Acute myeloid leukaemia is the most commonly diagnosed adult leukaemia. There are 20,000 new cases a year and the median age of diagnosis is 67 but it is also the most lethal adult leukaemia with an overall survival of 25%. As one ages the survival rate drops dramatically. We also know now that AML is a heterogeneous disease, it’s driven by the serial acquisition of mutations that leads to inter-patient heterogeneity in biological response and clinical response. This, coupled with the increasing evidence of efficacy for the targeted therapies in AML, we hypothesised that we could improve patient outcomes by matching patients to the appropriate therapies.
We used genomic analyses, three diagnostic assays. One is a cytogenetics assay done locally with a central review; we use a broad-acting next generation sequencing platform at Foundation Medicine and a PCR-based FLT3 assay at Invivoscribe. We used all three assays to make a treatment decision for the patients and all three assays must be completed within a seven day period of time.
Once a treatment decision has been made patients will either go on to a molecular group where they receive a targeted therapy or combination of therapies or on to a marker negative group where they’ll see a broad-acting agent or a novel combination. By having the marker negative group as part of our study all patients who want to participate in the trial have the opportunity to.
Technology continues to evolve over time so when we started this study two years ago having the seven day turnaround was much more challenging than it is today and we certainly believe that new technology in the future will help us to reduce this timeframe. But the reality of getting the seven day turnaround time is a little bit of brute force. Foundation Medicine had to put in three shifts, so it’s 24/7, to do an analysis so they could handle the time when any of our samples may arrive. But it’s also about prioritising and changing the workflow within any one diagnostic company of how the samples come in and what priority do they get for the analysis.
The results of the study, our primary endpoint for the master trial is the feasibility of being able to make the treatment decision within seven days and also the efficacy of the individual studies. Because the master trial has been set up as an umbrella study where you screen upon entry into the study and then there are individual efficacy arms.
We’ve achieved our primary endpoint in over 95% of the patients in the trial, demonstrating that we can do a precision medicine approach to making treatment assignments within seven days. We’ve also been able to demonstrate some efficacy across several of our studies, one being our enasidenib study which is with the IDH2 mutated patients where we see an overall response rate of 44.4% as monotherapy for the newly diagnosed AML patients.
We haven’t looked at the cost dramatically but we have certainly created an infrastructure where we can generate a clinical trial that is, we believe, cheaper than a pharmaceutical company could do it themselves. While we hired a CRO, we have a genomic provider and so forth, but having multiple arms across the study there’s a lot of efficiencies that can be harnessed. For example, normally a company would do a genomic analysis and they would stratify patients; all patients would screen and they would pay for all the genomic analyses themselves but only a fraction of those patients would go on to a clinical trial. Here all our patients screen and that cost is divided across all the study arms. So the same thing with project management fees and things like that. So where we have efficiencies built in they bring cost savings to conducting a clinical trial of this type.
The implications for clinical practice, this has been an extraordinary year in AML – there are a number of new drugs that have been approved where we haven’t seen any drugs approved in decades. With that, many of the drugs are very targeted and the precision medicine approach to utilising these drugs and making the appropriate treatment decisions for their patients is going to be even more important. So the clinical practice change is really the ability to be able to use this precision medicine approach and utilise the new drugs that have been approved and look at the future of new drugs in combinations that can be utilised.