Unlocking New Horizons in Small-Cell Lung Cancer Treatment: The Onset of Antibody–Drug Conjugates

SIMPLE SUMMARY: Small-cell lung cancer (SCLC) represents a highly aggressive form of lung cancer. Although SCLC initially responds to chemoimmunotherapy, it inevitably relapses. Antibody–drug conjugates (ADCs) have emerged as a promising treatment approach. ADCs consist of antibodies targeting specific tumor antigens, delivering cytotoxic drugs directly to cancer cells, and reducing side effects. In this review, we collected the available data regarding ADCs evaluated in SCLC. While some ADCs yielded negative results, others, such as those targeting B7-H3, SEZ6, CEACAM5, and TROP2 ADC, show promise. Further research is needed to determine ADCs’ role in SCLC treatment. ABSTRACT: Small-cell lung cancer (SCLC) is a highly aggressive disease, accounting for about 15% of all lung cancer cases. Despite initial responses to chemoimmunotherapy, SCLC recurs and becomes resistant to treatment. Recently, antibody–drug conjugates (ADCs) have emerged as a promising therapeutic option for SCLC. ADCs consist of an antibody that specifically targets a tumor antigen linked to a cytotoxic drug. The antibody delivers the drug directly to the cancer cells, minimizing off-target toxicity and improving the therapeutic index. Several ADCs targeting different tumor antigens are currently being evaluated in clinical trials for SCLC. Despite the negative results of rovalpituzumab tesirine (Rova-T), other ADCs targeting different antigens, such as B7-H3, seizure-related homolog 6 (SEZ6), and CEACAM5, have also been investigated in clinical trials, including for SCLC, and their results suggest preliminary activity, either alone or in combination with other therapies. More recently, sacituzumab govitecan, an anti-TROP2 ADC, demonstrated promising activity in lung cancer, including SCLC. Furthermore, an anti-B7-H3 (CD276), ifinatamab deruxtecan (DS7300A), showed a high response rate and durable responses in heavily pretreated SCLC. Overall, ADCs represent an intriguing approach to treating SCLC, particularly in the relapsed or refractory setting. Further studies are needed to determine their efficacy and safety and the best location in the treatment algorithm for SCLC. In this review, we aim to collect and describe the results regarding the past, the present, and the future of ADCs in SCLC.