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<p>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; <i>P</i> &lt; 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; <i>P</i> &lt; 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<sup>+</sup> T cells increased in the early ToD group, whereas they declined in the late ToD group (<i>P</i> &lt; 0.001). Furthermore, the ratio of activated (CD38<sup>+</sup> HLA-DR<sup>+</sup>) versus exhausted (TIM-3<sup>+</sup>PD-1<sup>+</sup>) CD8<sup>+</sup> T cells was higher in the early ToD group (<i>P</i> &lt; 0.001) compared with the late ToD group (<i>P</i> &lt; 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8<sup>+</sup> T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: <a href="https://clinicaltrials.gov/study/NCT05549037">NCT05549037</a>.</p>

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RETRACTED ARTICLE: Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial

  • 期刊论文

  • 发表日期：

    2026年2月2日

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  • Zhe Huang,
  • Liang Zeng,
  • Zhaohui Ruan,
  • Qun Zeng,
  • Huan Yan,
  • Wenjuan Jiang,
  • Yi Xiong,
  • Chunhua Zhou,
  • Haiyan Yang,
  • Li Liu,
  • Jiacheng Dai,
  • Nachuan Zou,
  • Shidong Xu,
  • Ya Wang,
  • Zhan Wang,
  • Jun Deng,
  • Xue Chen,
  • Jing Wang,
  • Hua Xiang,
  • Xiaomei Li,
  • Boris Duchemann,
  • Guoqiang Chen,
  • Yang Xia,
  • Tony Mok,
  • Christoph Scheiermann,
  • Francis Lévi,
  • Nong Yang,
  • Yongchang Zhang

摘要

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.