Oral Maintenance Drug Forestalls AML Relapse

Treatment with CC-486 (Bristol-Myers Squibb), an oral form of the DNA-hypomethylating agent azacitidine, extended overall survival and the time to relapse among older patients with acute myeloid leukemia (AML). The findings, reported at the 2019 American Society of Hematology Annual Meeting in Orlando, FL, on December 10, could usher in a new treatment paradigm for patients unable to tolerate stem-cell transplantation.

“Based on the positive results of this landmark clinical trial, we hope that maintenance therapy with CC-486 might represent a potential new therapeutic standard for patients aged 55 and older with AML in first remission,” says study investigator Andrew Wei, MBBS, PhD, of Alfred Hospital and Monash University in Melbourne, Australia, who presented the data.

In the phase III international QUAZAR trial, 473 patients ages 55 to 86 in first remission following intensive chemotherapy received CC-486 or placebo, usually once daily for 2 weeks in repeated 4-week cycles. Patients who received the drug lived about 10 months longer on average, with a median overall survival of 24.7 months compared with 14.8 months on placebo. The time until relapse was significantly improved as well—10.2 months among those taking CC-486 compared with 4.8 months in the placebo arm.

Despite differences in the pharmacological properties of CC-486 versus its injectable counterpart, their safety profiles were comparable. The most common side effects of CC-486 were nausea, vomiting, and other gastrointestinal problems, which proved manageable.

Christopher Hourigan, MD, DPhil, of the National Heart, Lung, and Blood Institute, described the findings as “the first convincing demonstration” that maintenance therapy could have a role in AML. However, the advent of newer targeted therapies—including the BCL2 inhibitor venetoclax (Venclexta; AbbVie), the IDH inhibitor enasidenib (Idhifa; Bristol-Myers Squibb), and the FLT3 inhibitor midostaurin (Rydapt; Novartis)—has opened up effective options beyond intensive chemotherapy as a first-line treatment.

As such, the long-term clinical relevance of the QUAZAR trial is an open question, Hourigan said, and it remains “unclear if the results presented here will be superior to those seen in similar patients treated continuously from initial diagnosis with therapy that includes a hypomethylating agent combined with other oral [targeted] agents.”

Thus, if approved, CC-486 could have its biggest impact as a replacement for injectable azacitidine in entirely oral, up-front combination treatment regimens. Or it could find wide off-label use as a maintenance therapy even in the absence of induction chemotherapy.

Clinicians in the UK are testing the value of CC-486 post-transplant in the phase III AMADEUS trial. That trial is scheduled to run until 2024, but “I am absolutely positive that people are going to give oral azacitidine maintenance following allogeneic transplant” before results are known, said Aaron Logan, MD, PhD, of the University of California, San Francisco. If CC-486 is approved for any indication, “it's going to be used much more broadly.”

However, one issue could be the drug's variable pharmacokinetics. “A lot of it gets degraded in the gut,” noted David Steensma, MD, of Dana-Farber Cancer Institute in Boston, MA. “So, when you look at the levels absorbed of CC-486, it can vary several-fold from one patient to the next.” A rival therapy, ASTX727 (Otsuka), which combines the hypomethylating agent decitabine and the cytidine deaminase inhibitor cedazuridine, could minimize that concern. By blocking the gut enzyme that breaks down decitabine, cedazuridine helps increase the bioavailability and efficacy of the therapeutic agent—allowing for lower doses of decitabine, which minimizes gastrointestinal toxicity. –Elie Dolgin