CAcTUS - Circulating Tumour DNA Guided Switch

Summary

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Description

The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At present, patients are treated with targeted therapy until acquired resistance develops, and then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results in an environment tha...

The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At present, patients are treated with targeted therapy until acquired resistance develops, and then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors but not resistant have been shown to have increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with decreased response to immune therapy reduces, which may improve efficacy of immunotherapy. A precise definition of response is required in order to decide upon a switch to immune therapy. A radiological definition of response is currently the standard assessment. However a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response dynamics or allow decision making on an individual patient basis. The investigators have developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which are able to accurately monitor tumour burden over time. The aim of this pilot study is to provide a signal as to whether: In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib. Changes in ctDNA levels can be used to accurately inform when to switch from targeted to immune therapy. Data from this study will provide the basis for follow on studies with sufficient power to assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can improve efficacy of immune therapy.

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