Chronotherapeutic Considerations in Immunotherapy: A Case of Durable Response in Metastatic Non-small Cell Lung Cancer.

Abstract

Chronotherapy, the alignment of treatments with biological rhythms, has been explored in oncology, particularly for chemotherapy and targeted therapies, but its impact on immune checkpoint inhibitor (ICI) efficacy remains underexplored. This research aimed to examine the potential chronotherapeutic effects of morning ICI administration on the long-term response to pembrolizumab in metastatic non-small cell lung cancer (NSCLC), emphasising immune function stability via the neutrophil-to-lymphocyte ratio (NLR), and to assess the clinical significance of circadian synchronisation in immunotherapy. This study utilised a retrospective case study methodology, examining the treatment records and serial hematologic data of a patient with metastatic NSCLC. A patient diagnosed with metastatic NSCLC in 2019 showed a lasting full response to pembrolizumab for more than 6 years. A retrospective analysis revealed consistent morning ICI administration (08:00-11:00 h) and a stable NLR (2.16-3.66) during the treatment period. In addition, serial haematologic analysis showed a stable NLR, ranging between 2.16 and 3.66 throughout the treatment course. This immunological stability may reflect enhanced immune function aligned with early-day innate immune activity, particularly neutrophil and antigen-presenting cell priming, which is known to follow circadian patterns. Although specific molecular circadian markers were not examined, this case highlights a significant issue in current medical practice: there is almost no consistency in the timing of immunotherapy treatments. Taken together with emerging retrospective data, these findings underscore the need for prospective studies evaluating the influence of treatment timing on immunotherapy efficacy and durable immune surveillance in solid tumours.