ChronoimmunoTOX: A Single-Institution Retrospective Study on How the Time of Administration Impacts Immune Checkpoint Inhibitor Efficacy and Toxicity in Melanoma

Sep 30, 2026

The timing of immune checkpoint inhibitor (ICI) administration may shape clinical outcomes and the frequency and severity of immune-related adverse events (irAEs), yet supporting evidence remains limited. A retrospective cohort study analyzed 41 patients with advanced melanoma treated with combined ipilimumab and nivolumab at a single institute between 2018 and 2024. Infusions completed before 2:00 p.m. defined the morning group, otherwise the afternoon group. Morning dosing showed improved progression-free and overall survival, while overall irAE incidence was comparable; afternoon treatment more often required systemic immunosuppression for grade ≥ 2 toxicities.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Abstract

Introduction

Article ChronoimmunoTOX: A Single-Institution Retrospective Study on How the Time of Administration Impacts Immune Checkpoint Inhibitor Efficacy and Toxicity in Melanoma Alessandro Nepote 1,2,†, Gilles Burghgraeve 1,†, Martino Pedrani 1, Anderson Junior Gomez Ramos 1, Isabella Saporita 1,2, Vito Spataro 1, Vittoria Espeli 1, Ricardo Pereira Mestre 1, Dario Sangiolo 2,3, Martina Imbimbo 1,‡ and Cristina Mangas 1,4, *,‡ Academic Editor: Stamatis Gregoriou Received: 14 November 2025 Revised: 14 December 2025 Accepted: 18 December 2025 Published: 22 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Istituto Oncologico Svizzera Italiana, Ente Ospedaliero Cantonale, Ospedale Regionale Bellinzona e Valli, 6500 Bellinzona, Switzerland; alessandro.nepote@unito.it (A.N.); [gilles.burghgraeve@usi.ch](gilles.burghgraeve@usi.ch) (G.B.); [martino.pedrani@eoc.ch](martino.pedrani@eoc.ch) (M.P.); [junioranderson.gomezramos@eoc.ch](junioranderson.gomezramos@eoc.ch) (A.J.G.R.); isabella.saporita@unito.it (I.S.); [vito.spataro@hin.ch](vito.spataro@hin.ch) (V.S.); [vittoria.espeli@eoc.ch](vittoria.espeli@eoc.ch) (V.E.); [ricardo.pereiramestre@eoc.ch](ricardo.pereiramestre@eoc.ch) (R.P.M.); [martina.imbimbo@eoc.ch](martina.imbimbo@eoc.ch) (M.I.) 2 Dipartimento di Oncologia, Università di Torino, Regione Gonzole 10, 10043 Orbassano, Italy; dario.sangiolo@unito.it 3 Candiolo Cancer Institute FPO-IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, Italy 4 Dermatology Department Ente Ospedaliero Cantonale, Ospedale Regionale Bellinzona e Valli, 6500 Bellinzona, Switzerland * Correspondence: cristina.mangas@eoch.ch † These authors contributed equally to this work. ‡ These authors jointly supervised this work. Abstract Background: The timing of immune checkpoint inhibitor (ICI) administration may influence clinical outcomes, incidence, and severity of immune-related adverse events (irAEs), but evidence remains limited. Methods: We conducted a retrospective analysis of 41 patients with advanced melanoma treated with combined ipilimumab and nivolumab atthe Istituto Oncologico della Svizzera Italiana between 2018 and 2024 . Infusions completed before 2:00 p.m. were classified as morning (AM). Patients receiving ≥50% of doses in the morning were assigned to the AM group; the remaining patients comprised the afternoon (PM) group. Results: Twenty-one patients were included in the AM group and twenty in the PM group. Median progression-free survival (PFS) was not reached in the AM group, compared with 7.8 months in the PM group (univariate HR 0.29, 95% CI 0.12–0.70; p = 0.006) . Overall survival (OS) was also significantly improved in the AM group (univariate HR 0.25, 95% CI 0.08–0.80; p = 0.019) . The overall incidence of irAEs was similar between groups. However, systemic immunosuppression for grade ≥ 2 toxicities was more frequently required in the PM group (80% vs. 52%, p = 0.06) . Conclusions: In this retrospective cohort, morning administration of ICIs was associated with improved PFS and OS in patients with advanced melanoma. While irAE incidence was comparable between groups, patients treated in the afternoon more often required systemic immunosuppression. Keywords: Chronoimmunotherapy; melanoma; Anti PD-1; anti CTLA-4; immune adverse events 1. Introduction The introduction of immune checkpoint inhibitors (ICIs) has deeply changed the management and prognosis of patients with metastatic melanoma (MM) over the past decade, unleashing T cells’ ability to mediate antitumor responses by targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) signals [1,2] . However, about 50% of treated patients do not achieve sustained benefits from immunotherapy and will therefore progress, highlighting the need for

FAQs

How did the study define morning versus afternoon administration?

Infusions completed before 2:00 p.m. were classified as morning (AM). Patients receiving ≥50% of doses in the morning were assigned to the AM group; the rest formed the afternoon (PM) group.

What impact did morning administration have on survival outcomes?

In the AM group, median progression-free survival was not reached, compared with 7.8 months in the PM group. Overall survival was also significantly improved with morning administration.

Did immune-related adverse events (irAEs) differ between the groups?

The overall incidence of irAEs was similar between AM and PM groups. However, systemic immunosuppression for grade ≥2 toxicities was required more frequently in the PM group.

Sep 30, 2026

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