Timing of immunotherapy administration affects oncologic outcome

MedNet.nl: In patients with metastatic NSCLC receiving first-line treatment with an immune checkpoint inhibitor, administration early in the day, before 3 p.m., leads to better outcomes than administration later in the day. A randomized study shows that progression-free and overall survival nearly double with early administration, possibly due to the influence of the circadian rhythm.

Circadian rhythm influences various biological mechanisms. For example, preclinical studies show a link between diurnal rhythm and immune system function. In this way, circadian rhythm may also influence the effectiveness of immunotherapy. Indeed, 20 retrospective studies have found that the effectiveness of immune checkpoint inhibitors is higher when administered early in the day. A group of researchers wanted to investigate this further and initiated the first prospective, randomized phase 3 study of administration early in the day versus administration late in the day.

The study randomized 210 patients without driver mutations to a group in which the administration of standard immunotherapy plus chemotherapy was completed before 3 p.m., and a group in which its administration started after 3 p.m. The primary endpoint of the study was progression-free survival (PFS).

After a median follow-up of 23.2 months, the median PFS in the early- and late-treated groups was 11.3 and 5.7 months, respectively, which was a significant difference (HR=0.42). The median overall survival (OS) was also significantly longer in the early-treated group; it had unreached, compared with 16.4 months in the late-treated group (HR=0.45). Furthermore, the early-treated patients also had a significantly higher objective response rate (75.2 vs 56.2%).

A possible biological explanation for the differences in outcomes the researchers found when they looked at the immune cells of patients. For example, the number of CD8+ T-cells increased during treatment in the patients treated early in the day, while this type of cell decreased in the group treated late in the day.

Given the impact of circadian rhythm on the effectiveness of immunotherapy, the researchers recommend that future clinical trials document the timing of administration and stratify accordingly.

Zhang Y, Huang Z, Zeng L, et al. Randomized trial of relevance of time-of-day of immunochemotherapy for progression-free and overall survival in patients with non-small cell lung cancer. ASCO 2025, abstract 8516.

This article was originally published in Dutch on MedNet.nl