Enasidenib plus azacitidine vs azacitidine monotherapy in mutant-IDH2 ND-AML

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Published: 13 Jun 2020
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Dr Courtney DiNardo - MD Anderson Cancer Center, Houston, USA

Dr Courtney DiNardo speaks to ecancer in an online interview for the virtual EHA 2020 meeting.

She provides an overview of the trial, which is investigating enasidenib plus azacitidine versus azacitidine alone in patients with mutant-IDH2 newly diagnosed acute myeloid leukaemia (ND-AML).

Dr DiNardo outlines the design of this randomised phase II portion of the trial, and notes that this treatment combination significantly improved complete remission and overall response rates in these patients.

She also presents the toxicity profile of this novel combination, which was generally well-tolerated in this population 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’d like to tell you a little bit about the combination of enasidenib with azacitidine in patients with IDH2 mutated AML. Just as a bit of a background and a reminder, IDH2 mutations happen in about 12-15% of our AML patients and, in general, they’re happening in our older patients where our non-intensive chemotherapy strategies like azacitidine tend to be our standard of care. So what this clinical trial was doing was randomising patients to receive azacitidine alone versus azacitidine with enasidinib which is an FDA approved oral targeted IDH2 mutant inhibitor.

It was an international study and it was a 2-to-1 randomisation that was not blinded. About a hundred patients were enrolled, 2-to-1 with the combination getting enasidenib with azacitidine. Again, as you would expect for an older patient population, the median age was 75 in this study and about a quarter of patients had secondary AML.

The primary endpoint of the study was looking at response and, indeed, the response rate with the combination was quite significant. So, compared to azacitidine alone where you see an overall response rate of about 40% and a true CR rate of only 12% with azacitidine alone, we saw an overall response rate of 71% with a CR rate of 53%, so a true CR meaning full count recovery with that combination. So that is really quite compelling. In addition, the duration of response in people getting the combination was over two years. So people with an IDH2 mutation that are getting this combination are having really durable responses.

In terms of safety, the key safety thing to be aware of when you’re using the IDH inhibitors is there is a risk of differentiation syndrome which is a constellation of symptoms where you can have shortness of breath, fusions, infiltrates. It often happens about 2-4 weeks into therapy and is treated with steroids. So very similar to ATRA-related syndrome in patients with APL which the audience is well aware of, so very similar to that. So just something to have in the back of your mind in a patient who is put on an IDH inhibitor and who starts to develop some usually pulmonary symptoms, think steroids for differentiation syndrome.

In terms of outcomes like event free survival and overall survival, the event free survival showed that there is starting to be a nice splay between the two. So with azacitidine alone there was an event free survival of about 10-11 months and with the combination 17 months. So people on the combination were staying on a bit longer, that’s not yet statistically significant. Median overall survival, interestingly enough, was impressive in both arms at 22 months but very similar. So one thing that’s an interesting aspect of this study, I think, is that because it’s not blinded some people who were randomised to azacitidine alone who did not have a response within the first few cycles potentially came off the study and were able to receive enasidenib or other targeted therapies like venetoclax in the relapsed setting and were able to then attain a response. So just something to keep in mind is we’re getting more and more effective therapies in AML EFS versus OS tends to be an important consideration.

So there’s more detail that I go into in the presentation about the depth of remission and the variant allelic frequency of the IDH2 which are really interesting but a bit outside the scope of this talk, I think. So the end result is, I would say, one, make sure you’re looking at genomic annotation of your patients with AML because if you’re not aware that they have an IDH mutation or a FLT3 mutation you’re not going to be thinking about these targeted strategies which are very effective for them. Then, two, this combination of azacitidine with enasidenib is really quite effective, dramatic improvements and complete remission in overall response rates. It was a smaller study not powered for survival but indeed the outcomes were quite impressive.

So, with that, I will close. Thank you for your attention.