In a single-institution study reported in The Lancet Oncology, Qian et al found that the administration of immune checkpoint inhibitors after 4:30 PM was associated with poorer overall survival vs infusion earlier in the day in patients with metastatic melanoma.
As stated by the investigators, “The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy.”
Study Details
The study involved data from the longitudinal MEMOIR study including all patients with melanoma who received standard-of-care doses of ipilimumab, nivolumab, or pembrolizumab, or a combination of these agents, at Winship Cancer Institute between 2012 and 2020. The current analysis included 291 patients with stage IV disease who received four or more immune checkpoint inhibitor infusions.
The primary outcome measure was overall survival calculated from the date of the first infusion. The study analyzed the relationship of overall survival with proportion of infusions for each patient received after 4:30 PM—a composite time cutoff derived from studies of the immune-circadian rhythm as representing onset of evening. The association was assessed in the total cohort and in a propensity score-matched analysis including age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy.
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Key Findings
Median follow-up in the entire cohort was 27 months (interquartile range [IQR] = 14–47 months).
In the total cohort, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR = 51–72 years). A total of 74 patients (25%) received ≥ 20% of immune checkpoint inhibitor infusions after 4:30 PM. Overall survival was poorer among those receiving ≥ 20% of immune checkpoint inhibitor infusions after 4:30 PM (hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.03–2.78, P = .038). Every additional 20% of immune checkpoint inhibitor infusions received by a particular patient after 4:30 PM was associated with an overall survival hazard ratio of 1.31 (95% CI = 1.00–1.71, P = .046).
In the propensity score–matched cohort of 146 patients who did (n = 73) or did not (n = 73) receive ≥ 20% of infusions after 4:30 PM, 54 (37%) were women and 92 (63%) were men, with a median age of 58 years (IQR = 48–68 years). Median overall survival was 4.8 years (95% CI = 3.9 years–not estimable) among patients who received ≥ 20% of infusions after 4:30 PM vs not reached among those receiving < 20% of infusions at that time (HR = 2.04, 95% CI = 1.04–4.00, P = .038). Overall survival at 5 years was 49% (95% CI = 31%–76%) vs 68% (95% CI = 53%–86%).
In multivariate analysis, receipt of ≥ 20% of infusions after 4:30 PM remained significantly associated with poorer overall survival in the entire cohort (HR = 1.80, 95% CI = 1.08–2.98, P = .023) and in the propensity score–matched cohort (HR = 2.16, 95% CI = 1.10–4.25, P = .025).
In the propensity score–matched cohort, there were no significant differences between patients receiving ≥ 20% vs < 20% of infusions after 4:30 PM in toxicity leading to change of immune checkpoint inhibitor treatment (18% vs 22%, P = .68) or discontinuation of all immune checkpoint inhibitors (27% vs 34%, P = .48)
In the entire cohort, the most common adverse events were colitis (18%), hepatitis (9%), and hypophysitis (5%). No treatment-related deaths were observed.
The investigators concluded, “Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma.”
Zachary S. Buchwald, MD, of the Department of Radiation Oncology, Winship Cancer Institute of Emory University, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was supported by the National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute. For full disclosures of the study authors, visit thelancet.com.
