Is enasidenib plus azacitidine better than with azacitidine alone for AML patients?
Dr Courtney DiNardo - MD Anderson Cancer Center, Houston, USA
Standard of care for older patients with AML is often Vidaza and Vidaza alone has a complete remission rate of about 20%, overall response rate of about 30%, survival under a year. So that’s the expectations. So what we did is we took Vidaza as a backbone and we added the IDH2 inhibitor enasidenib which is approved as a single agent in the relapsed population. So we added enasidenib up front with Vidaza to see if we could improve upon outcomes in our newly diagnosed AML patients.
This was a phase II study which was randomised, not blinded, in a two to one fashion. So about two-thirds of patients, which was a total of 101 patients, received the combination of Vidaza with enasidenib and then a third of patients, or 33 patients, received Vidaza alone. Again, it was not blinded and patients were enrolled from October 2016 through the data cut being in earlier 2019.
The remission rate in patients receiving the combination was really quite compelling and statistically significantly better – from about 12% up to 53% complete remission rate, so that’s pretty impressive, as well as an overall response rate including other non-CR responses went from 40% up to 70%, so really quite remarkable. The event free survival in newly diagnosed patients was about 11 months with Vidaza alone, 17 months with the combination. Then the one thing that was kind of interesting and initially was hard for us to figure out is that the median overall survival was 22 months and it really wasn’t different between both arms. Again, remember that the average overall survival in this population is under a year and so both arms did really well. So we did a bit of digging and what it turns out is likely at least part of the issue is that over 20%, maybe even more, of the patients that were on the Vidaza alone arm actually went on to receive enasidenib once they came off study as a commercial supply since it was FDA approved. That was likely confounding the results given that we now have more effective salvage therapies.
This study really clearly, since it was a randomised study, showed that that that combination improves response rates as well as no concerning increase in safety signals were identified by putting the two compounds together. So that was encouraging and leads to potentially the incorporation of these agents together as a standard of care for newly diagnosed AML. One of the next steps would be figuring out whether there is a role to actually add a third agent into this combination because right now azacitidine and venetoclax, which is a BCL2 inhibitor, is an FDA approved standard for newly diagnosed and we now know azacitidine with enasidenib is also effective in that newly diagnosed population. So whether or not it’s safe and effective and even more… patients do even better by putting all three together, Vidaza as the backbone and then adding the IDH2 inhibitor enasidenib and figuring out whether we can add venetoclax to that as well. So that is going to be the next question.