T-Cell Engagers in Lung Cancer: A Comprehensive Literature Review from Tarlatamab Approval to Next-Generation Strategies
Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach. Methods: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy. Results: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development. Conclusions: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer.