Current and emerging therapies targeting cell surface antigens and epigenetics in extensive stage small cell lung cancer: primer for clinicians

Extensive stage small cell lung cancer (ES-SCLC) carries a very poor prognosis and has been the focus of intensive research. Targeting cell surface molecules is paying off. Moving beyond immune checkpoint inhibitors (ICI), targeting DLL3 with tarlatamab in previously treated ES-SCLC generated an unprecedented response. Use of a combination of vascular endothelial growth factor (VEGF)/PD-1/PD-L1 antibody and chemotherapy seemed more effective than ICI plus chemotherapy. Bispecific antibodies targeting PD-1/PD-L1/VEGF in combination with chemotherapy are being tested in the first-line setting. B7H3 and SEZ6 antibody-drug conjugates yielded encouraging results in the early phase. Modulation of epigenetic processes is being pursued for its potential to reprogram cancer cells to a disadvantage for growth and immune evasion. Due to tumor heterogeneity and plasticity, rational combinations pursuing broader cancer cell vulnerabilities are likely necessary in the future to prevent relapse. Better tools for response monitoring are urgently needed to gauge progress.