{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T06:01:15Z","timestamp":1785477675113,"version":"3.56.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In advanced EGFR-mutant non\u2013small cell lung cancer (NSCLC) after EGFR-TKI failure, chemotherapy alone offers limited benefit, while heterogeneous efficacy and safety across combination regimens complicate treatment selection. We systematically compared chemotherapy-anchored regimens in this setting to establish an evidence-informed treatment prioritization framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Following PRISMA 2020 guidelines, we searched PubMed, Embase, Cochrane Library, and oncology conference for randomized controlled trials evaluating patients with advanced EGFR-mutant NSCLC progressing after EGFR-TKI therapy, comparing experimental regimens (with or without chemotherapy) against platinum-based doublet chemotherapy (chemotherapy-anchored, chemo-anchored) for efficacy and safety outcomes. Primary outcomes were progression-free survival (PFS) and overall survival (OS), analyzed using hazard ratios (HRs). Fixed-effects pairwise meta-analyses and Bayesian random-effects network meta-analyses were performed to evaluate 8 treatment strategies: chemotherapy alone (Chemo, platinum-based doublet chemotherapy); chemotherapy plus immune checkpoint inhibitors (Chemo_ICI); chemotherapy plus anti-angiogenic therapy (Chemo_Antiangio); chemotherapy plus immune checkpoint inhibitors and anti-angiogenic therapy (Chemo_ICI_Antiangio); chemotherapy plus ivonescimab (Chemo_Ivo); sacTMT (sacituzumab tirumotecan); chemotherapy plus amivantamab (Chemo_Ami); and chemotherapy plus amivantamab and lazertinib (Chemo_Ami_Laz). Probabilistic multi-criteria decision analysis (pMCDA) integrated multi-criteria outcomes under three clinically informed weighting schemes (survival-focused, balanced, and safety-focused). All analyses were conducted using R software.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Eleven RCTs (n=3,606) were analyzed. In pairwise analyses versus Chemo, pooled results showed significant PFS benefit for Chemo_Ivo (HR 0.50, 95% CI 0.41\u20130.60), Chemo_ICI_Antiangio (HR 0.55, 95% CI 0.45\u20130.68), and Chemo_ICI (HR 0.77, 95% CI 0.67\u20130.88), while Chemo_Ivo also improved OS (HR 0.76, 95% CI 0.64\u20130.91). Under random-effects models, HR point estimates remained identical; significance was maintained in overall analyses but lost in several subgroups as confidence intervals encompassed 1. In network meta-analysis, Chemo_Ami_Laz (HR 0.44, 95% CrI 0.32\u20130.61), Chemo_Ami (HR 0.48, 95% CrI 0.33\u20130.70), sac-TMT (HR 0.49, 95% CrI 0.35\u20130.68), and Chemo_Ivo (HR 0.49, 95% CrI 0.38\u20130.64) showed the greatest PFS benefit versus Chemo. For OS, only sac-TMT (HR 0.60, 95% CrI 0.41\u20130.90) and Chemo_Ivo (HR 0.76, 95% CrI 0.60\u20130.98) were associated with a significant survival advantage. Chemo_Ami_Laz (OR 12.06, 95% CrI 3.64\u201353.50) and Chemo_Ami (OR 3.71, 95% CrI 1.12\u201312.19) were associated with a higher risk of grade \u22653 TRAEs. In pMCDA integrating efficacy and safety, sac-TMT, Chemo_Ami, and Chemo_Ivo consistently ranked as the top three strategies across all weighting schemes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Integrating efficacy and safety, sac-TMT, Chemo_Ami, and Chemo_Ivo appear to be the most favorable treatment options after EGFR-TKI failure in EGFR-mutant NSCLC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/<\/jats:ext-link>\n                      , identifier CRD420251268510.\n                    <\/jats:p>\n                  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