Circulating tumour DNA guided therapy switch (CAcTUS)
Research type
Research Study
Full title
A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumour DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma
IRAS ID
227794
Contact name
Paul Lorigan
Contact email
Sponsor organisation
The Christie NHS Foundation Trust
Duration of Study in the UK
3 years, 11 months, 31 days
Research summary
Research Summary
There are two main types of treatment, which are commonly used to treat melanoma that has spread;
1. Immune therapy (using the immune system to kill cancer cells) and,
2. Targeted therapy (affects how cancer is able to grow and survive).Presently, it is not clear whether we should give immune therapy or targeted therapy first. This trial is investigating whether we should use targeted therapy (dabrafenib and trametinib) prior to immune therapy (nivolumab and ipilimumab) in order to boost the immune response.
All these drugs can be very effective, however they do not work for all patients and some melanomas can become resistant. Therefore, we need to find ways to improve their efficacy. There is some evidence that in patients responding to targeted therapy potentially the immune therapy will be more effective. This is not the case when the cancer has become resistant to treatment. Some patients only respond to targeted therapy for a short time so we need an accurate way of monitoring response to treatment. Traditionally, therapy response has been evaluated through CT scans, every few months. We have developed a blood test, which gives a picture of how the cancer is responding to treatment and can be taken more frequently. The blood test looks for DNA known to have come from the cancer. If the cancer is responding to treatment the amount of cancer DNA in the blood decreases.CAcTUS will test whether the blood test can inform us whether the melanoma is responding to targeted therapy and to switch to immune therapy in response. We need to ensure we switch treatment at the right level of cancer DNA and the trial will provide us the information for this decision. Furthermore, we’ll obtain an initial indication as to how well patients respond to this treatment schedule.
Summary of Results
The final analysis of all study data has not yet been concluded, however an initial analysis focused on the primary endpoints has been conducted, with an abstract submitted to the Society of Melanoma Research in August 2023.
In total, 21 patients were recruited, which was deemed sufficient numbers to analyse the primary endpoints of the study. The cohort had poor prognostic features; the majority having M1c/d disease (≥60%), raised LDH (≥80%), ≥3 sites of disease (≥70%), balanced between arms. CAcTUS met both of its primary endpoints. The primary feasibility outcome was achieved with 100% (61/61, 1-sided 97.5% CI, 94-100%) critical results (required in real-time) returned within 7 days of being received at the laboratory. Assessment of whether a decrease in ctDNA mutant BRAF by ≥80% on targeted therapy could be used to instruct switching to immunotherapy was performed in 17 patients who commenced dabrafenib plus trametinib (D+T) first (Arm A=6 + Arm B=11). 100% (1-sided 97.5% CI, 80-100%) had a decrease in ctDNA BRAF VAF by ≥80%, with the drop achieved by week 2 of D+T.
The initial analysis of trial data has shown that real-time treatment switch is possible using ctDNA and that maximal BRAF VAF response (≥80% decrease) to targeted therapy is achieved within 2 weeks of therapy. There was no evidence of a difference in overall survival outcome in this small cohort of patients.REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
19/NW/0046
Date of REC Opinion
25 Feb 2019
REC opinion
Favourable Opinion