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Time of day of neoadjuvant immune checkpoint inhibitor administration is associated with survival but not pathological response in resectable stage III–IV melanoma : A retrospective cohort study

Nelson, Axel ; Alghaib, Safa ; Björkström, Karl ; Isaksson, Karolin LU ; Krabbe, Ellen ; Orme, Sophie ; Kadefors, Måns ; Wallander, Mikael ; Bjursten, Sara and Ullenhag, Gustav J. , et al. (2026) In European Journal of Cancer 243.
Abstract

Background Circadian rhythms regulate immune cell trafficking and function, and emerging clinical data suggest that the timing of immune checkpoint inhibitor (ICI) administration may influence efficacy. In advanced disease, later-day administration has been associated with inferior outcomes. Whether this applies to neoadjuvant ICI in resectable stage III–IV melanoma is unknown. Methods This retrospective cohort study included patients with resectable stage III–IV cutaneous melanoma treated with neoadjuvant ICI at four Swedish academic centers. Patients were categorized by timing of ICI across two infusions (morning, both <12:00; afternoon, both ≥12:00; mixed, one <12:00 and one ≥12:00). The primary endpoint was major pathological... (More)

Background Circadian rhythms regulate immune cell trafficking and function, and emerging clinical data suggest that the timing of immune checkpoint inhibitor (ICI) administration may influence efficacy. In advanced disease, later-day administration has been associated with inferior outcomes. Whether this applies to neoadjuvant ICI in resectable stage III–IV melanoma is unknown. Methods This retrospective cohort study included patients with resectable stage III–IV cutaneous melanoma treated with neoadjuvant ICI at four Swedish academic centers. Patients were categorized by timing of ICI across two infusions (morning, both <12:00; afternoon, both ≥12:00; mixed, one <12:00 and one ≥12:00). The primary endpoint was major pathological response. Secondary endpoints were event-free (EFS), distant metastasis–free (DMFS), melanoma-specific (MSS), and overall survival (OS). Associations were assessed using logistic regression and Cox models. Results A total of 265 patients were included (morning, n = 94; mixed, n = 96; afternoon, n = 75). Major pathological response rates were similar across groups (morning 47%, mixed 44%, afternoon 40%; p = 0.68). After a median follow-up of 17.4 months, morning administration was associated with a lower hazard of events across survival endpoints versus afternoon, including DMFS (HR 0.47, 95% CI 0.23–0.96), MSS (HR 0.18, 95% CI 0.04–0.71), and OS (HR 0.13, 95% CI 0.04–0.50) but not EFS (HR 0.58, 95% CI 0.31–1.08), compared with afternoon administration. Associations remained after adjustment for pathological response. Conclusions Time of day of neoadjuvant ICI administration was not associated with pathological response. However, afternoon administration was associated with worse survival outcomes. These findings suggest treatment timing may influence long-term outcomes, although prospective validation is needed.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Immune checkpoint inhibitor, Melanoma, Neoadjuvant treatment, PD-1, Surgery, Time of day
in
European Journal of Cancer
volume
243
article number
116833
publisher
Elsevier
external identifiers
  • pmid:42218102
  • scopus:105040546762
ISSN
0959-8049
DOI
10.1016/j.ejca.2026.116833
language
English
LU publication?
yes
id
c1ee75ba-6fe6-43fd-9d45-8e2078242f1b
date added to LUP
2026-09-02 13:52:33
date last changed
2026-09-02 13:53:22
@article{c1ee75ba-6fe6-43fd-9d45-8e2078242f1b,
  abstract     = {{<p>Background Circadian rhythms regulate immune cell trafficking and function, and emerging clinical data suggest that the timing of immune checkpoint inhibitor (ICI) administration may influence efficacy. In advanced disease, later-day administration has been associated with inferior outcomes. Whether this applies to neoadjuvant ICI in resectable stage III–IV melanoma is unknown. Methods This retrospective cohort study included patients with resectable stage III–IV cutaneous melanoma treated with neoadjuvant ICI at four Swedish academic centers. Patients were categorized by timing of ICI across two infusions (morning, both &lt;12:00; afternoon, both ≥12:00; mixed, one &lt;12:00 and one ≥12:00). The primary endpoint was major pathological response. Secondary endpoints were event-free (EFS), distant metastasis–free (DMFS), melanoma-specific (MSS), and overall survival (OS). Associations were assessed using logistic regression and Cox models. Results A total of 265 patients were included (morning, n = 94; mixed, n = 96; afternoon, n = 75). Major pathological response rates were similar across groups (morning 47%, mixed 44%, afternoon 40%; p = 0.68). After a median follow-up of 17.4 months, morning administration was associated with a lower hazard of events across survival endpoints versus afternoon, including DMFS (HR 0.47, 95% CI 0.23–0.96), MSS (HR 0.18, 95% CI 0.04–0.71), and OS (HR 0.13, 95% CI 0.04–0.50) but not EFS (HR 0.58, 95% CI 0.31–1.08), compared with afternoon administration. Associations remained after adjustment for pathological response. Conclusions Time of day of neoadjuvant ICI administration was not associated with pathological response. However, afternoon administration was associated with worse survival outcomes. These findings suggest treatment timing may influence long-term outcomes, although prospective validation is needed.</p>}},
  author       = {{Nelson, Axel and Alghaib, Safa and Björkström, Karl and Isaksson, Karolin and Krabbe, Ellen and Orme, Sophie and Kadefors, Måns and Wallander, Mikael and Bjursten, Sara and Ullenhag, Gustav J. and Carneiro, Ana and Helgadottir, Hildur and Ny, Lars and Olofsson Bagge, Roger}},
  issn         = {{0959-8049}},
  keywords     = {{Immune checkpoint inhibitor; Melanoma; Neoadjuvant treatment; PD-1; Surgery; Time of day}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{European Journal of Cancer}},
  title        = {{Time of day of neoadjuvant immune checkpoint inhibitor administration is associated with survival but not pathological response in resectable stage III–IV melanoma : A retrospective cohort study}},
  url          = {{http://dx.doi.org/10.1016/j.ejca.2026.116833}},
  doi          = {{10.1016/j.ejca.2026.116833}},
  volume       = {{243}},
  year         = {{2026}},
}