Early Morning Checkpoint Inhibitor Infusion and Overall Survival of Patients with Metastatic Cancer: an In-depth Chronotherapeutic Study

Abstract Introduction Recent retrospective studies suggest potential large patient’s benefit through proper timing of immune checkpoint inhibitors (ICI). The association between ICI 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). ICI 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 5.5-fold ([2-20], 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 ICI 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.