Small-cell lung cancer's brutal biology — rapid progression, early metastasis, and near-universal resistance to second-line chemotherapy — has made it one of oncology's most persistent challenges. The emergence of antibody-drug conjugates (ADCs) as a precision-delivery platform offers a mechanistically distinct approach that could meaningfully shift survival curves in a disease where median overall survival after first-line chemoimmunotherapy rarely exceeds 12 months.
This narrative review maps the clinical development landscape across seven tumor-associated antigen targets in extensive-stage SCLC. The most mature data involve DLL3, a Notch pathway ligand overexpressed in approximately 80–85% of SCLC tumors, which has already attracted T-cell engager competition (notably tarlatamab). TROP2- and B7-H3-directed ADCs show encouraging early signals in second- and later-line cohorts, while SEZ6-targeted agents add another layer of therapeutic diversity. Earlier-phase constructs against CEACAM5 and PTK7 broaden the pipeline further. The review addresses CNS penetration — critical given SCLC's high rate of brain metastasis — as well as payload design, linker chemistry, and the emerging toxicity profiles that distinguish agents within the class. Combination strategies pairing ADCs with immune checkpoint inhibitors and DNA-damage response (DDR) inhibitors are also evaluated, alongside sequencing questions raised by the simultaneous development of DLL3-directed T-cell engagers.
From a translational standpoint, this review arrives at a pivotal moment: several ADCs are transitioning from Phase I to randomized Phase II trials, and the field is beginning to confront resistance mechanisms and biomarker inadequacy that plagued prior SCLC drug development waves. The lack of validated predictive biomarkers for patient selection remains a structurally limiting problem — one that has undermined precision oncology efforts in SCLC repeatedly. This review is valuable as a synthesis tool for clinicians navigating a rapidly fragmenting therapeutic space, though its conclusions are bounded by predominantly single-arm, early-phase data. Confirmatory randomized evidence will be essential before any of these agents redefines the standard of care.