Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial
Summary
Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC-IV non-small cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 ag
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# Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial
*Published: 2026 Apr*
Retrospective studies suggest that early time-of-day (ToD) infusions of
immunochemotherapy may improve efficacy. However, prospective randomized
controlled trials are needed to validate it. In this randomized phase 3
LungTIME-C01 trial, 210 patients with treatment naive stage IIIC-IV non-small
cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a
1:1 ratio to either an early or late ToD group, defined by the administration of
the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary
endpoint was progression-free survival (PFS), while secondary endpoints included
overall survival (OS) and objective response rate (ORR). After a median
follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence
interval (CI) = 9.2-13.4) in the early ToD group and 5.7 months (95%
CI = 5.2-6.2) in the late ToD group, corresponding to a hazard ratio (HR) for
earlier disease progression of 0.40 (95% CI = 0.29-0.55; P < 0.001). The median
OS was 28.0 months (95% CI = not estimable (NE)-NE) in the early ToD group and
16.8 months (95% CI = 13.7-19.9) in the late ToD group, corresponding to an HR
of an earlier death of 0.42 (95% CI = 0.29-0.60; P < 0.001). Treatment-related
adverse events were consistent with the established safety profile, with no new
safety signals observed. No significant differences in immune-related adverse
events were observed between the two groups. Over the first four cycles, morning
circulating CD8+ T cells increased in the early ToD group, whereas they declined
in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+
HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD
group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our
study indicates that early ToD immunochemotherapy substantially improves PFS and
OS and is associated with enhanced antitumor CD8+ T cell characteristics
compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037 .
DOI: 10.1038/s41591-025-04181-w