FDA Grants CC-486 Priority Review for Maintenance AML

The FDA has granted a priority review designation to CC-486 for the maintenance treatment of adult patients with acute myeloid leukemia.

The FDA has granted a priority review designation to a new drug application (NDA) for CC-486 for the maintenance treatment of adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment, and who are not candidates for, or who choose not to proceed to, hematopoietic stem cell transplantation.1

The NDA is based on findings from the phase 3 QUAZAR AML-001 trial in which the oral hypomethylating agent CC-486, an oral formulation of azacitidine, extended median overall survival (OS) by 9.9 months compared with placebo for older patients with AML in first remission.2

After a median follow-up of 41.2 months, the median OS with CC-486 was 24.7 months (95% CI, 18.7-30.5) compared with 14.8 months for placebo (95% CI, 11.7-17.6), representing a 31% reduction in the risk of death with the hypomethylating agent (HR, 0.69; 95% CI, 0.55-0.86; P = .0009). The median relapse-free survival (RFS) was 4.8 months with placebo compared with 10.3 months for CC-486 (HR, 0.65; 95% CI, 0.52-0.81; P = .0001).

The FDA is scheduled to make a decision on the NDA by September 3, 2020.

“Often, newly diagnosed adult patients with AML achieve a complete response with induction therapy, however many patients will relapse and experience a poor outcome. Patients in remission are seeking treatment options that decrease the likelihood of relapse and extend overall survival,” Noah Berkowitz, MD, PhD, senior vice president, Global Clinical Development, Hematology, Bristol Myers Squibb, the developer of CC-486, said in a statement. “Today’s acceptance of our submission for CC-486 represents an important step towards a potential new maintenance treatment to address an urgent medical need for AML patients and we look forward to working with the FDA during its review of CC-486.”

CC-486 has a distinct pharmacokinetic and pharmacodynamic profile from injected azacitidine. Earlier studies showed the agent to be tolerable with efficacious, even in patients who have progressed on prior azacitidine injections. The oral dosing of the drug is felt to provide better drug exposure, in addition to superior patient convenience, which potentially prolongs therapeutic activity.

In the phase 3 trial, 472 patients were enrolled within 4 months of complete remission (CR) or CR with incomplete hematologic recovery (CRi). Patients were evenly randomized to receive therapy with daily CC-486 (n = 238) or placebo (n = 234). CC-486 was administered daily for 14 days followed by 14 days off therapy. If a CR/CRi was not maintained, CC-486 dose could be escalated to 21 days on drug with 7 days of rest.

The median age of patients was 68 years, with over two-thirds ≥65 years. The most common ECOG performance scores were 0 (47% to 49%) and 1 (42% to 45%). Most patients had de novo AML (approximately 90%) and most had intermediate cytogenetic risk (approximately 86%).

In the CC-486 groups, the best responses to prior therapy consisted of CR for 79% of patients and CRi for 21%. In the placebo arm, the best responses were CR for 84% of patients and CRi for 16%. Across both groups, approximately one-fifth of patients had not received consolidation therapy prior to study entry and approximately half of patients tested negative for minimal residual disease.

At 1 year, 47% of patients were free of relapse in the CC-486 arm compared with 29% in the placebo group. Benefits in both RFS and OS were seen across key prognostic AML subgroups.

The median treatment duration was 12 cycles with CC-486 compared with 6 in the placebo group, which speaks to the tolerability of the agent. Some patients in the CC-486 arm received up to 80 cycles of treatment.

The safety profile was consistent with injectable azacitidine, with infrequent treatment discontinuation related to adverse events (AEs). There were no treatment-related deaths. The most common all-grade AEs with CC-486 were gastrointestinal in nature, including nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3/4 AEs in the CC-486 and placebo groups, respectively, were neutropenia (41% vs 24%), thrombocytopenia (23% vs 22%), anemia (14% vs 13%), diarrhea (5% vs 1%), vomiting (3% vs 0%), fatigue (3% vs 1%), and nausea (3% vs 0.4%).


  1. U.S. Food and Drug Administration (FDA) Accepts for Priority Review Bristol Myers Squibb’s Application for CC-486 for Maintenance Treatment of Adult Patients in Remission with Acute Myeloid Leukemia. Posted May 1, 2020. https://bit.ly/2KSh7lj. Accessed Posted May 1, 2020.
  2. Wei AH, Dӧhner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 in Patients with Acute Myeloid Leukemia (AML) in First Remission. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract LBA3.