Evidence for kinase inhibitor activity in acute myeloid leukaemia

Share :
Published: 12 Jun 2015
Views: 4580
Rating:
Save
Dr Gerhard Ehninger - University Hospital Dresden, Dresden, Germany

Dr Ehninger talks to ecancertv at EHA 2015 about the results of a phase II randomised study on the safety and efficacy of sorafenib in leukaemia.

Read the news story or watch the press conference video for more.

ecancer's filming at EHA has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

EHA 2015

Evidence for kinase inhibitor activity in acute myeloid leukaemia

Dr Gerhard Ehninger - University Hospital Dresden, Dresden, Germany


The idea of adding a TKI to treatment of acute myeloid leukaemia, it sounds good but it has been difficult to add anything to standard therapies and get a significant improvement in the past, hasn’t it? So what were you trying to do in this study?

We were interested to improve the data on relapse free survival and event free survival in patients with acute myeloid leukaemia. In fact it’s not easy to add additional compounds because you are adding toxicity and the current treatment with daunorubicin Ara-C makes a lot of toxicity, infectious disease complication, aplasia, and therefore it’s not an easy task to add an additional compound.

So could you tell me what you decided to do in this study?

We decided to put the compound sorafenib in between two induction cycles, stop the treatment of sorafenib when new chemotherapy came on board and put it again between the consolidation cycles and at the end as one year of treatment without any additional treatment.

And the reason for using sorafenib was what?

Sorafenib blocks several important enzymes in the cells which are relevant for leukemic cells. For example, the Raf pathway is blocked, VEGF is blocked and also FLT3 mutated enzymes are blocked by the compound. Our interest was to have a multi-targeting compound because if you target too narrow you target only selective parts of the leukaemia and as we know that there are several clones we would like to have a broad  ... of targeted enzymes.

And the evidence for thinking that sorafenib had a chance of doing well was what, up to now?

It was coming out of in vitro data but also in single agent treatment of patients relapsing after standard treatment and we did see efficacy in AML patients having about 10-20% complete remission rate despite having resistant or refractory disease. Therefore it was the time to add it during induction chemotherapy.

Now you took younger patients with newly diagnosed acute myeloid leukaemia, what happened?

In the definition of younger this would mean that I’m also still very close to being young and it’s below the age of 60. We do know comorbidities are increasing in the age above 60 and in a previous trial we did see no advantage in these patients, we did even see more toxicity with hypertension and other complications. Therefore it means younger below the age of 60.

And the findings?

The findings were we have one year of prolongation of the median relapse free survival, that’s a tremendous increase. Looking on event free survival we did see that it’s even not reached 50%. We have event free survival of 60% which is tremendous compared to 40% in those patients receiving placebo. Overall survival was not yet showing a significant difference at 7% but that’s not significant in this population because our sample size with 260 overall was not large.

Impressive then, in a refined clinical study. What about the real world, what do you think could be the clinical implications?

The clinical implication would be if it would be a very new compound it would get a label, the company would be interested. In an older compound companies are not so much interested, they would like to sell a compound and it’s sold in some countries but overall we would be interested to have a label on it to get reimbursement and that’s the important task. Therefore we will fight hard to push companies to have a label on it.

So given an ideal world where that becomes possible, what’s your advice to clinicians about adding sorafenib to therapy for AML?

I’m convinced that we should add it if we could have the reimbursement for it, but because it costs €60,000 per patient the risk to be punished by the insurance companies or to pay it out of their own pocket is too high. Therefore, as today, it is not standard of care but it’s strong evidence that it’s improving event free and relapse free survival tremendously.

So you’re getting an anti-neoplastic effect, what about toxicities to pay for that?

Toxicities are tolerable in the younger age group, below the age of 60. We have hypertension but we can treat it. This has also some abdominal toxicities but again which are manageable in the younger population.

Do you think it could be extended to older patients?

It should not be extended in combination, chemotherapy can be extended in single agent treatment but in combination it would be too toxic in the age above 60.

So what’s the take home message for cancer doctors?

The cancer doctors should know, yes, multi-targeting compounds in addition to chemotherapies are increasing efficacy and decreasing relapse rate but it’s not the time today to get reimbursement but we have strong evidence that we should follow the road.