Retro TIMing: A multicentric retrospective analysis of immunotherapy timing in metastatic melanoma.
Authors: Gonçalves Lisa , Goncalves Duarte , Casanelles Teresa Esteban , Guerra Laura Pratas , Menezes Maria B , Duarte Branco Vanessa , Alves Luís Joana , Simões Filipa , Gramaça João , PINHO INES S , Barroso Tiago , Patel Vanessa , Esperança-Martins Miguel , Bras Raquel Lopes , Teixeira de Sousa Rita , Mansinho Andre , Torres Sofia , Costa Luis 
Published: July 2024

9542 Background: Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now the standard of care in the treatment of metastatic melanoma (mM). The interplay between cancer cells and tumor microenvironment cells (e.g. immune cells) impacts cancer cell survival, local invasion, and metastatic dissemination. Chrono-immunotherapy is an emerging field as circadian oscillations are observed in the immune landscape (e.g immune cell numbers) as well as in the expression of immunotherapy targets (e.g. PD-1). Recently, a growing body of evidence suggests the outcome can be influenced by the time of the day when immunotherapy is administered (morning versus in the afternoon). This work aims to evaluate the impact of immunotherapy with ICIs administration timing on the overall survival (OS) and progression-free survival (PFS) of patients with mM. Methods: Multicentric, retrospective cohort study of mM patients under immunotherapy (ipilimumab/nivolumab, nivolumab, or pembrolizumab) with PS 0-1, between July 2016 and June 2023. Clinical, demographic characteristics, and time of treatment administration were obtained from medical records. Patients were distributed in two groups: those who received less than 75% of infusions after 2pm (morning group), and those who received at least 75% of infusions after 2pm (afternoon group). OS and PFS were calculated with Kaplan-Meier method and tested using a Cox regression model, with a 95% confidence interval. Results: We identified 168 patients from the 7 Oncology Centers included. The majority were men (n=100, 59.5%), with a median age of 69 years old, and 22% of the patients (n=37) were included in the afternoon group. No significant demographic or tumor burden differences were found between the morning and afternoon groups. The median follow-up time was 29 months, the estimated median PFS was 11.8 months (CI 95%, 8.0 - 14.6) and median OS was 31.4 months (CI 95%, 20.6 - NR). Patients in the afternoon group presented with shorter OS compared with those in the morning group (14.4 vs 37.6 months; HR 1.94 [CI 95% 1.16 to 3.23]; p 0,014). No statistically significant differences were observed in PFS. Subgroup analysis showed an increased detriment of performing ICIs infusions in the afternoon in women (OS 8.7 (4.2, 21.2) versus 30.9 months (18.9, NR), p=0.002; afternoon versus morning) and those older than 65 years old (OS 14.2 months (4.7, 31.4) versus 24.2 months (18.3, NR), p=0.002); afternoon versus morning). Conclusions: This work provides valuable insights into the potential role of the circadian timing of immunotherapy treatments for mM, suggesting patients may benefit from having ICIs infusion in the morning. Prospective randomized studies with a translational approach are needed to validate and fully understand the underlying mechanisms at play in circadian timing efficacy.