Beyond platinum sensitivity: immune-engaging therapies and multidimensional treatment stratification in relapsed small-cell lung cancer

Although platinum sensitivity remains a convenient way to categorize relapsed small-cell lung cancer (SCLC), it no longer captures the full range of factors that may influence response to newer treatments. The interval to relapse still carries useful clinical information because it reflects the initial response, the pace of disease, and the emergence of resistance. It does not, however, identify whether a relapsed tumor can support checkpoint blockade, be efficiently recognized by a T-cell engager, or support delivery and respond to an antibody-drug conjugate (ADC). This Review considers treatment vulnerability through five interconnected features: lineage plasticity, antigen-presentation competence, T-cell function, surface-target availability, and susceptibility to the delivered payload. We integrate clinical and translational findings for DLL3-directed T-cell engagers, B7-H3-directed ADCs, and SEZ6-directed ADCs, emphasizing that resistance may arise from the target, the immune effector compartment, or the payload. We then introduce a Time-Immune-Target framework. Time represents relapse kinetics; Immune denotes the functional capacity to mount or redirect an antitumor immune response; and Target denotes the accessibility of a therapeutically relevant surface antigen. Prior therapy is superimposed on these dimensions as a record of evolutionary pressure. This proposal is intended to guide hypothesis development, not current treatment assignment. Its clinical value will need to be tested prospectively using serial tissue and blood sampling, imaging, and formal biomarker-by-treatment interaction analyses.