Use of circulating tumour DNA to prospectively guide a switch from targeted to immune therapy in BRAF mutant advanced melanoma: the randomised phase II CAcTUS trial

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Rebecca J Lee Dominic G Rothwell Nigel Smith Shien Chow Juan Delgado-SanMartin Hitesh Mistry Yvonne Sylvestre Shih-Chieh Chiang Harry Clarke Gabriela Gremel Avinash Gupta Kimberley Hockenhull Noel Kelso Rohit Kochhar Damian Mullan Ruth Plummer Patricio Serra Heather Shaw Holly Summersgill Samra Turajlic Florent Mouliere Richard Marais Caroline Dive Paul Lorigan
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Abstract

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.

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Journal Nature Communications
Pages Epub ahead of print
Available online
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Publisher website (DOI) 10.1038/s41467-026-72735-8
Europe PubMed Central 42168180
Pubmed 42168180

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