In a single-institution study reported in The Lancet Oncology, David C. Qian, MD, PhD, and Zachary S. Buchwald, MD, PhD, of Winship Cancer Institute of Emory University, Atlanta, and colleagues found that patients with metastatic melanoma who received at least 20% of immune checkpoint inhibitor (ICI) infusions after 4:30 PM had significantly poorer overall survival vs those receiving less than 20% of infusions after 4:30 PM.1
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.”
David C. Qian, MD, PhD
Zachary S. Buchwald, MD, PhD
The study involved data from the longitudinal MEMOIR trial including all patients with melanoma who received standard-of-care doses of ipilimumab, nivolumab, pembrolizumab, or a dual combination of these agents at Winship Cancer Institute between 2012 and 2020. The current analysis included 299 patients with stage IV disease who received at least four ICI infusions.
The primary outcome measure was overall survival, measured from the date of the first ICI infusion. The study analyzed the relationship of overall survival with the proportion of infusions for each patient received after 4:30 PM, a composite time cutoff derived from studies of 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.
Association of Infusion Time of Day and Overall Survival in Total Cohort
In the total cohort, 299 adults received 4,001 ICI infusions. The median age of patients was 61 years, and 102 (34%) were female. Median follow-up was 27 months (interquartile range [IQR] = 14–47 months). In total, 74 patients (25%) received at least 20% of their infusions after 4:30 PM. There were no significant differences in patient characteristics or radiotherapy techniques or sites between patients receiving at least 20% vs less than 20% of infusions after 4:30 PM.
Overall survival was poorer among those receiving at least 20% of infusions after 4:30 PM (hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.03–2.78, P = .038). Every additional 20% of infusions received by a 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 a multivariate analysis, receipt of at least 20% of infusions after 4:30 PM remained significantly associated with poorer overall survival (HR = 1.80, 95% CI = 1.08–2.98, P = .023). No association between overall survival and year of initiation of ICI therapy was observed. No treatment-related deaths were observed.
Patients who received at least 20% of their infusions after 4:30 PM had poorer 1-year progression-free survival (40% vs 56%, P = .041) and a lower rate of complete response (22% vs 34%, P = .069).
Findings in Propensity Score–Matched Analysis
The propensity score–matched cohort consisted of 146 patients who did (n = 73) vs did not (n = 73) receive at least 20% of infusions after 4:30 PM. The median age of patients was 58 years (IQR = 48–68 years), and 54 (37%) were women. For those receiving at least 20% vs less than 20% of infusions after 4:30 PM, the total numbers of infusions were 4 to 10 for 63% vs 45%, 11 to 15 for 18% vs 21%, 16 to 20 for 10% vs 15%, and at least 21 for 10% vs 19% (overall P = .14). The immune checkpoint inhibitors ever received were pembrolizumab in 38% vs 42% (P = .74), single-agent ipilimumab in 23% vs 29% (P = .57), single-agent nivolumab in 19% vs 23% (P = .69), and dual inhibitors in 52% vs 45% (P = .51). Median follow-up was 23 months (IQR = 10–40 months) vs 27 months (IQR = 15–47 months; P = .48).
Median overall survival was 4.8 years (95% CI = 3.9 years to not estimable) among patients who received at least 20% of infusions after 4:30 PM vs not reached among those receiving less than 20% of infusions after 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 a multivariate analysis, receipt of at least 20% of infusions after 4:30 PM remained significantly associated with poorer overall survival (HR = 2.16, 95% CI = 1.10–4.25, P = .025). Season of initiation of treatment did not significantly differ between groups and was not associated with differences in overall survival.
There were no significant differences between patients receiving at least 20% vs less than 20% of infusions after 4:30 PM in toxicity leading to change of ICI (18% vs 22%, P = .68) or discontinuation of all ICIs (27% vs 34%, P = .48).
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…. Immunotherapy has improved the outcomes of patients with melanoma and numerous other malignancies. Immune checkpoint inhibitors have emerged to become standard of care in many settings, and so maximizing their efficacy is essential. Although prospective studies on the timing of immune checkpoint inhibitors are warranted, efforts toward scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma.”
DISCLOSURE: The study was supported by the National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute. Dr. Qian reported no conflicts of interest. For all study authors’ disclosures, visit thelancet.com. Dr. Buchwald has received patent royalties from Ultragenyx.
1. Qian DC, Kleber T, Brammer B, et al: Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): A propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol 22:1777-1786, 2021.
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