Why Is Morning Immunotherapy More Effective in Kidney, Esophageal, and Lung Cancer and Melanoma?

Could the time of day when people with cancer receive immunotherapy infusions affect survival?

ESMO Open published in February 2024 a meta-analysisshowing that in several cancers, including metastatic melanoma, renal cell carcinoma, esophageal cancer, and both locally advanced and metastatic non-small cell lung cancer (NSCLC), early-day immunotherapy significantly improved progression-free survival (PFS) and overall survival (OS).

Timing Makes a Difference

For example, Cell published a study in 2023 in which stage 4 melanoma patients, more than 75% of whom received immunotherapy after 14:00, had a median overall survival of only 14.9 months . In contrast, patients treated earlier in the day had overall survival reaching 38.1 months (HR: 0.45).

A study published in December 2024 in Radiotherapy and Oncology examined locally advanced NSCLC. Patients receiving at least half of their durvalumab infusions within three hours after sunset had a risk of distant metastasis that more than doubled (HR: 2.13), along with poorer progression-free survival.

Regardless of cancer type, similar results emerge when we examine immunotherapy timing. A real biological mechanism is thought to underlie this pattern.

Why Might Earlier Treatment Be More Effective?

Previously recognized by a Nobel Prize, biological clocksmaintain internal balance and regulate processes including immunity, DNA repair, and cell proliferation. Research suggests that disrupting this balance may increase cancer risk, while optimizing circadian rhythms during treatment may improve outcomes. In cancer care, this approach is called chronotherapy .

Research has identified several biological mechanisms suggesting that immunotherapy may work better in the morning:

• Lymphocyte Levels: Tumor lymphocyte levels have been shown to peak in the morning and fall as the day progresses. Because immunotherapy depends on lymphocyte activity, morning treatment may produce better results.

• T-cell Activity: A study in metastatic renal cell carcinoma found that T-cell activity in response to immunotherapy peaked in the morning, with survival advantages also more apparent at those times.

Does This Apply to All Cancer Treatments?

Although evidence favoring earlier immunotherapy is growing, the picture is less clear for other treatments.

For example, a study examining durvalumab and chemoradiotherapy timing in NSCLC found that radiation therapy later in the day produced better results . Patients receiving radiation within three hours after sunset had significantly lower progression risk (HR: 0.39) and distant metastasis risk (HR: 0.27).

Other studies, however, have produced conflicting results. Among men receiving radiation for prostate cancer, timing did not significantly affect biochemical failure or distant metastasis. Nevertheless, morning treatment appeared more advantageous for White patients.

Chemotherapy timing studies have also been inconsistent. One NSCLC study found no effect on cancer outcomes, while another found morning chemotherapy associated with poorer survival and more side effects in women with diffuse large B-cell lymphoma . Preliminary data in glioblastoma, however, suggest better outcomes with morning treatment.

Turkish Nobel laureate Dr. Aziz Sancar and Dr. Russell Van Gelder, in a review published in Science , discussed this issue and said: "The complexities of clock-cancer interactions make the effects of timed drug administration difficult to predict." They also wrote: "There is no support for a clear benefit of chronochemotherapy in any cancer type, and this approach is not widely used."

More Data and Practical Challenges

Evidence emphasizing immunotherapy timing has not yet substantially changed clinical practice. The main reasons include:

• Logistical Challenges: Timing is often determined by when pharmacies prepare infusions.

• Lack of Large Randomized Trials: Large, multicenter randomized trials clearly establishing the importance of immunotherapy timing have not yet been conducted.

• Lack of Funding: Drug companies are thought unlikely to fund a study concluding that immunotherapy should be given only at certain times, as restricting administration windows could reduce medication use and sales.

A single-center randomized trial involving metastatic melanoma is now being launched at Emory University in Atlanta. Patients will be randomly assigned to three time windows to examine how early immunotherapy needs to be given. Funding is entirely internal, however, and other institutions have not yet made firm commitments to participate.

Although the oncology community remains cautious, some patients have learned about the issue and already request early immunotherapy appointments.

Conclusions and Commentary

As oncologists, we were initially skeptical about treatment timing, but evidence increasingly suggests it may be important in cancer care. More data and large studies are needed before incorporating this information into practice. While research continues, some patients closely following developments have begun requesting earlier immunotherapy. Scientists continue working to clarify the issue.