Evolution of Immune Checkpoint Blockade in Metastatic NSCLC: A Narrative Review of Emerging Bispecific Antibodies and the Practical Challenges of Clinical Integration

Background/Objectives: Metastatic non-small cell lung cancer (mNSCLC) is challenged by toxicity, pharmacokinetic (PK) mismatch, and resistance inherent in current immune checkpoint inhibitor (ICI) regimens. Bispecific antibodies (BsAbs), which unify dual-target engagement within a single, structurally engineered molecule, offer a next-generation strategy to transcend these therapeutic ceilings. Their engineering formats—ranging from IgG-like full-size antibodies to non-IgG-like fragment-based or smaller scaffolds—are selected to further optimize target affinity and enhance therapeutic efficacy. Methods: This narrative review analyzes landmark trials establishing the current standard of care (SoC) and evaluates the mechanistic rationale and status of emerging BsAb, including dual checkpoint blockers and tumor microenvironment (TME)-modulating BsAbs, using the data from the latest early-phase clinical studies. Results: The review critically focuses on comparing the theoretical benefits of BsAbs, such as PK consistency and synergistic efficacy via affinity-controlled dual targeting, against the practical drawbacks of conventional combination therapies. Most importantly, it assesses the BsAbs’ potential to secure superior overall survival (OS) or progression-free survival (PFS) against established SoC and deeply reviews the clinical feasibility of managing their unique safety profiles. Conclusions: While BsAbs offer a potent, innovative approach to enhancing anti-tumor immunity, substantial hurdles remain for their widespread clinical integration. Key challenges include: (1) demonstrating clear survival benefits over high-efficacy SoCs in late-stage trials; (2) establishing guidelines for managing novel toxicity profiles; and (3) addressing logistical barriers related to complex manufacturing and high costs. Furthermore, the validation of predictive biomarkers is essential to guide the personalized application of BsAb-based immunotherapies.