Dose, Schedule, and Duration De-Escalation of Immune Checkpoint Inhibitors in Advanced Melanoma: Pharmacological Rationale and Clinical Evidence

Objective: Immune checkpoint inhibitors (ICIs) have transformed advanced melanoma treatment, but optimal dosing intensity and treatment duration remain uncertain. This narrative review critically evaluates dose, schedule, and duration de-escalation with an emphasis on the directness and limitations of clinical evidence. Methods: A narrative literature review was conducted using a structured search of PubMed/MEDLINE, Embase, and CENTRAL from January 2015 through 12 September 2026, supplemented by targeted identification of pivotal clinical trials, observational cohorts, pharmacokinetic studies, systematic reviews, clinical guidelines, and relevant congress reports. Evidence was critically evaluated and synthesised qualitatively. Results: CheckMate 511 demonstrated lower grade 3-5 treatment-related toxicity with NIVO3+IPI1 than NIVO1+IPI3 without establishing efficacy non-inferiority. Me-ta-analyses across malignancies support a more favourable toxicity profile but provide indirect evidence for melanoma. EORTC 1612-EBIN used NIVO3+IPI1 in both groups and did not directly test dose reduction. Extended-interval anti-PD-1 schedules are exposure-matched alternatives, while very-low-dose therapy remains investigational. DANTE and Safe Stop illustrate the distinct evidence for fixed-duration and re-sponse-guided discontinuation. Conclusions: ICI de-escalation requires strategy-specific interpretation. Reduced-dose ipilimumab has reproducible safety signals but unproven efficacy equivalence; ex-tended dosing intervals maintain validated exposure; very-low-dose regimens require prospective testing; and shorter treatment remains an individualised decision without a universal stopping threshold.