Sorafenib is a multi-kinase inhibitor that blocks various pathways in the cells potentially involved in the development and progression of acute myeloid leukaemia and could therefore be an efficacious drug to treat patients with acute myeloid leukaemia.
As you can see, there is evidence for clinical efficacy of the drug which stems from more than 30 reports. But, as you can see, most of these publications are from case series or from a few clinical trials, either early phase or they are non-randomised. There is one exception: our study group did a randomised trial in elderly patients with sorafenib and the outcome of this trial was that the addition of sorafenib to standard chemotherapy had no beneficial anti-leukemic effect but was associated with a significant morbidity.
Since the biology of AML in younger patients is supposed to be different and the tolerability of an additional drug should be better in younger patients we decided to set up a very similar trial. That’s the design of the trial, let me guide you through it. After AML initial diagnosis patients were randomised to receive two cycles of induction chemotherapy with an anthracycline and cytarabine plus either sorafenib or placebo. Once in a complete remission intermediate risk patients with a family donor and high risk patients with a matched donor were transplanted whereas all other patients proceeded to high dose cytarabine based consolidation treatment plus sorafenib or placebo followed by one year of maintenance treatment.
These are the main inclusion and exclusion criteria and I’m just going to focus on newly diagnosed AML and patients aged 18-60 years. All the other inclusion and exclusion criteria are common within clinical trials and with AML.
The trial recruited between 2009 and 2011 and a total of 276 patients received at least one dose of study medication therefore forming the so-called full statistical analysis set. That’s the result of the primary endpoint of the trial, event free survival, and event was either primary treatment failure or a relapse or a death, whichever occurred first. As you can see, after a median follow up of three years we see a significant prolongation of event free survival in the sorafenib arm with a median event free survival of 21 months compared with 9 months in the placebo group. The p-value is highly statistically significant with 0.13.
If you look at relapse free survival, an important secondary endpoint, we can see a similar pattern with a prolongation and 56% of patients being relapse free and alive after three years compared with 38%. The p-value was 0.017. Interestingly, at this point of time we can see no clear overall survival benefit for the patients treated in the sorafenib arm.
To sum up the results, we could show that sorafenib plus chemotherapy is a feasible treatment for younger patients. It produces a significant and relevant prolongation of event free survival and overall survival but had no overall survival benefit at this point of time. I haven’t shown you the toxicity data but I can summarise that sorafenib increases the risk for fever, diarrhoea, bleeding events, liver toxicity, hand foot syndrome and rash in these patients. The reasons for potentially an efficacy of sorafenib in this mainly FLT3/IDT negative patient population must remain speculative. We can speculate that the inhibition of other kinases apart from FLT3 might be responsible for the efficacy of this drug in this patient population.
Last but not least, our conclusions: we conclude that first these data provide a high level of evidence for the efficacy of sorafenib in the younger AML patients. Second, and most importantly, and this might be the reason why this talk is in the plenary session, these data constitute the first randomised evidence that actually kinase inhibitors work in AML. Last but not least, what we judge is that according to evidence based medicine principles, a confirmatory trial would be desirable in order to establish sorafenib in AML treatment.