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    CAcTUS: A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumor DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma

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    Authors
    Lee, Rebecca J
    Rothwell, Dominic G
    Chow, Shien
    Shaw, H. M.
    Turajlic, S.
    Smith, N.
    Clipson, A.
    Clarke, H.
    Kelso, N.
    Mitchell, J.
    Sutton, C.
    Sylvestre, G.
    Nathan, P. D.
    Larkin, J.
    Corrie, P. G.
    Plummer, E. R.
    Marais, Richard
    Dive, Caroline
    Lorigan, Paul C
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    Affiliation
    The Christie NHS Foundation Trust, Manchester
    Issue Date
    2021
    
    Metadata
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    Abstract
    Background: Circulating tumor DNA (ctDNA; the tumour derived fraction of circulating free DNA in the blood) has been shown to be a biomarker of tumor burden/progression in many cancers. We recently accurately monitored treatment response and resistance in stage IV melanoma by ctDNA analysis in serial peripheral blood samples. Pre-clinical data has previously revealed that BRAF inhibition provokes a micro-environment with increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines that could enhance immune responses. We aimed to test the hypothesis that ctDNA could be implemented as a personalised, real-time liquid biopsy to identify when tumours are responding to targeted therapy in order optimise a switch to immunotherapy. Methods: We validated the ctDNA assays for BRAF mutation calling as a primary trial endpoint. We designed a phase II multicenter, parallel arm study across 6 UK sites, to assess primary objectives of i). Whether a ctDNA result can be turned around within 7 days and actioned in a clinically relevant timeframe ii). to assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% from baseline on targeted therapy is an appropriate ‘cut off’ to instruct switching to immunotherapy. Secondary endpoints include Overall Response Rate (ORR) to immunotherapy, radiological/clinical and ctDNA determined progression free survival (PFS) on each treatment. Forty patients are planned based on inclusion criteria of stage IV or stage III unresectable cutaneous BRAF mutant melanoma, baseline ctDNA BRAF variant allele frequency (VAF) ≥1.5%, ECOG 0/1/2, no symptomatic brain metastases, no prior adjuvant nivolumab plus ipilimumab (N+I). Prior adjuvant dabrafinib + trametinib (D+T) is allowed as long as recurrence is >6 months from completion. Patients are randomised 1:1 to either standard Arm A; investigator choice of either D+T (150mg BD +2mg OD respectively) or N+I (1 mg/kg N +3 mg/kg I q3 wkly, then N 480mg q4 wkly) first line, then switch on progression to the other treatment. In the experimental Arm B; all patients start on D+T and have BRAF ctDNA monitored q2 wkly for 4 wks then q4 wkly. When ≥80% decrease vs. baseline in ctDNA BRAF VAF occurs, patients switch to N+I. If patients subsequently progress on N+I, they will resume D+T. The study is open with 9 patients enrolled at time of submission.
    Citation
    Lee R, Rothwell DG, Chow S, Shaw HM, Turajlic S, Smith N, et al. CAcTUS: A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumor DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma. Vol. 39, Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2021. p. TPS9587–TPS9587.
    Journal
    Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/624812
    DOI
    10.1200/JCO.2021.39.15_suppl.TPS9587
    Additional Links
    https://dx.doi.org/10.1200/JCO.2021.39.15_suppl.TPS9587
    Type
    Meetings and Proceedings
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1200/JCO.2021.39.15_suppl.TPS9587
    Scopus Count
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