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

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
Published
2026-05-21
DOI
https://doi.org/10.1038/s41467-026-72735-8
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
0.00

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article

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

N.J.T. Smith, Noel Kelso, Kimberley Hockenhull, Caroline Dive et al.
Nature Communications
Cancer Genomics and Diagnostics
article

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

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

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.

Nature Communications
Royal Marsden NHS Foundation Trust (GB), University College London Hospitals NHS Foundation Trust (GB), Manchester Academic Health Science Centre (GB), Health Forecasting (US), The Francis Crick Institute (GB), Cancer Research UK (GB), Freeman Hospital (GB), Macclesfield College (GB), Clatterbridge Cancer Centre NHS Foundation Trust (GB), University of Manchester (GB), Sir Bobby Robson Foundation (GB), NIHR Imperial Biomedical Research Centre (GB), Cancer Research UK Manchester Institute (GB), The Christie NHS Foundation Trust (GB), Institute for Forecasting of the Slovak Academy of Sciences (SK), University College London (GB), Imperial College London (GB), Newcastle University (GB)
Wellcome, Cancer Research UK, National Institute for Health and Care Research
Openalex Percentile: Top 8%
Cancer Genomics and Diagnostics
DOIOpen Access PDFOpenAlex
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