Ramón Salazar
Head of Medical Oncology at the Catalan Institute of Oncology (ICO), head of the Colorectal Cancer Research Group, Oncobell programme (IDIBELL) and associate professor of Medicine at the University of Barcelona
“Overall, this is a randomised phase 3 trial that addresses a very specific clinical question—whether the time of administration influences the efficacy of immunochemotherapy—and does so with a prospective design and an independent, blinded committee to evaluate responses and progression, which reinforces the quality of the data.
The results are very striking: administration before 3 p.m. is associated with statistically significant improvement in both PFS and OS, with HRs of 0.40, which is associated with a clinically relevant effect size, more than sufficient for the approval of new drugs, for example."
How does this fit with the evidence already known, and what implications could it have? Is such a difference in response plausible based solely on the time of administration?
"It fits with previous, mainly retrospective literature and a meta-analysis that already suggested better results when PD-1/PD-L1 inhibitors are administered earlier in the day; the relevant contribution here is that it confirms this in a phase 3 randomised trial in advanced lung cancer.
From a biological point of view, it is plausible that the circadian clock modulates immune function; the study itself shows differences in peripheral blood consistent with greater cytotoxic “tone” (e.g., increased CD8+ and a more favourable balance between activation and exhaustion) in the early-treated group.
If confirmed in other contexts, the practical implication is enormous because changing the time of infusion would be a simple and cost-free intervention, potentially capable of improving outcomes with the same treatment".
Are there any important limitations to consider?
"The effect size is too large to depend “only” on the time, so the prudent interpretation is that the trial provides a very strong signal but needs replication and analysis of possible organisational bias factors or actual exposure to the intervention.
It is a single-centre study (China) with a highly male population (≈90% men), which means that generalisation to other healthcare systems and populations needs to be confirmed.
Randomisation was without stratification and the trial is open-label for logistical reasons; although progression was assessed by an independent committee, the absence of blinding may influence clinical decisions or indirect exposures. Some of the biological data (activated/exhausted subpopulations) comes from small subsamples and is exploratory, with comparisons not adjusted for multiplicity; this supports plausibility but is not definitive mechanistic evidence.
In summary, this work suggests that something as routine as scheduling immunotherapy in the morning could have a relevant clinical impact on advanced lung cancer, but the magnitude of the benefit requires multicentre confirmation before changing standards across the board".