Redefining the Fight Against SCLC: Standards, Innovations, and New Horizons

Abstract

Background: Small cell lung cancer (SCLC) remains a highly aggressive malignancy with a poor prognosis. Despite multimodal standard therapies, most patients relapse within months, and second-line treatment options such as topotecan offer only limited benefit. Novel therapeutic strategies are therefore urgently needed. Methods: This narrative review is based on a selective literature search conducted via PubMed and ClinicalTrials.gov (last updated June 2025). Results: Emerging treatment strategies include bispecific T-cell engagers (e.g., tarlatamab), antibody-drug conjugates (ADCs) such as sacituzumab govitecan, DS-7300, and ZL-1310, as well as targeted therapies. Among these, tarlatamab has demonstrated improved survival outcomes with an acceptable safety profile and is poised to become the new second-line standard. In contrast, ADCs and targeted agents have shown only modest efficacy and have yet to deliver meaningful survival benefits, often accompanied by increased toxicity. Additionally, the identification of molecular subtypes of SCLC has revealed subtype-specific differences in treatment response. However, clinical translation is challenged by intratumoral heterogeneity, plasticity, and the lack of standardized diagnostic assays. Conclusions: While tarlatamab represents a major therapeutic advancement, other agents remain in early clinical development and require validation in large, randomized trials. The clinical implementation of molecular subtyping remains limited, though it holds promise for future personalized treatment approaches. Despite recent progress, SCLC continues to pose substantial therapeutic challenges, emphasizing the need for improved treatment strategies and validated predictive biomarkers.

Keywords: antibody-drug conjugates; immunotherapy; molecular subtypes; prognosis; small cell lung cancer; targeted therapy.

Figure 1

Flowchart illustrating the thematic structure of this review. Abbreviations used in this figure include ADCs (antibody-drug conjugates), BCL-2 (B-cell lymphoma 2), B7-H3 (B7 Homolog 3, CD276), cCRT (concurrent chemoradiotherapy), CTX (chemotherapy), DLL3 (Delta-like protein 3), ED (Extensive Disease), EZH2 (enhancer of zeste homolog 2), IO (immunotherapy), LD (Limited Disease), PARPi (poly ADP-ribose polymerase inhibitor), SEZ6 (seizure protein 6 homolog), SG (sacituzumab govitecan), SOC (standard of care), TKI (Tyrosine Kinase Inhibitor), Trop-2 (Tumor-associated calcium signal transducer 2), and VEGF (Vascular Endothelial Growth Factor).

Figure 2

Graphical overview of emerging therapeutic strategies in small cell lung cancer (SCLC). This schematic illustrates key classes of novel agents under investigation for the treatment of SCLC. Antibody-drug conjugates (ADCs) such as Rova-T, ZL-1310, sacituzumab govitecan, infinatamab-deruxtecan, and ABBV-011 deliver targeted cytotoxic payloads to tumor-associated antigens. Tarlatamab represents a novel bispecific T-cell engager targeting DLL3. Additional compounds include inhibitors of anti-apoptotic BCL2 proteins (venetoclax, navitoclax), epigenetic regulators EZH1/2 (tazemetostat, merumetostat, valemetostat), and DNA repair enzymes PARP (olaparib, talazoparib, niraparib). Lurbinectedin, a cytotoxic agent, induces DNA damage independently of targeted pathways. Image created in BioRender. Reitnauer, L. (2025) https://BioRender.com/miyx8lj (accessed on 25 May 2025).