The Time of Day of Immunotherapy Infusions Affects Survival

M. Alexander Otto, MMS, PA

November 22, 2021

The time of day of immunotherapy infusions matters for cancer patients' survival, a recent review found.

The study, which included almost 300 patients with stage IV melanoma, revealed that overall survival was longer for those who received immunotherapy infusions more frequently in the morning or early afternoon compared with those who received late afternoon or evening infusions.

The time of day of immunotherapy was an independent prognostic factor for overall survival in a multivariable analysis, regardless of corticosteroid or radiotherapy use.

"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," according to the investigators, led by David Qian, MD, PhD, a radiation oncology resident at Emory University School of Medicine, Atlanta, Georgia.

Qian and colleagues also suggest that suboptimal timing of infusions may help explain why 40% of cancer patients don't benefit from immune checkpoint inhibitors.

These findings, published on November 12 in The Lancet Oncology, "could be used to guide immunotherapy infusion scheduling with the goal of optimizing treatment response," Qian and colleagues write.

Francis Levi, MD, PhD, a medical oncologist at the University of Warwick, in Coventry, United Kingdom, agrees. In an editorial, Levi writes that the results could "change clinical practice" if they hold up in prospective, randomized trials.

The recent analysis adds to a growing body of literature that synching immunotherapy infusions with patients' circadian rhythms can lead to a more robust immune response.

Levi, who has been studying the timing of cancer therapies for decades, recently reported that morning infusions of nivolumab substantially reduced the risk for early progression and death among 95 patients with stage IV non–small cell lung cancer. These morning infusions were an independent predictor of progression-free and overall survival.

In addition, other analyses have shown that morning vaccinations elicit a stronger adaptive immune response than ones given in the afternoon or evening.

Despite the "well-known" influence of circadian clocks on peoples' immune response, timing immunotherapy infusions to coincide with this more favorable immune response window has not gotten much attention in the medical community, Levi noted.

Inside the Emory Analysis

The latest study focused on 299 adults with stage IV melanoma who had received four or more infusions of ipilimumab, nivolumab, or pembrolizumab, either alone or in combination, between 2012 and 2020.

At a median follow-up of 27 months, Qian and colleagues found that on average, patients who had received at least 20% of their infusions after 4:30 PM faced a 31% greater risk for all-cause death (P = .046). This effect was particularly robust early in the treatment course and was more pronounced in women, patients with brain metastases, and those who had received dual immune checkpoint inhibitor therapy.

To control for confounders, the researchers matched 73 patients who had received at least 20% of their infusions after 4:30 PM with 73 who had not. The patients were matched as to age, performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. This 4:30 PM threshold was based, in part, on previous vaccine studies, the authors say.

In the matched pairs, later infusions were associated with shorter overall survival — it was 4.8 years in the later group and was not reached in the early group (P = .038).

"We were somewhat surprised but also delighted that the effect direction is completely consistent with the vaccine literature," Qian told Medscape Medical News. "Within our own institution, earlier infusions may be encouraged, but it will likely not gain widespread appeal until stronger evidence is presented, and we don't know whether this phenomenon applies outside of melanoma."

Qian said he and his team are designing a randomized trial in patients with advanced melanoma "to rigorously assess the effect of immune checkpoint inhibitor time-of-day infusion patterns on patient outcomes."

Lancet Oncol. Published online November 12, 2021. Abstract, Editorial

Levi and Qian have disclosed no relevant financial relationships. Several of Qian's co-authors have recieved grants and consultant payments and have other ties to various companies, including BMS, Merck, and Pfizer.

M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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