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Lookup NU author(s): Professor Ruth PlummerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026.Checkpoint inhibitor immunotherapy (CPI) for BRAF mutant advanced melanoma first-line results in a better long-term survival compared to targeted therapy (TT), however TT induction may benefit poor prognosis groups. The parallel-arm, randomised phase II, multicentre, feasibility CAcTUS trial (Clinicaltrials.gov NCT03808441) randomised 21 patients to receive standard of care investigators choice TT or CPI, switching to the alternative upon progression (n = 10), or commencing TT and switching to CPI upon an ≥80% reduction of BRAF variant allele frequency (VAF) in circulating tumour DNA (ctDNA; n = 11). The study achieved its primary endpoints with 100% (95% confidence interval [CI]: 94-100%) of critical results provided within 7 days to inform a decision to switch and 100% of patients commencing TT achieving an ≥80% reduction of BRAF VAF (95% CI: 80-100%). Secondary outcomes included progression-free survival and overall survival. No new safety signals were observed for TT/CPI. Post-hoc analysis of clinical features, circulating cytokines and chemokines at ctDNA nadir following TT induction suggested a more favourable profile prior to CPI initiation. Longitudinal ctDNA dynamics revealed ctDNA provided an early signal of CPI benefit and that rechallenge with TT following CPI progression resulted in a further ctDNA response. These data support the utility of ctDNA to guide treatment decision-making within a clinically relevant timeframe to optimise treatment scheduling strategies.
Author(s): Lee RJ, Rothwell DG, Smith N, Chow S, Delgado-SanMartin J, Mistry H, Sylvestre Y, Chiang S-C, Clarke H, Gremel G, Gupta A, Hockenhull K, Kelso N, Kochhar R, Mullan D, Plummer R, Serra P, Shaw H, Summersgill H, Turajlic S, Mouliere F, Marais R, Dive C, Lorigan P
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2026
Volume: 17
Issue: 1
Print publication date: 22/07/2026
Online publication date: 21/05/2026
Acceptance date: 24/04/2026
Date deposited: 04/08/2026
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-026-72735-8
DOI: 10.1038/s41467-026-72735-8
Data Access Statement: The study protocol is available in the Supplementary Information. Individual patient-level clinical data cannot be provided for ethical reasons. Sharing of additional clinical data not within the manuscript or in supplementary materials will be considered upon request to the Sponsor (The Christie NHS Foundation Trust) and Chief Investigator Prof. Paul Lorigan. The remaining data are available within the article, Supplementary Information or Source data file. Source data are pro vided with this paper.The code is available here: https://doi.org/10.5281/zenodo.19337944.
PubMed id: 42168180
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