Exploring Novel Immune-Related Toxicities and Endpoints with Immune-Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Abstract

Because of dramatic tumor regressions reported with the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PDL-1) antibodies inhibiting the PD-1 immune checkpoint, non-small cell lung cancer (NSCLC) is now recognized as an immune-modifiable disease. As responses were observed in smaller numbers in phase I trials, the immunologic profiles and unique toxicities of these agents have not been fully established in NSCLC. Moreover, PD-1 checkpoint inhibitors in development by different companies may demonstrate diverse spectrums of activity and toxicity. Although the cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors in earlier phase studies appeared to have less impressive responses in NSCLC, their safety profile has been more broadly defined. The anti-CTLA-4 antibody, ipilimumab, has the best characterized immune-related toxicities (predominantly skin, gastrointestinal, hepatic, and endocrine) and management strategies in melanoma. Despite the lack of studies directly comparing these agents, toxicities from PD-1 inhibition seem milder than those of CTLA-4 inhibition, with distinct toxicities of pneumonitis infrequently observed with the BMS-936558 anti-PD-1 antibody, nivolumamb, and frequent mild infusion reactions reported with the BMS-936559 anti-PDL-1 antibody. As lungs are critical organs often already compromised in NSCLC patients, immune-mediated pneumonitis can cause worrisome morbidity and mortality. Even though immune checkpoint inhibitors are being rapidly developed in a multitude of trials, optimal immune-mediated toxicity management has not been determined, is evolving, and will be further explored. Early diagnosis and symptom management with corticosteroids form the basis of treatment. Assessment of new immune-response criteria and use of primary endpoints of overall survival (OS) will be important in the development of these immunotherapies in NSCLC.