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

However, prospective randomized controlled trials are needed to validate it.

然而，需要前瞻性随机对照试验来验证这一点。

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.

在这项随机III期LungTIME-C01试验中，210名未接受治疗的IIIC-IV期非小细胞肺癌（NSCLC）患者，缺乏驱动基因突变，按照1:1的比例随机分配到早期或晚期ToD组，通过在15:00之前或之后进行抗PD-1药物的前四个周期来定义。

The primary endpoint was progression-free survival(PFS), while secondary endpoints included overall survival(OS) and objective response rate(ORR).

主要终点是无进展生存期（PFS），次要终点包括总生存（OS）和客观缓解率（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).

中位随访时间为28.7个月后，早期治疗组的中位无进展生存期（PFS）为11.3个月（95%置信区间（CI）= 9.2-13.4），晚期治疗组的中位无进展生存期为5.7个月（95% CI = 5.2-6.2），早期疾病进展的风险比（HR）为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).

早期治疗组的中位总生存期（OS）为28.0个月（95%置信区间（CI）= 不可估计（NE）-NE），晚期治疗组的中位总生存期为16.8个月（95% CI = 13.7-19.9），早期死亡的风险比（HR）为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.

治疗相关的不良事件与已知的安全性特征一致，未观察到新的安全信号。

No significant differences in immune-related adverse events were observed between the two groups.

两组间免疫相关不良事件没有显著差异。

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).

在最初的四个周期中，早晨循环的CD8+ T细胞在早期ToD组中增加，而在晚期ToD组中减少（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).

此外，早期ToD组中活化的（CD38+ HLA-DR+）与耗竭的（TIM-3+PD-1+）CD8+ T细胞的比例高于晚期ToD组（P < 0.001）（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.

总结来说，我们的研究表明，早期ToD免疫化疗显著改善了无进展生存期（PFS）和总生存期（OS），并且与晚期ToD治疗相比，与增强的抗肿瘤CD8+ T细胞特性相关。

ClinicalTrials.gov registration: NCT05549037 .

ClinicalTrials.gov注册号：NCT05549037。