Does Immunotherapy Late in the Day Affect Survival in Melanoma?

Advanced melanoma patients with more immune checkpoint inhibitor infusions administered late in the day appeared to have worse survival outcomes, the single-center MEMOIR (Melanoma Outcomes Following Immunotherapy) study found.

In a propensity score-matched analysis of patients who did and did not (73 in each group) receive at least 20% of their infusions after 4:30 pm, median overall survival (OS) was lower for the group with more later-day infusions (4.8 years vs not reached, respectively; HR 2.04, 95% CI 1.04-4.00, P=0.038), reported Zachary S. Buchwald, MD, of Winship Cancer Institute of Emory University in Atlanta, and colleagues.

“Our findings suggest that avoidance of evening infusions of immune checkpoint inhibitors might extend overall survival through better integration with the immune system’s intrinsic circadian rhythm, which promotes a more effective immune-mediated antitumor response,” Buchwald and co-authors wrote in Lancet Oncology. They added that for advanced melanoma, the findings justify the design and implementation of a randomized trial to “rigorously assess” the effect of time-of-day infusion patterns on patient outcomes.

The findings were similar in multivariable analysis (HR 2.16, 95% CI 1.10-4.25, P=0.025) that adjusted for age, ECOG performance status, pretreatment lactate dehydrogenase concentrations, receipt of corticosteroids within 1 month of a checkpoint inhibitor infusion, and receipt of radiotherapy at any time for melanoma. Comparable results were also seen for the entire unmatched study cohort (HR 1.80, 95% CI 1.08-2.98, P=0.023).

The researchers noted that the findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening rather than during the day. “Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma,” the team wrote.

Writing in an accompanying commentary, Francis Lévi, MD, PhD, of the University of Warwick in Coventry, England, noted that the study observed a more pronounced association between OS and infusion timing among women than in men. This, along with the further investigation of circadian biomarkers, Lévi suggested, could help personalize optimal immunotherapy timing.

The team’s “research on the effect of timing of infusions of immune checkpoint inhibitors is challenging and clinically driven, and could change clinical practice at no additional cost,” Lévi said. “The further development of circadian rhythm-based immunochemotherapy would indeed shift cancer medicine into true precision oncology.”

MEMOIR is an ongoing, longitudinal study of patients with melanoma treated with ipilimumab (Yervoy), nivolumab (Opdivo),or pembrolizumab (Keytruda), or combinations of those drugs. The current analysis included adults with stage IV melanoma who started immunotherapy between January 2012 and December 2020.

Checkpoint inhibitors were administered intravenously, with initial doses per standard of care; infusion start times ranged from 8 am to 5:30 pm. Of the 299 patients in the study, 74 (25%) received at least 20% of their infusions after 4:30 pm.

The median follow-up was 27 months. In the unmatched population, the team also found:

• Patients who had more evening infusions had a lower 1-year progression-free survival rate than those with fewer evening infusions (40% vs 56%; P=0.041)

• Patients who had more evening infusions also had a lower complete response rate (22% vs 34%, respectively; P=0.069)

The most common adverse events (AEs) in the full cohort were colitis (18%), hepatitis (9%), and hypophysitis (5%). AEs leading to a change or discontinuation of checkpoint inhibitors were balanced between the two groups and were not associated with OS, the authors said.