Immunotherapy for small-cell lung cancer: rationale and clinical evidence

Recent advances in the molecular biology of small cell lung cancer (SCLC) translate into improved outcomes for patients (1-5). This includes rovalpituzumab tesirine (Rova-T), that targets delta-like protein 3 (DLL3). DLL3 is a ligand in the Notch signaling pathway, that is transcriptionally regulated by achaete-scute homolog-1 (ASCL1) and is overexpressed in SCLC (6). In neuroendocrine tumors, Notch action suppresses tumor growth, in contrast to other tumor types in which acts as an oncogenic stimulus. DLL3 is unable to activate the Notch signaling pathway (6). In an early phase clinical trial, patients whose tumors overexpressed DLL3 and received Rova-T as third-line treatment, tumor reduction was achieved in 50% of the patients and 92% experienced at least stabilization of disease (7). In addition, pharmacogenomics approaches to identify drug sensitivity in SCLC (8,9) have shown that DNA repair proteins are overexpressed in SCLC, including poly (ADP-ribose) polymerase 1 (PARP1) (9,10). PARP inhibitors are investigated in patients with SCLC in several clinical trials (11).