Time-of-day immunochemotherapy in nonsmall cell lung cancer: a randomized phase 3 trial

An international team confirms in a pioneering phase 3 clinical trial the decisive role of the time of day on the success of anti-tumour immunotherapies.

Basic research had already shown the decisive influence of biological clocks on tumour biology by influencing the behaviour of immune cells and their response to treatment. A Sino-European research consortium involving the University of Geneva (UNIGE) and Paris-Saclay University has confirmed this discovery in a clinical setting. People with advanced lung cancer who received immunochemotherapy before 3 p.m. saw their disease progress more slowly than those treated later in the day. These results, published in Nature Medicine as part of a phase 3 randomised trial involving 210 volunteers, suggest that scheduling treatment early in the day could be a simple and inexpensive way to improve the effectiveness of treatments already in routine use.  

Circadian clocks, which regulate most physiological processes on a roughly 24-hour cycle, are one of the most fundamental biological mechanisms. At the UNIGE Faculty of Medicine, Pr Christoph Scheiermann and his team (Department of Pathology and Immunology, Geneva Inflammation Research Centre & Translational Research Centre in Onco-Haematology) have been working for several years on the influence of circadian cycles on cancer. "We have discovered that the activation of the immune system is modulated according to the time of day, with a peak in the early morning in humans," explains Christoph Scheiermann. "In cancer, the growth and severity of tumours is therefore strongly linked to the biological clock of the immune system."

In 2024, the Geneva team showed, in a mouse model, that the success of immunotherapeutic anti-tumour treatments depended on the time of day at which they were administered. These results were confirmed by retrospective analysis of patient survival rates following these immunotherapies. "At the right time, the cells to be fought are immediately recognised. At the wrong time, the target molecules are expressed very little, and the drug has no effect," noted Christoph Scheiermann at the time.

A clear clinical validation

Based on this pioneering work, Yongchang Zhang of Central South University in Hunan and his colleagues conducted a phase 3 randomised clinical trial involving 210 people with non-small cell lung cancer who had not received any treatment. The patients were divided into two groups: the first received immunochemotherapy before 3 p.m. (early group) and the second at or after 3 p.m. (late group) during the first four cycles of treatment.

After a median follow-up of approximately 28.7 months, the early group experienced no worsening of their cancer (progression-free survival) for an average of 11.3 months, compared with 5.7 months for the late group. Median overall survival was 28.0 months in the early group and 16.8 months in the late group. Treatment response rates were 69.5% in the early group and 56.2% in the late group, and there were no significant differences in immune-related adverse events. The scientists also observed a greater quantity of CD8⁺ T cells (a type of immune cell) circulating in the blood and a higher ratio of activated CD8⁺ T cells to exhausted CD8⁺ T cells in the early group than in the late group, which could explain the higher therapeutic efficacy in this group. 

While further research is needed to determine long-term survival outcomes, as well as within a more diverse population, these results are encouraging. "Further studies will also need to be conducted to better understand the exact mechanisms linking the circadian rhythm to the efficacy of immunotherapies," concludes Christoph Scheiermann.

Professor Christoph Scheiermann was interviewed by CNN TV on February 14th 2026 to explain the promising results of the recently published study:

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