Evening-dose immune checkpoint inhibitors were associated with worse survival outcomes

1. Receiving at least 20% of infusions after 1630h was associated with decreased overall survival in patients treated with immune-checkpoint inhibitors for metastatic melanoma

2. Both progression-free survival and disease response were worse in patients receiving at least 20% of infusions after 1630h.

Evidence Rating Level: 2 (Good)

Study Rundown: The immune system has circadian rhythm variability, such that weaker responses are noted in the evening. This study examined the outcome on overall survival (OS), progression-free survival (PFS), and disease response in patients receiving checkpoint inhibitor infusion treatment for stage IV melanoma at different times of the day. Evening was considered to begin at 1630h. Patients receiving a minimum of 20% of their treatment after 1630h were found to have reduced OS, with 5 year OS rates for these patients at 49% as compared to 68% for patients who had less than 20% evening treatments. PFS at 1 year in patients with a greater number of evening infusions was 40%, compared with 56% for patients with fewer evening infusions. Additionally, there was a decreased rate of disease response for patients receiving more evening infusions compared to patients receiving less (22% vs. 34%). The most common adverse events associated with checkpoint inhibitor treatment were colitis, hepatitis, and hypophysitis. No deaths due to treatment were reported. Limitations to the study include the retrospective format, the exclusion of patients receiving less than 4 infusions, as well as restriction of the study to one site. Additionally, the study results may not be applicable in all clinical scenarios due to variation of treatment sequence and duration for each patient. Overall, patients with stage IV melanoma may benefit from daytime, rather than evening, infusions of immune checkpoint inhibitors.

Click to read the study in The Lancet Oncology

Click to read an accompanying editorial in The Lancet Oncology

Relevant Reading: Circadian rhythms in adaptive immunity

In-Depth [retrospective cohort]: This retrospective cohort study based out of one site in the United States recruited 299 adult patients with stage IV melanoma who received at least 4 infusions of immune checkpoint inhibitor therapy (nivolumab, pembrolizumab, ipilimumab, or a combination). Total and 5 year overall survival (OS) were primary outcomes, with both progression-free survival (PFS) and disease response being secondary outcomes. Analysis of all 299 patients found a crude OS hazard ratio of 1.31 (95% confidence interval (CI), 1.00-1.71) for each additional 20% infusion received in the evening. A greater number of evening infusions was also associated with reduced PFS at 40% (95% CI, 30-54%) compared to those with fewer at 56% (95% CI, 50-63%). Disease response was also reduced in patients with more evening infusions (22%) compared to those with fewer (34%). Using a propensity score-matched analysis and multivariable adjustment, infusions in the evening were associated with a decreased OS (HR 2.04, 95% CI, 1.04-4.00, p = 0.038). Five year OS for patients receiving at least 20% of their treatment in the evening was 49% (95% CI, 31-76%) compared to 68% (95% CI, 53-86%) for patients with fewer than 20%. During treatment, 18% of 299 patients experienced colitis, 9% experienced hepatitis, and 5% had hypophysitis. No treatment related-deaths were recorded.

Image: PD

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