapeutic option with demonstrable OS improvement. These findings provide a basis for second-line treatment decisions and support the conduct of head-to-head trials among high-value regimens.
Liu et al. (Thu,) studied this question.