Oral azacitidine sparks hope for older AML patients

CC-486, a hypomethylating agent and an oral formulation of azacitidine, demonstrated clinically significant benefits in older patients with acute myeloid leukaemia (AML) in first remission following intensive chemotherapy with or without consolidation, highlighting its potential as a new therapeutic standard in this setting, according to the results of the QUAZAR AML-001 maintenance trial presented at ASH 2019.

“The standard treatment for AML is intensive chemotherapy … Unfortunately, while most patients achieve complete remission, relapse is very common, particularly in older patients and those with adverse risk factors, such as poor cytogenetic risk and the presence of measurable residual disease (MRD),” said study investigator Dr Andrew Wei from the Monash University in Melbourne, Australia.

The objective of maintenance therapy is to deliver nontoxic therapy to reduce relapse to subsequently prolong overall survival (OS). However, no particular maintenance therapy has been shown to improve OS, and the only standard post-remission therapy is hematopoietic stem cell transplant which, according to Wei, is not suitable for older AML patients. Therefore, the QUAZAR AML-001 investigators sought to address whether the administration of an oral medication could improve OS.

A total of 472 individuals (median age 68 years) who were within 4 months of achieving first remission were randomized 1:1 to receive either CC-486 (300 mg daily for 14 days in each 28-day cycle) or placebo. Increasing the duration of exposure to 21 days was allowed for early relapse cases. [ASH 2019, abstract LBA3]

At 2 years, half of the CC-486 recipients were still alive as opposed to 37 percent in the placebo arm.

After a median follow-up of 41.2 months, OS was improved by almost 10 months with CC-486 vs placebo (median, 24.7 vs 14.8 months), translating to a hazard ratio (HR) of 0.69 (95 percent confidence interval [CI], 0.55–0.86; p=0.0009).

Relapse-free survival (RFS) was also improved by 5 months with CC-486 vs placebo (median, 10.2 vs 4.8 months; HR, 0.65, 95 percent CI, 0.52–0.81; p=0.0001).

Subgroup analyses demonstrated clear trends across the board in favour of CC-486, which were more pronounced among those with poor cytogenetic risk (HR, 0.61 for both OS and RFS), those who did not have consolidation therapy (HR, 0.55 for both OS and RFS), and those who were MRD-positive (HR, 0.69 and 0.58, respectively).

“[These findings showed that] CC-486 is the first maintenance therapy to provide statistically significant and clinically meaningful improvements in both OS and RFS across a broad range of subgroups [in this setting],” said Wei.

One measure of safety is the number of cycles that patients can tolerate, Wei pointed out, and in this trial, participants in the CC-486 arm received a median of 12 cycles (with some receiving up to 80 cycles) vs only 6 in the placebo arm.

Major adverse events (AEs) associated with CC-486 were gastrointestinal in nature (eg, nausea, vomiting, diarrhoea, and constipation). Nonetheless, most AEs were low-grade and ameliorated by prophylactic therapy. “The AEs were markedly reduced beyond cycle two with adequate supportive care,” said Wei. Moreover, no treatment-related deaths were reported.

CC-486 also had no detrimental impact on health-related quality of life (HRQoL) as measured by the FACIT*-Fatigue and EQ-5D** index scores, noted Wei.

The oral route: The pros

Although the potential for an easily delivered oral monotherapy to provide OS improvements initially represented a major therapeutic challenge, the findings showed that CC-486 enabled patients to remain on therapy much longer than what has been achievable with injectable azacitidine, explained Wei.

Despite the molecular similarity between azacitidine and CC-486, Wei underlined the advantage of the latter. “Imagine a future where we can utilize an oral medication [delivered over a 14-day period in each cycle] instead of azacitidine which is given 7 days a month for long term. Having an oral form of azacitidine gives us enormous potential in many other AML settings … That is a major step forward,” he said.

“[Moreover,] CC-486 may become the fundamental building block for new drug combinations*** that are already being explored in the clinical setting … which would hopefully have transformative potential in AML,” he added.

“It may be easy to get older, poor-risk AML patients into remission; however, these are usually very short-lived and there has never been any consolidation that is really effective,” commented ASH Secretary Dr Robert Brodsky from Johns Hopkins School of Medicine in Baltimore, Maryland, US, during the press briefing. “For the first time, there is an oral drug that can lead to not only RFS but OS benefits in these patients, so I think this is indeed practice changing.”