SYSTEMATIC REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1605877
This article is part of the Research TopicBispecific Antibodies and their Conjugates in Solid Tumors and Hematological MalignanciesView all 11 articles
Dual-target Immunotherapies in NSCLC: A Systematic Review and Meta-analysis of Randomized Clinical Trials
Provisionally accepted
- School of Basic Medical Sciences, Naval Medical University, Shanghai, China
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Background: Despite advances in targeted therapies and immune checkpoint inhibitors (ICIs), the prognosis for advanced non-small cell lung cancer (NSCLC) remains poor. Bispecific antibodies (BsAbs) represent an emerging class of dual-target immunotherapies, yet their comparative efficacy and safety profiles lack comprehensive quantitative synthesis. Methods: This systematic review and meta-analysis (PROSPERO CRD420251005168) adhered to PRISMA guidelines. We systematically searched PubMed, Web of Science, Scopus, and Embase through March 2025 for phase III randomized controlled trials (RCTs) comparing dual-target immunotherapies with conventional therapies in advanced NSCLC. Primary outcomes were progression-free survival (PFS) and overall survival (OS); secondary outcomes included objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs). Risk of bias was assessed using Cochrane RoB 2.0. Random-effects models were used for data synthesis. Results: Six RCTs (n=3,063 patients) were included. Dual-target immunotherapies significantly improved PFS (HR= 0.58, 95% CI: 0.43-0.78; p<0.001) and ORR (RR=1.29,95%CI: 1.01-1.64; p=0.04) compared to conventional therapies. No significant OS (HR=0.84,95% CI: 0.68-1.05; p=0.13) or DCR (RR=1.09, 95% CI: 0.92-1.30; p=0.30) benefits were observed. Subgroup analyses stratified by mechanism showed no statistically significant differences in efficacy and safety between dual-target immunotherapies with different targets of action. Safety analyses revealed increased risks of any adverse events (RR=1.05; 95%CI: 1.02-1.09), grade≥3 AEs (RR=1.63; 95% CI: 1.37-1.94), serious AEs (RR=1.49; 95%CI:1.31-1.69) and AEs leading to treatment discontinuation (RR=2.49; 95% CI: 1.72-3.62) with dual-target immunotherapies. Conclusion: Our findings, based on phase III RCTs, are limited by substantial heterogeneity among included studies. Dual-target immunotherapies demonstrate superior PFS and ORR in NSCLC but are associated with increased toxicity, particularly with EGFR/MET-targeted agents. While offering a promising therapeutic advance, safety optimization and biomarker-driven patient selection are critical for clinical translation. Further trials are needed to validate long-term survival benefits and refine risk-benefit profiles. Funding: This work was supported by grants from the Project of Incubation Base for Innovative Practical Ability of Cadets of Naval Medical University (FH2024061) and the Incubation Program for Innovative Capabilities in the School of Basic Medical Sciences of Naval Medical University (JCCXFH-017).
Keywords: bispecific antibodies, NSCLC, Immunotherapy, Meta-analysis, dual-target immunotherapies
Received: 04 Apr 2025; Accepted: 07 Aug 2025.
Copyright: © 2025 Zhang, Wang, Yang and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Changhai Lei, School of Basic Medical Sciences, Naval Medical University, Shanghai, China
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