Enasidenib Plus Azacitidine Expands Treatment Landscape for IDH2-Mutant AML

Courtney D. DiNardo, MD

Courtney D. DiNardo, MD

The combination of enasidenib (Idhifa) plus azacitidine (Vidaza), led to significant improvements in both the complete remission (CR) and overall response rate (ORR) in patients with newly diagnosed acute myeloid leukemia (AML) harboring anIDH2mutation compared with azacitidine alone, according to an interim analysis of the phase II AG221-AML-005 trial, presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

The oral small molecule inhibitor of mutant IDH2 proteins, enasidenib, was previouslyapproved by the FDA as treatment of patients withIDH2-mutated relapsed/refractory AMLin August 2017. Azacitidine is also the current standard of care for older patients who are ineligible for intensive chemotherapy. However, the combination of the 2 drugs may provide patients with a new option following these interim data.

After a median follow-up of 14 months, the ORR was 71% with the combination (95% CI, 58-81) and 42% in the azacitidine-alone arm (95% CI, 26-61;P= .0064). The CR rate was 53% in the combination arm(95% CI, 41-65) compared with 12% with the single-agent arm (95% CI, 3-28; P = .0001). The median event-free survival (EFS) was 17.2 months in the combination arm versus 10.8 months with azacitidine alone (HR, 0.59; 95% CI, 0.30-1.17; P= .1278).

Although the CR and ORR data are promising, the overall survival (OS) was not significantly improved with the combination compared to single-agent azacitidine alone. However, 21% of patients received subsequent enasidenib following treatment discontinuation, which account for the lack of difference in OS data. The trial was also not powered to evaluate OS.

A total of 101 patients with newly diagnosedIDH2-mutant AML who were not eligible to receive intensive chemotherapy were randomized 2:1 to receive the combination of enasidenib plus azacitidine or azacitidine alone on a repeated 28-day cycle. Patients received subcutaneous treatment of azacitidine at 75 mg/m2 each day for the first 7 days of each treatment cycle. For those randomized to receive the combination, they then received a continuous dose at 100 mg of enasidenib once daily. At the data cutoff on August 19, 2019, 94% of patients in the azacitidine arm discontinued treatment versus 69% in the combination arm.

In an interview withTargeted Oncology, Courtney D. DiNardo, MD, an assistant professor in the Department of Leukemia, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, discussed the interim analysis results from the ongoing phase II trial evaluating the combination of enasidenib plus azacitidine in newly diagnosed patients with AML.

TARGETED ONCOLOGY: What was the rationale for this trial?

DiNardo:For our older patients who are ineligible for intensive chemotherapy, the standard of care has been azacitidine. In the United States, this is what we often use. We have CR rates of about 20% and ORR of about 30%. The median OS is under 12 months. That is the standard of care, but it’s not great. There is now an IDH2 inhibitor called enasidenib, which works and has been approved for patients with relapsed/refractoryIDH2-mutated AML. The idea was to combine enasidenib with azacitidine for the treatment of newly diagnosed patients with AML to see if we can improve upon expectations with either agent on their own.

TARGETED ONCOLOGY: How was this trial designed?

DiNardo:This was a randomized phase II study. It was not blinded. It was a 2:1 randomization. All 101 patients were treated, so two-thirds received the combination enasidenib plus azacitidine, and one-third were treated with azacitidine alone.

TARGETED ONCOLOGY: What were the interim analysis data?

DiNardo:The interim analysis identified that there were significantly improved responses in the combination arm. Compared to a CR rate of about 12% [in the control arm], it was 53%, which is a dramatic difference. The ORR was similarly improved from 40% [with the combination] to 70%. The event-free survival (EFS) in these newly diagnosed patients went from 11 months to about 17 months [with the combination].

These were dramatic improvements in overall responses, including CRs as well as EFS. It was interesting that OS wasn’t different. The OS was 22 months in both arms, which is much better than you would anticipate seeing with azacitidine alone, so even the control arm did well. The thinking on why this is the case is that almost a quarter of the patients that were in the control arm came off study and received enasidenib as commercial supply because the drug is FDA approved for relapsed patients with AML. That was likely why we are not seeing a difference in survival at this point, although the study was powered for OS analysis.

TARGETED ONCOLOGY: What are the next steps for this research?

DiNardo:The next steps are incorporating this therapy into the standard of care for older patients with AML andIDH2mutations. For the leukemia community in general, we need to make sure we are getting mutational profiling back in a reasonable amount of time. For me, a reasonable amount of time is about a week so we can then use this information to use a targeted inhibitor for the frontline treatment of a patient with AML.

Another next step is trying to identify whether or not there is a role for incorporating venetoclax (Venclexta) to this combination because azacitidine and venetoclax and now azacitidine and enasidenib  are both known to be effective therapies for our newly diagnosed patients. Whether there is a role for incorporating all 3 agents that are changing the standard of care would be the next question to figure out to see if that’s even a better option without increasing toxicity.

TARGETED ONCOLOGY: Were there any concerning safety signals with the combination?

DiNardo:Because it was a randomized study, you could see how this compared with the combination versus single-agent azacitidine alone. There weren’t any differences between the 2 arms in terms of safety signals. You saw some cytopenias as expected in this AML population, as well as some mild and usually grade 1/2 gastrointestinal side effects. Constipation is common with azacitidine.

The only difference that was significant between the 2 arms was IDH-differentiated syndrome, which only happens if you are getting the IDH inhibitor. That happened about 18% of the time and was manageable with a differentiation syndrome management, which includes initiation of steroids.

TARGETED ONCOLOGY: Is it feasible that molecular profiling results get back to the physician within 1 week, as you mentioned?

DiNardo:At many major academic centers, molecular testing in a next-generation sequencing panel between 10 and 20 genes is commonly performed and is usually back within 3 to 7 days, 5 on average. This is definitely doable. Many community oncologists use send-out panels that are done through different groups, and those results take longer. The process of sending them out, waiting for results, and then receiving them back, it can often take 2 to 3 weeks. It is not reasonable to wait that long for a lot of patients. That needs to change, and I think we as a leukemia community need to push to make sure we are getting results back within a week now that we have treatments in the newly diagnosed patient population that depend on that information.

Reference:

DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone in patients with newly diagnosed acute myeloid leukemia (AML) with isocitrate dehydrogenase 2 (IDH2) mutations: interim phase II results from an ongoing, randomized study. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 643. bit.ly/2LBNSUu.