Immune-Checkpoint Inhibitors Combinations in Metastatic NSCLC: New Options on the Horizon?

Abstract

Francesco Passiglia, Maria Lucia Reale, Valeria Cetoretta, Silvia Novello Department of Oncology, University of Turin, S. Luigi Gonzaga Hospital, Orbassano (TO), ItalyCorrespondence: Silvia NovelloDepartment of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, ItalyEmail [email protected]: The therapeutic targeting of the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis marked a milestone in the treatment of non-small cell lung cancer (NSCLC), leading to unprecedented response duration and long-term survival for a relevant subgroup of patients affected by non-oncogene-addicted, metastatic disease. However, the biological heterogeneity as well as the occurrence of innate/acquired resistance are well-known phenomena which significantly affect the therapeutic response to immunotherapy. To date, we are moving towards the second phase of the “immune-revolution”, characterized by the advent of new immune-checkpoint inhibitors combinations, aiming to target the main resistance pathways and ultimately increase the number of NSCLC patients who may derive long-term clinical benefit from immunotherapy. In this review, we provide an updated and comprehensive overview of the main PD-1/PD-L1 inhibitors’ combination approaches under clinical investigation in non-oncogene addicted, metastatic NSCLC patients, including checkpoints (other than CTLA-4) as well as “immune-metabolism” modulators, DNA repair pathway inhibitors, antiangiogenic agents, cytokines, and a new generation of vaccines, with the final aim of identifying the most promising options on the horizon.Keywords: immune-checkpoint, PD-1/PD-L1, resistance, combinations, non-small cell lung cancer

Keywords

• immune-checkpoint
• pd-1/pd-l1
• resistance
• combinations
• non-small cell lung cancer.