EARLY immunochemotherapy delivery significantly improves progression free survival and overall survival in advanced non-small cell lung cancer, according to findings from a randomised Phase three trial evaluating time of day treatment effects.
Early Immunochemotherapy Improves Survival
The Phase three LungTIME C01 trial enrolled 210 patients with treatment naive stage IIIC to IV non-small cell lung cancer lacking driver mutations. Participants were randomly assigned in a one-to-one ratio to receive the first four cycles of an anti-programmed cell death protein one agent either before or after 15:00 h, defining early and late time of day groups respectively. The primary endpoint was progression free survival, while secondary endpoints included overall survival and objective response rate.
After a median follow up of 28.7 months, median progression free survival was longer in the early group: 11.3 months; 95% CI: 9.2–13.4 versus 5.7 months; 95% CI: 5.2–6.2. This corresponded to a hazard ratio for earlier disease progression: 0.40; 95% CI: 0.29–0.55; p<0.001. Median overall survival also favoured early immunochemotherapy: 28.0 months; 95% CI: not estimable–not estimable versus 16.8 months; 95% CI: 13.7–19.9, with a hazard ratio for earlier death: 0.42; 95% CI: 0.29–0.60; p<0.001.
Immune Correlates of Treatment Timing
Immunological analyses demonstrated divergent circulating CD8 positive T cell dynamics over the first four cycles. Morning circulating CD8 positive T cells increased in the early group but declined in the late group, with significant differences between groups: p<0.001. Furthermore, the ratio of activated CD38 positive human leucocyte antigen DR positive versus exhausted T cell immunoglobulin and mucin domain containing three positive programmed cell death protein one positive CD8 positive T cells was higher in the early group: p<0.001, compared with the late group: p<0.001. These data suggest enhanced antitumour CD8 positive T cell characteristics with early immunochemotherapy.
Safety Profile and Clinical Implications
Treatment related adverse events were consistent with the established safety profile, and no new safety signals were observed. No significant differences in immune related adverse events were identified between groups.
Regarding clinical implications, these findings indicate that early immunochemotherapy may substantially improve outcomes in advanced non-small cell lung cancer, without compromising safety. Prospective evidence from this trial supports the consideration of treatment timing as a modifiable factor in optimising immunochemotherapy efficacy.
Reference
Huang Z et al. Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial. Nat Med. 2026; doi:10.1038/s41591-025-04181-w.
