Dual-target immunotherapies in NSCLC: a systematic review and meta-analysis of randomized clinical trials
Yike Zhang1, Haozhe Wang1, Xinyue Yang1
1Department of Biophysics, College of Basic Medical Sciences, Naval Medical University, Shanghai, China.
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.
Systematic Review Registration:
https://www.crd.york.ac.uk/prospero/, identifier CRD420251005168.
Insights
Dual-target immunotherapies improve progression-free survival (PFS) and objective response rate (ORR) in advanced non-small cell lung cancer (NSCLC). However, these novel therapies increase toxicity risks, necessitating further research for safety optimization and patient selection.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Advanced non-small cell lung cancer (NSCLC) has a poor prognosis despite current treatments.
- Bispecific antibodies (BsAbs) are emerging dual-target immunotherapies.
- Limited quantitative data exists on the comparative efficacy and safety of BsAbs in NSCLC.
Purpose of the Study:
- To systematically review and meta-analyze phase III RCTs comparing dual-target immunotherapies with conventional therapies in advanced NSCLC.
- To evaluate the impact of dual-target immunotherapies on progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR).
- To assess the safety profile, including treatment-related adverse events (AEs).
Main Methods:
- Systematic literature search of PubMed, Web of Science, Scopus, and Embase.
- Inclusion of six phase III randomized controlled trials (RCTs) involving 3,063 patients.
- Random-effects models used for meta-analysis of PFS, OS, ORR, DCR, and AEs.
Main Results:
- Dual-target immunotherapies significantly improved PFS (HR=0.58) and ORR (RR=1.29) compared to conventional therapies.
- No significant improvements were observed in OS (HR=0.84) or DCR (RR=1.09).
- Increased risks of any AEs (RR=1.05), grade ≥3 AEs (RR=1.63), serious AEs (RR=1.49), and treatment discontinuation due to AEs (RR=2.49) were associated with dual-target immunotherapies.
Conclusions:
- Dual-target immunotherapies show superior PFS and ORR in advanced NSCLC but are linked to increased toxicity.
- EGFR/MET-targeted agents, in particular, are associated with heightened toxicity.
- Further research is crucial for safety optimization, biomarker-driven patient selection, and validation of long-term survival benefits.
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