Intracranial Activity of Deruxtecan-Based Antibody–Drug Conjugates in Non-Small Cell Lung Cancer Brain Metastases: A Systematic Review and Meta-Analysis of Prospective Trial Cohorts

Background/Objectives: Brain metastases are common in advanced non-small cell lung cancer (NSCLC). Antibody–drug conjugates (ADCs) have shown intracranial activity in trial subgroups, but intracranial data had rarely been pooled. Methods: MEDLINE, Scopus, Web of Science, registries, and congress sources were searched through 21 September 2026 for prospective trials reporting central nervous system (CNS) outcomes of ADC monotherapy in NSCLC (PROSPERO CRD420261516140). Intracranial objective response rate (icORR) in measurable brain metastases was pooled with a random-intercept logistic model. Risk of bias and GRADE certainty were assessed. Results: Eight prospective cohorts (139 patients; six molecularly selected) of deruxtecan-based ADCs were included. Pooled icORR was 32% (95% CI, 25–41%; 45/139; I2 = 0%; prediction interval, 24–43%), and pooled intracranial disease control was 83% (69–92%; five cohorts). In TUXEDO-3, the only dedicated prospective CNS trial, restricted to active metastases, icORR was 30% (6/20). CNS progression-free survival hazard ratios versus chemotherapy were 0.48 (0.23–0.98) and 0.75 (0.53–1.06). Certainty was very low for single-arm response and low for comparative outcomes. Conclusions: Deruxtecan-based ADCs produced intracranial responses in one third of patients with measurable brain metastases from previously treated, predominantly oncogene-driven NSCLC, including active disease. Limited randomized data are compatible with delayed CNS progression. Prospective trials with CNS-specific endpoints are needed.