Antibody-Based Therapeutics in Small Cell Lung Cancer: A Narrative Review

Abstract

Small-cell lung cancer (SCLC) is the most aggressive lung cancer, mostly diagnosed at advanced stage, and with few therapeutic options for patients failing the first-line treatment. Antibody-based therapies, such as antibody-drug conjugates and T-cell engagers, are emerging as a promising option in the treatment of various solid tumors, including SCLC. T-cell engagers are molecules able to trigger the T-cell-mediated tumor cell death binding, at the same time, a T-cell and a tumor cell target. Tarlatamab is a DLL3-directed bi-specific T-cell engager (BiTE) whose efficacy was evaluated in a Phase 2 study. Antibody-drug conjugates (ADC) consist of a tumor-directed monoclonal antibody conjugated to a cytotoxic payload able to selectively kill tumor cells through different mechanisms. Ifinatamab-deruxtecan is an anti-B7-H3 ADC showing efficacy in pretreated SCLC patients in a phase 2 clinical trial. Sacituzumab govitecan is a Trop-2-directed ADC already used in other tumor types and evaluated in SCLC in the phase 2 TROPiCS-03 trial, with positive results. Bispecific antibodies targeting VEGF and PD-(L)1 showed antitumor activity in phase 1 and 2 clinical trials. Other antibody-based agents are currently at an earlier phase of their clinical development and showed a promising activity. Novel antibody-based agents could potentially acquire a prominent role in the treatment of SCLC, a field with few therapeutic options. Direct comparisons with the current standard of care still lack, however Phase 3 trials are currently ongoing.

Keywords: T-cell engager; antibody; antibody–drug conjugate; bispecific antibody; small-cell lung cancer; treatment.

Figure 1

The main antibody-based agents used for the treatment of SCLC and their mechanisms of action are shown in Figure 1. Tarlatamab is a bi-specific T-cell engager (BiTE) targeting both DLL3 on tumor cells and CD3 on T-cells, leading to T-cell activation and tumor cell lysis. The other three drugs described in the figure are ADCs: Sacituzumab govitecan (SG), which consists of a humanized anti-Trop-2 antibody linked through a hydrolyzable linker to SN-38, an irinotecan metabolite with TOP1 inhibition effects. Ifinatamab-deruxtecan (I-DXd) is a B7-H3-directed ADC consisting of an anti-B7-H3 antibody, a cleavable tetra-peptide linker, and the payload deruxtecan, a DNA topoisomerase I inhibitor. Finally, ABBV-011 is a SEZ6-directed ADC consisting of an anti-SEZ6 monoclonal antibody, SC17, conjugated through a non-cleavable linker to the payload LD19.10, a DNA-damaging calicheamicin linker drug. Created in BioRender. Ciappina, G. (2025) https://BioRender.com/ v97z557.