Timing of Immunotherapy in Practice: Feasibility and Impact of Morning Checkpoint Inhibitor Administration

Immune checkpoint inhibitors (ICI) are a core mainstay of cancer care. In routine practice, the Time of Day of Administration (ToDA) of ICIs invariably is not stipulated in the clinical notes. Thus, treatment timing of administration is mainly dictated by constraints related to the organization and planning of the outpatient infusion centers, the clinical pharmacy, which reconstitutes the parenteral drugs, and the patients themselves. A growing body of evidence, recently including a prospective randomized trial, has shown a significant halving of risk reduction of an earlier death by early rather than late ToDA of ICIs in patients with 10 different advanced cancer primaries. The ToDA-dependent effect was found irrespective of the ICI type, and its use as a single agent or in combination. Similar favorable impact of early ToDA has been found on pharmacologic or clinical outcomes for a range of immunomodulated therapies including vaccines, chimeric antigen receptor T cells, and allo-HSCT. Physiologic mechanisms underpinning these clinical observations involve circadian (ie, of about a day) changes in immune cell trafficking and functions, altogether making the adaptive branch of the immune system more susceptible to pharmacologic intervention in the morning. Here, we critically discuss the available evidence, the knowledge gaps, and the impediments to deliver time-stipulated ICI in progressively busier cancer outpatient infusion centers. With numerous retrospective studies involving over 8,000 patients, we discuss consistencies and heterogeneities in these reports, including cutoff times associated with clinical benefit. We appraise the provision of care, particularly focusing on the workflows of the cancer outpatient infusion centers and the clinical pharmacy. Additionally, we propose here some practical quality improvement approaches to make morning ToDA of ICIs feasible in clinical practice.