Targeted Therapy and Immune Therapy for Small Cell Lung Cancer

Opinion statement

Approximately 15% of the over 220,000 new lung cancers diagnosed each year in the USA are small cell lung cancer (SCLC). The standard of care for SCLC patients has not changed for many years. Therefore, there remains a need to evaluate novel drugs for the management of SCLC patients. In recent years, there is a greater understanding of the molecular alterations that occur in SCLC. There is an expectation that targeting these molecular alterations could provide clinical benefit. Targeting angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) pathway has been evaluated in SCLC patients and has shown only limited clinical benefit. Alterations in DNA repair make these tumors susceptible to DNA repair pathway inhibitors and formed the basis for PARP inhibitor trials. Initial trials with PARP inhibitors have shown promising activity in some SCLC patients. Due to increased expression of anti-apoptotic Bcl-2 proteins, drugs targeting these proteins may also provide clinical benefit. Pre-clinical studies have shown that pathways of self-renewal such as the hedgehog and NOTCH pathways may be altered in SCLCs and could be targeted for therapeutic benefit. Initial trials with drugs targeting these pathways, including drugs-targeting DLL3, a NOTCH ligand, suggest the need for appropriate biomarkers to identify SCLC patients most likely to benefit from these strategies. Trials of immune checkpoint inhibitors have shown that these agents may have therapeutic role in SCLC. As is true in other tumor types, these agents benefit only a proportion of patients but the benefit when observed can be sustained. Tumor mutational burden and PD-L1 expression may predict for clinical benefit with these agents. Ongoing trials will define the role of these agents in management of SCLC patients.