The clinical trial landscape of bispecific antibodies in non-small cell lung cancer: mechanistic trends and developmental strategies.

Background: Non-small cell lung cancer (NSCLC) management remains constrained by acquired resistance to targeted therapies and refractoriness to immune checkpoint inhibitors (ICIs), the latter driven largely by the immunosuppressive tumor microenvironment (TME). Bispecific antibodies (bsAbs) represent a promising modality capable of circumventing these therapeutic hurdles through proximity-driven dual-targeting mechanisms that co-block bypass signaling pathways and reverse immunosuppression. This study systematically analyzes the clinical trial landscape and developmental trajectory of bsAbs in NSCLC. Methods: We systematically queried the Trialtrove database for interventional clinical trials evaluating bsAbs in NSCLC with an actual or anticipated study start date on or before 8 February 2026. Following the application of predefined inclusion and exclusion criteria, 374 trials were identified. Data concerning trial phase, mechanistic targets, sponsor typology, and geographic distribution were extracted and analyzed using a mechanism-based classification framework. Results: The clinical pipeline has expanded rapidly, with 78.9% (295/374) of included trials initiated since 2021, predominantly led by industry sponsors (82.9%). The landscape is characterized by a predominance of early-phase studies, with Phase I and I/II trials comprising 62.6% (234/374) of the cohort, compared with 9.9% (37/374) advancing to late-stage pivotal validation. Dual-signaling inhibitors and checkpoint-TME bsAbs constitute the majority of late-stage investigations, whereas T-cell engagers (TCEs) form a rapidly expanding early-phase cohort. Geographically, the United States and China collectively participate in 94% of trials with available location data, but their strategic priorities diverge. The US pipeline emphasizes early-stage, high-risk mechanistic exploration (74% in Phase I or I/II), whereas trials conducted in mainland China are concentrated in late-stage validation of established target combinations. Conclusion: The clinical development of bsAbs in NSCLC has shifted decisively toward rationally engineered constructs designed to address specific resistance mechanisms. The global landscape reflects complementary regional strategies that balance high-risk mechanistic innovation with accelerated clinical execution. The integration of these precision-engineered modalities into standard care has the potential to reshape the therapeutic paradigm for advanced NSCLC.