Is Immunotherapy More Effective Earlier in Day?

Does the time of day of immunotherapy infusions affect patients’ survival outcomes?

A recent meta-analysis that examined data from over a dozen studies concluded that immunotherapy provided earlier in the day substantially improves progression-free and overall survival across a range of cancers, including metastatic melanoma, renal cell carcinoma, and esophageal cancer, as well as both locally advanced and metastatic non–small cell lung cancer (NSCLC).

In stage IV melanoma, for instance, a 2023 study found that patients who had more than 75% of infusions after 2 PM had shorter median overall survival — 14.9 months vs 38.1 months for those with earlier infusions (hazard ratio [HR], 0.45).

One of the latest studies on the topic, published earlier this year, found that older patients with locally advanced NSCLC who received at least half of durvalumab infusions within 3 hours of sunset had more than a twofold higher risk for distant metastases (HR, 2.13) as well as worse progression-free survival.

“Cancer type after cancer type, when you try this with immunotherapy, it replicates,” said David Qian, MD, PhD, a thoracic radiation oncologist at MD Anderson Cancer Center, Houston, and an author on the meta-analysis. “I think there’s real underlying science going on.”

Still, despite the growing body of evidence, many clinicians remain skeptical about the association. The reality is there has not yet been a large, robust multicenter randomized trial to demonstrate that immunotherapy timing matters, Qian noted, so “for now, I think we’re in a fringe group.”

Why Would Time of Day Matter?

Circadian clocks keep people’s internal systems in balance. This internal timepiece modulates the expression of many genes, including those linked to immunity, DNA repair, and cell proliferation.

A growing body of research has explored whether disrupting that balance could increase a person’s risk for cancer and whether manipulating these rhythms could improve outcomes among patients receiving treatment for cancer. In oncology, the latter idea — known as chronotherapy — typically means delivering cancer therapy during specific circadian windows to optimize treatment efficacy.

However, “the complexities of clock-cancer interactions make prediction of the effects of timed drug administration challenging,” according to Aziz Sancar , MD, PhD, a biochemist at University of North Carolina, Chapel Hill, North Carolina, and Russell N. Van Gelder, MD, PhD, from University of Washington Medicine, Seattle, in a recent review on the topic, published in Science.

Biologic mechanisms are emerging that may help explain why immunotherapy seems to work better in the morning.

One central explanation is that lymphocyte levels in tumors are highest earlier in the day and drop off as the day goes on. Because immunotherapy relies on lymphocytes to work, these agents would likely be more effective at the start of the day when lymphocyte concentrations are higher.

Another mechanistic clue came from a recent immunotherapy time-of-day study in metastatic renal cell carcinoma. The team, which included Qian, found that T-cell activity in response to immunotherapy was highest earlier in the day, which is also when immunotherapy showed the greatest survival benefits.

Depends on the Therapy

While research largely suggests that immunotherapy is more effective earlier in the day, the evidence is less clear for other cancer treatments.

In the recent NSCLC study, which explored the timing of durvalumab and chemoradiotherapy on tumor control, the benefit of radiotherapy appeared stronger later in the day. Providing at least half of radiotherapy treatments within 3 hours of sunset was associated with significantly lower risks for progression (HR, 0.39) and distant metastases (HR, 0.27), according to lead investigator Matthew McMillan, MD, a radiation oncology resident, and colleagues at Memorial Sloan-Kettering Cancer Center in New York City.

McMillan’s team found that at the end of chemoradiation, absolute lymphocyte counts were higher in patients who had the bulk of radiation treatments later, suggesting that radiation may have killed fewer lymphocytes later in the day.

But other research findings conflict. One recent study in men receiving external beam radiotherapy for prostate cancer, for instance, found no overall differences in biochemical failure or distant metastasis by treatment time. When looking at patients by race, a benefit did emerge for White men, who had higher rates of freedom from biochemical failure and distant metastasis when treated early in the day versus late in the afternoon.

Studies evaluating the timing of chemotherapy have also been inconsistent. The NSCLC study found, for instance, that the timing of chemotherapy did not affect cancer outcomes. Another recent study found chemotherapy in the morning was associated with worse survival and toxicity in women, but not men, with diffuse large B-cell lymphoma. And preliminary data in glioblastoma suggested the morning was better.

“On the whole, available data do not support the claim that chrono-chemotherapy is broadly beneficial for the treatment of any form of cancer, and it is not commonly practiced,” Sancar and Gelder explained.

More Data Needed, Feasibility Concerns

The evidence to date highlighting the potential importance of immunotherapy timing has yet to affect clinical practice.

Despite the positive findings, Qian noted, immunotherapy treatment timing is still dictated by logistical factors, such as when pharmacies can have infusions ready.

The lack of large, randomized trials has also posed a barrier. Qian said he has faced “a lot of disappointment” trying to get a big trial off the ground.

After leading an investigation on the timing of immunotherapy in metastatic melanoma, Qian and colleagues approached cancer consortiums to try to get a large, randomized study off the ground but had no luck. Consortium leaders either didn’t believe immunotherapy timing made a difference or didn’t think it was possible for pharmacies across multiple cancer centers to coordinate infusions at particular times of day.

Funding was also an issue. Drug companies would likely not be interested in funding a trial that might find, for instance, that immunotherapies should be given in the morning instead of any time of day because it could potentially lead to lower use, Qian noted.

That likely means funding for a large multicenter trial would have to come from elsewhere. Qian and his colleagues are working on launching a single-center randomized trial at Emory University in Atlanta with just over 100 patients with metastatic melanoma. Patients will be randomly assigned to one of three 3-hour time slots for immunotherapy, either early in the day, midday, or later, with the goal of finding out exactly how early immunotherapy should be given.

Colleagues from other institutions have shown interest, but there are no commitments yet, and all funding so far has been internal, Qian added.

Although the oncology community remains to be convinced, Qian has had patients who have researched the topic and asked him for immunotherapy infusions earlier in the day.

McMillan said he has also encountered skepticism about treatment timing, but he feels optimistic and plans to continue studying the issue.

“There are definitely people who are interested in the field,” McMillan said.

The MSKCC study was funded by the National Cancer Institute, among others. McMillan, his co-investigators, and Qian didn’t have any disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Email: [email protected].