Abstract：
BACKGROUND: Recent retrospective studies suggest potential large patient\'s benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex.
METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied.
RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4).
CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.
METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied.
RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4).
CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.
摘要：
背景：最近的回顾性研究表明，通过适当的时机使用免疫检查点阻断剂（ICB），大患者可能受益。ICB治疗时机与患者生存之间的关系，研究了肿瘤反应和毒性，以及与绩效状态(PS)和性别的互动。
方法：一组转移性或局部晚期实体瘤患者，谁接受了帕博利珠单抗，Nivolumab,阿替珠单抗,durvalumab,或者阿维鲁单抗，单独或伴随化疗，2015年11月至2021年3月，在法国莱昂·贝拉德中心，进行了回顾性研究。
结果：调查了361例患者（80％的非小细胞肺癌患者，平均[SD]年龄：63[11]岁，39%的女性83％PS0-1在第一次输注，19%接受伴随化疗)。ICB从07:25至17:21施用,并且最佳上午/下午截止时间为11:37。与下午相比，上午输注与OS增加相关(中位数为30.3vs15.9个月，p=0.0024；HR1.56[1.17-2.1]，p=0.003)。发现了很强的PS定时相互作用(PS0-1名患者，HR=1.53[1.10-2.12]，p=0.011;PS2-3患者，HR=0.50[0.25-0.97]，p=0.042)。早晨PS0-1患者的OS增加（中位数为36.7vs21.3个月，p=0.023),部分/完全缓解率（58%vs41%，p=0.027),和1-3级毒性(49%对34%，p=0.028)。在一天中最糟糕的时间输注之间的死亡率风险比，估计在13:36[12:48-14:23]，而在清晨等于4.8([2.3-10.1]，p=0.008)。毒性的时间差异仅在女性患者中产生显着（女性与男性：p<0.001vs0.4）。
结论：清晨ICB输注与OS增加有关，回应,和PS0-1患者的毒性，与当天内的后期输注相比。需要前瞻性随机试验来证实这项回顾性研究。
方法：一组转移性或局部晚期实体瘤患者，谁接受了帕博利珠单抗，Nivolumab,阿替珠单抗,durvalumab,或者阿维鲁单抗，单独或伴随化疗，2015年11月至2021年3月，在法国莱昂·贝拉德中心，进行了回顾性研究。
结果：调查了361例患者（80％的非小细胞肺癌患者，平均[SD]年龄：63[11]岁，39%的女性83％PS0-1在第一次输注，19%接受伴随化疗)。ICB从07:25至17:21施用,并且最佳上午/下午截止时间为11:37。与下午相比，上午输注与OS增加相关(中位数为30.3vs15.9个月，p=0.0024；HR1.56[1.17-2.1]，p=0.003)。发现了很强的PS定时相互作用(PS0-1名患者，HR=1.53[1.10-2.12]，p=0.011;PS2-3患者，HR=0.50[0.25-0.97]，p=0.042)。早晨PS0-1患者的OS增加（中位数为36.7vs21.3个月，p=0.023),部分/完全缓解率（58%vs41%，p=0.027),和1-3级毒性(49%对34%，p=0.028)。在一天中最糟糕的时间输注之间的死亡率风险比，估计在13:36[12:48-14:23]，而在清晨等于4.8([2.3-10.1]，p=0.008)。毒性的时间差异仅在女性患者中产生显着（女性与男性：p<0.001vs0.4）。
结论：清晨ICB输注与OS增加有关，回应,和PS0-1患者的毒性，与当天内的后期输注相比。需要前瞻性随机试验来证实这项回顾性研究。
