Targeted therapy in small cell lung cancer: can DLL3 notch up a victory?

Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma, responsible for ~13–18% of lung cancer death with no appreciable improvements in outcomes or treatment options for the last 30 years. The clinical behavior of SCLC is tailor made for nihilism with excellent initial overall response rates transforming to inevitable chemotherapy resistant recurrence in the majority of patients. Targeted therapies to date have failed with little to no efficacy in unselected populations. Naturally, this state of affairs has led to an underfunded SCLC research community, and historical pharmaceutical disinterest in this “graveyard of drug development”. The National Cancer Institute (NCI) and worldwide refocus upon “recalcitrant” carcinomas has led to renewed interest in SCLC making this the perfect opportunity to consider how and why targeted therapy in unselected SCLC has failed so consistently. The critical factors are both biological factors and structural limitations to previous targeted therapy studies in SCLC.