Survival benefit for daytime vs evening infusions of checkpoint inhibitors


By Michael Woodhead

15 Nov 2021

The timing of immune checkpoint inhibitor infusions may be crucial to outcomes, according to findings from a study that found a significant survival benefit associated with daytime compared to evening administration of therapy for patients with advanced melanoma.

In a retrospective study, oncologists at the Winship Cancer Institute of Emory University, Atlanta, Georgia, analysed outcomes for 299 patients with stage IV malignant melanoma treated with ipilimumab, nivolumab, or pembrolizumab.

They found that more frequent morning or early afternoon dosing of checkpoint inhibitors resulted in significantly longer overall survival compared with more frequent late afternoon or evening dosing. Every additional 20% of infusions after 4.30pm resulted in a crude overall survival hazard ratio of 1·31 (95% CI 1·00 to 1·71; p=0·046).

In a propensity score-matched analysis in 146 patients (37% women), receiving at least 20% of infusions after 4.30pm was significantly associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [95% CI 1·04 to 4·00]; p=0·038).

Similarly, one-year progression-free survival rates (40% vs 56; p=0·041) and rates of complete response (22% vs 34%; p=0·069), were lower among patients who had at least 20% of infusions in the evening than in those received most of them in the morning or afternoon.

The Melanoma Outcomes Following Immunotherapy (MEMOIR) study investigators said immunotherapy timing was an independent prognostic factor for overall survival in multivariable analyses, and remained unaffected by previous corticosteroids or radiotherapy.

“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,” they wrote in Lancet Oncology. 

The results were also supported by previous research showing that circadian rhythms could influence the efficacy of some chemotherapies, with improved responses seen when treatment was given earlier in the day.

“For advanced melanoma, this study justifies the design and implementation of a randomised trial to rigorously assess the effect of immune checkpoint inhibitor time-of-day infusion patterns on patient outcomes,” they suggested.

In the meantime, the results “could be used to guide immunotherapy infusion scheduling with the goal of optimising treatment response … efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma,” they added.

An accompanying commentary noted that the impact of infusion timing seemed to be greater for women, adding to evidence from other studies that sex could also moderate the impact of circadian rhythms on tumour susceptibility and immune responses.

“Prospective randomised trials should identify optimal timing of infusions of immune checkpoint inhibitors, which might be sex specific and tailored to individual patients’ circadian biomarkers. The further development of circadian rhythm-based immunochemotherapy would indeed shift cancer medicine into true precision oncology.

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