Konstantinos Lallas ¹ Eftychia Chatziioannou ² Derya Durak ² Georg Frey ^2* Lina Maria Serna-Higuita ³ Marie-Lena Rasch ^2* Athanassios Kyrgidis ⁴ Eleni Timotheadou ^1* Zoe Apalla ⁵ Ulrike Leiter-Stöppke ^2* Lukas Flatz ^2,6* Aimilios Lallas ⁷ Teresa Amaral ^2,6*

• ¹ Department of Medical Oncology, School of Medicine, Aristotle University of Thessaloniki, Greece, Thessaloniki, Greece
• ² Center for Dermato-oncology, Department of Dermatology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany, Tubingen, Germany
• ³ Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany, Tübingen, Germany
• ⁴ Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, Greece, Thessaloniki, Greece
• ⁵ Second Department of Dermatology, School of Medicine, Aristotle University of Thessaloniki, Greece, Thessaloniki, Greece
• ⁶ Cluster of Excellence for Individualization of Tumor Therapies through Molecular Imaging and Functional Identification of Therapeutic Target Structures, University of Tübingen, Tübingen, Baden-Württemberg, Germany
• ⁷ Department of Dermatology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

Background: Despite durable responses achieved with Immune Checkpoint Inhibitors (ICIs), data about optimal duration of treatment, especially in the context of adverse events, remain scarce.Objective: To systematically review the evidence concerning the impact of treatment discontinuation with ICIs for reasons other than progressive disease (PD) on relapse rates and survival of melanoma patients.Methods: A systematic literature search was conducted in three electronic databases until July 2024.Studies referring to melanoma patients who ceased ICIs electively (i.e. due to complete response (CR), protocol completion or patient/physician's wish) or due to treatment-limiting toxicities (TLTs) were selected. Relapse rates (RRs) post cessation, time to PD, rechallenge and disease control rate (DCR) after 2 nd course were the main outcomes. Random-effects models were preferred, and subgroup and sensitivity analyses were conducted to investigate possible sources of heterogeneity.Results: 38 and 35 studies were included in qualitative and quantitative synthesis, respectively. From 2542 patients discontinued treatment with ICIs electively or due to TLTs, 495 experienced progression [number of studies (n)=34, RR 20.9%, 95%CI 17.1 -24.7%, I 2 85%) and higher rates were detected in patients with TLTs compared to elective discontinuation. Mean time to PD was 14.26 months (n=18, mean time 14.26,, I 2 93%) and was numerically higher in patients who ceased for CR compared to patients with TLTs. Treatment duration before cessation was not associated with risk and time to relapse, while mucosal melanomas and non-CR as BOR during treatment led to increased risk for relapse and shorter time to PD compared to other histologic subtypes or CR. Rechallenge with ICI resulted in 57.3% DCR and 28.6% pooled CR rates (n=22, CR rate 28.6%, 95%CI 17.1 -40.2, I 2 68%). Heterogeneity among studies was high, but subgroup analysis based on type of ICI used (anti-CTL4 and anti-PD1 inhibitor or anti-PD1 monotherapy) and type of study (RCTs or observational studies), along with sensitivity analyses did not reveal significant alterations in results.Discontinuation of ICIs in patients without progression is possible. Outcomes to rechallenge with ICIs may differ depending on the reason for discontinuation, but remains a considerable option.