AXL inhibitor bemcentinib in combination with chemotherapy exerts anti-leukaemic activity in AML patients

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Published: 1 Jun 2019
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Dr Sonja Loges - University Hospital Eppendorf, Hamburg, Germany

Dr Sonja Loges talks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the use of the AXL inhibitor bemcentinib in combination with LDAC or decitabine in AML patients unfit for intensive chemotherapy.

She explains that a promising overall response rate of 46% was seen with most of the responses coming after one or two cycles of treatment.

Dr Loges acknowledges that the sample size of the study is still small but that an expansion of the cohorts is planned to increase the number of patients.

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

I am presenting an abstract which is focussed on acute myeloid leukaemia patients which is based on pre-clinical research which we have been conducting in my laboratory about six years ago where we identified a novel target in acute myeloid leukaemia which is called AXL which is a receptor tyrosine kinase belonging to the TAM receptor family of kinases. We showed that AXL represents a novel prognostic factor in acute myeloid leukaemia and we also gathered some pre-clinical evidence that immunotherapy with a novel AXL inhibitor that is called bemcentinib prolongs the survival of AML bearing mice. Interestingly, we also observed some additive efficacy with chemotherapy, in particular with cytarabine and with anthracyclines.

So, based on these data we planned a clinical trial, BGBC003, which is a phase I/II clinical trial. We started with a dose finding phase with a classical 3 3 design in relapsed refractory acute myeloid leukaemia patients. The primary endpoints here were safety and identification of the recommended phase II dose. In this dose escalation part we did not reach the maximum tolerated dose, the drug was fairly well tolerated which is most likely due to its specific activity hitting AXL. It is also quite specific about this drug in comparison to other AXL inhibitors such as gilteritinib which also inhibit other kinases. So bemcentinib is quite selective towards AXL over tyrose 3 and MER. So we observed little toxicity, some nausea, some GI toxicity, some QTc prolongation, but all of this was quite well manageable with supportive care.

We also observed an initial efficacy signal in this phase I population; we saw a response rate of 22%. So then we moved the trial forward and this is mainly what I will be presenting at ASCO this year. We moved on towards a combination trial with decitabine and also with low dose ARA-C in the elderly AML patient population non-eligible for intensive care. So this is a demographically rapidly growing population with an increasing medical need for novel treatments because there are few drugs approved in this indication.

So basically we treated patients first line but we also treated relapsed refractory patients in this disease space. What we saw was that especially with the low dose ARA-C combination we observed a very promising overall response rate of 46% and the responses occurred early, so mostly after one or two cycles of treatment, and they were durable. So the treatment is still ongoing in many patients but we have, for instance, one patient who is on the trial for 19 cycles. So clearly this response rate is very promising. We still have quite a low number of patients so we have about twelve patients who are informative for response and here we have 46% response rate. Importantly, these responses also occur in pre-treated patients which is somewhat a bit surprising as the efficacy with decitabine seems to be a little bit less. So we have about 22% of responses here. Obviously the numbers are still small so we are currently planning to further expand the cohorts to reach maybe a number of thirty patients being treated. But if this response rate holds up, especially in the low dose ARA-C combination, there could be some space for this combination in the second line setting because many patients will be treated, elderly AML patients will be treated, with a venetoclax azacitidine combination or venetoclax decitabine combination because these regimens are approved in the United States and the drugs are orally applicable so this is very convenient. So the mainstay of first line treatment will be venetoclax with these HDACs. So after failure of this regimen there is a need for effective second line treatments and if the response rates hold up we will be very eager to move the LDAC bemcentinib combination most likely further in clinical development.

You mentioned that the patients were pre-treated, what were they pre-treated with?

They were pre-treated with different regimens, mostly with decitabine or azacitidine as this is the approval situation in Germany.

How can these results affect clinical practice when treating de novo and relapsed AML?

Basically, as I said, there is a clear need. The first line combination of venetoclax, decitabine, azacitidine yields a response rate of 65% approximately. Of course it would also be interesting to introduce a third drug into this combination but I think the medical need is higher in second line after failure of this regimen. So we are, at least based on the data as they are now, will be pushing for the second line treatment. We are also considering to maybe also include bemcentinib in the first line therapy of younger patients eligible for intensive chemotherapy in combination with the 3 7 schema.