Association Between Time of Day of Combination Immune Checkpoint Inhibitor Administration and Overall Survival in Advanced Melanoma Patients

Immune checkpoint inhibitor (ICI) therapy has significantly improved the median overall survival of melanoma patients; however, many patients do not have clinical benefit from ICI therapy. The prognostic role of modifiable factors, such as the time of ICI administration, in immunotherapy treatment outcomes has not been well examined. Recent studies suggest that administration of ICIs earlier in the day may be associated with improved survival outcomes among cancer patients. In this study, we examined the association of treatment timing of the first dose of combination ICI (nivolumab + ipilimumab) with overall survival (OS) in patients with unresectable or metastatic melanoma without prior systemic therapy. Methods: We conducted a retrospective cohort study of electric health record data of patients with unresectable or metastatic melanoma at the Fred Hutchinson Cancer Center (N = 74). Patients assigned to the “early group” were administered the first dose of combination ICI therapy before 13:00h and the “late group” if administration was after 14:00h. The Kaplan-Meier method was used to estimate OS of the early and late groups. Additionally, Cox proportional hazard regression models were used to estimate the association between OS and time of ICI administration. Results: There was a statistically significant difference in the 1-year and 3-year OS estimates of the early and late infusion groups (p<0.05). Differences were also observed at 5 years but were not statistically significant. The estimated hazard of death during follow-up among patients who received the first dose of their combination ICI therapy after 14:00h was 2.76 (95% CI: 0.79, 9.69) times as great as that among patients who had their first dose before 13:00h. Although not statistically significant, the magnitude and direction of the hazard ratio is consistent with more favorable survival among those who receive their initial ICI infusion earlier in the day. Conclusion: This study found longer OS among unresectable and metastatic melanoma patients who were administered their first dose of combination ICI therapy earlier in the day compared to later in the day. Modulating the timing of initial ICI exposure could potentially improve outcomes in patients treated with ICIs.