Dr John Kirkwood discusses ctDNA as a new treatment option for patients with melanoma.
Matthew Fowler: I want to transition to ctDNA [circulating tumor DNA] to monitor response. You spoke a little about ctDNA. Could you briefly describe what it is?
John Kirkwood, MD, PhD: CtDNA is the molecular profile of the DNA of tumor tissue of that given patient. There are some corporate ventures using the DNA obtained at initiation of therapy to then create a profile for the given patient and to monitor whether this is going up or going down over treatment with an immunotherapy or targeted therapy. One of the simplest DNA markers of tumor progression is the DNA markers of BRAF. We don’t have BRAF in our blood. BRAF has been shown by Mark Middleton, and others in his group at [the University of] Oxford, to be useful in the monitoring of patients on a VEGF inhibitor that was given as an adjuvant therapy. They predicted, well before manifest, clinical evidence of progression—those patients who would have progression. Because BRAF is elevating in the blood, the ctDNA of BRAF is a valuable predictor of relapse in those patients. We look forward to increasingly specific and precise ctDNA profiles for our patients being used to monitor the status of tumor. This is still investigational and needs prospective validation. It’s something that, at the moment, is done in clinical trials but not in standard care.
Matthew Fowler: What do clinical trials tell us about how ctDNA can help assess response to treatment?
John Kirkwood, MD, PhD: Clinical trials will tell us whether the use of ctDNA prospectively in the context of large phase 3 trials is going to be a useful surrogate. Ideally the hope we would have is that we don’t need to wait until tumor burden assessed by radiological or clinical features are manifest and the freight train is right at our doorstep. If we can do molecular markers by ctDNA that—long ahead of clinical manifestations of relapse—allow us to change our approach, we may achieve ultimately greater antitumor benefits. Effects that are now limited with particular agents may, with succession of agents chosen on the basis of flux in ctDNA, be superior to therapy guided by clinical assessment. Manual, palpable disease is obviously the last thing we want to deal with. Radiological manifestations of pulmonary, hepatic, brain, and other sites of metastatic disease are also something that—if we could avoid them by having molecular markers that, long ahead of that, predict disease progression—would be a wonderful advent in our field.
Matthew Fowler: How do ctDNA levels or changes in those levels correlate with patient outcomes like overall survival or progression-free survival?
John Kirkwood, MD, PhD: Those are understudied, and that’s what we need to see in prospective trials. There are a variety of trials in the United States and globally using ctDNA markers. One of the first of these was the VEGF inhibitor trial that I mentioned. Mark Middleton and Dr Pippa Corrie had reported from the United Kingdom, but many more trials need to be done like that. That will allow us to assess ctDNA flux on a monthly or 3-monthly basis as the index of therapeutic strategy change so that we’re not staying with an agent that’s already, by ctDNA parameters, manifestly ineffective. It may take months longer to see the gross evidence of relapse that validate this. But if we can change with the ctDNA flux, we’ll be way ahead of the curve.
This transcript has been edited for clarity.