Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer

Simple Summary Initial clinical observations revealed strikingly longer follow-up for metastatic non-small-cell lung cancer (NSCLC) patients receiving nivolumab infusions predominantly in the morning as compared to those treated in the afternoon. Prior experimental and human studies have demonstrated the temporal distributions of immune cells' proliferation, trafficking, and antigen recognition and destruction over the 24 h. Here, we hypothesized that circadian timing could play an important role in nivolumab's efficacy, as previously shown for the toxicity and/or efficacy of chronomodulated chemotherapy in colorectal and lung cancer patients. Following project validation by an internal scientific review board, the dosing times of each of the 1818 nivolumab infusions given to 95 consecutive patients as a standard treatment for metastatic NSCLC were retrieved from the day-hospital records. Adverse events and radiologically documented tumor responses were retrieved and reviewed from patients' clinical charts. Patients were allocated to 'morning' (N = 48 patients) or 'afternoon' (N = 47 patients) groups, according to whether they had received the majority of nivolumab infusions before or after 12:54, i.e., the median time of all infusions, respectively. 'Morning' nivolumab dosing nearly quadrupled median progression-free and overall survival as compared to 'afternoon' dosing. 'Morning' nivolumab was significantly more effective irrespective of age, sex, performance status, prior treatments, tumor histology, or PD-L1 expression. In contrast, nivolumab primary resistance was most often observed following 'afternoon' dosing. Randomized trials are warranted both to further identify the optimal timing of checkpoint inhibitors in individual cancer patients, and to determine the main mechanisms that precisely drive immunotherapy efficacy and resistance along the circadian timescale. Hypothesis: Prior experimental and human studies have demonstrated the circadian organization of immune cells' proliferation, trafficking, and antigen recognition and destruction. Nivolumab targets T(CD8) cells, the functions, and trafficking of which are regulated by circadian clocks, hence suggesting possible daily changes in nivolumab's efficacy. Worse progression-free survival (PFS), and overall survival (OS) were reported for malignant melanoma patients receiving more than 20% of their immune checkpoint inhibitor infusions after 16:30 as compared to earlier in the day. Methods: Consecutive metastatic non-small-cell cancer (NSCLC) patients received nivolumab (240 mg iv q 2 weeks) at a daily time that was 'randomly' allocated for each course on a logistical basis by the day-hospital coordinators. The median time of all nivolumab administrations was computed for each patient. The study population was split into two timing groups based upon the median value of the median treatment times of all patients. CTCAE-toxicity rates, iRECIST-tumor responses, PFS and OS were computed according to nivolumab timing. PFS and OS curves were compared and hazard ratios (HR) were computed for all major categories of characteristics. Multivariable and sensitivity analyses were also performed. Results: The study accrued 95 stage-IV NSCLC patients (PS 0-1, 96%), aged 41-83 years. The majority of nivolumab administrations occurred between 9:27 and 12:54 for 48 patients ('morning' group) and between 12:55 and 17:14 for the other 47 ('afternoon' group). Median PFS (95% CL) was 11.3 months (5.5-17.1) for the 'morning' group and 3.1 months (1.5-4.6) for the 'afternoon' one (p < 0.001). Median OS was 34.2 months (15.1-53.3) and 9.6 months (4.9-14.4) for the 'morning' group and the 'afternoon' one, respectively (p < 0.001). Multivariable analyses identified 'morning' timing as a significant predictor of longer PFS and OS, with respective HR values of 0.26 (0.11-0.58) and 0.17 (0.08-0.37). The timing effect was consistent across all patient subgroups tested. Conclusions: Nivolumab was nearly four times as effective following 'morning' as compared to 'afternoon' dosing in this cohort of NSCLC patients. Prospective timing-studies are needed to minimize the risk of resistance and to maximize the benefits from immune checkpoint inhibitors.