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FDA Approves Oral Azacitidine for AML Treatment

By Kristi Rosa
General Discussions - Discussions
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The FDA has approved CC-486 for the continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or CR with incomplete blood count recovery following intensive induction chemotherapy who are not able to complete intensive curative therapy.1

The regulatory decision is based on data from the pivotal phase 3 QUAZAR AML-001 trial in which CC-486, an oral formulation of azacitidine, lengthened median overall survival (OS) by 9.9 months versus placebo in patients with AML who were in first remission.2

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

The pharmacokinetic and pharmacodynamic profile of CC-486 is distinctly different from injectable azacitidine. Results from earlier studies with the agent demonstrated that the hypomethylating agent is not only efficacious, but tolerable—even in patients who had received prior azacitidine injections and progressed.

A total of 472 patients were enrolled on the phase 3 trial within 4 months of CR or CRi. Patients were randomized to receive daily treatment with CC-486 (n = 238) or placebo (n = 234). The hypomethylating agent was given daily for 14 days followed by 14 days off therapy. If a CR/CRi was not maintained, the dose of the agent could then be escalated to 21 days on drug with 7 days of rest.

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

The best responses to previous treatment consisted of CR for 79% of patients; for 21% of patients, it was CRi. In the placebo arm, the best responses were CR in 84% of patients and CRi in 16% of patients. Across both treatment arms, about one-fifth of participants had not received consolidation treatment before entering the study. Approximately half of patients had minimal residual disease negativity.

At 1 year, 47% versus 29% of patients in the CC-486 and placebo arms, respectively, were free of relapse. Benefits in both RFS and OS were observed across key prognostic patient subgroups.

Moreover, the median treatment duration with CC-486 was 12 cycles versus 6 cycles with placebo. Notably, some participants who received CC-486 received up to 80 cycles of treatment.
With regard to safety, toxicities proved to be consistent with what have been reported with injectable azacitidine. Treatment discontinuation associated with adverse effects (AEs) proved to be infrequent. No treatment-related deaths were reported. The most commonly observed all-grade AEs with the hypomethylating agent included nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3/4 toxicities reported with CC-486 versus placebo included neutropenia (41% vs 24%, respectively), 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%).

Additional results from the trial focused on the safety of the agent specifically in patients who were 75 years of age or older at the time of study entry were presented during the 2020 ASCO Virtual Scientific Program. Overall, the hypomethylating agent was found to be well tolerated, and rates of individual AEs were found to be generally similar between all patients who received the drug and this specific subgroup.3

Notably, a lower incidence of thrombocytopenia was observed in this population compared with all patients who received CC-486. Gastrointestinal effects were the most commonly reported toxicities in this subgroup, with diarrhea being the most comment effect to lead to treatment discontinuation.

Although older patients with AML are known to be at increased risk of relapse, CC-486 was found to result in statistically significant improvements in both OS (HR, 0.48; 95% CI, 0.25-0.94; P = .0281) and RFS (HR, 0.40; 95% CI, 0.20-0.79; P = .0061) in this patient population.

At the meeting, additional data from the trial demonstrated that patients who relapsed early who had 5% to 15% blasts and went on to receive escalated 21-day/cycle dosing tolerated the escalated dose well; the dosing was observed to reduce blasts to less than 5% in approximately one-fourth of these patients.4 Notably, these patients did not experience an increase in new toxicities following dose escalation. As such, investigators concluded that the 21-day dosing schedule for the hypomethylating agent should be considered for patients with AML who relapse with 15% blasts or less.

Finally, patient-reported health-related quality of life (HRQOL) outcomes were also reported. Results showed that patients with CR or CRi who were in first remission following induction chemotherapy reported numerically low levels of fatigue and a favorable overall HRQOL at baseline, with scores comparable to those of the general populations.5

Notably, HRQOL was preserved in patients who received maintenance treatment with the agent, remaining at, or slightly above, baseline levels over the entire treatment duration. Changes from baseline in FACIT-Fatigue and EQ-5D-3L scores were comparable between CC-486 and placebo.

1. FDA Approval
2. Wei AH, Döhner 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. Blood. 2019;134(suppl 2):LBA-3. doi:10.1182/blood-2019-132405
3. Ravandi F, Wei A, Dohner H, et al. CC-486 is safe and well-tolerated as maintenance therapy in elderly patients (≥75 years) with acute myeloid leukemia (AML) in first remission following induction chemotherapy: results from the phase III QUAZAR AML-001 trial. J Clin Oncol. 2020;38(suppl 15):7530. doi:10.1200/JCO.2020.38.15_suppl.7530
4. Dohner H, Wei A, Montesinos P, et al. Escalated dosing schedules of CC-486 for patients experiencing first acute myeloid leukemia (AML) relapse: results from the phase III QUAZAR AML-001 maintenance trial. J Clin Oncol. 2020;38(suppl 15):7513. doi: 10.1200/JCO.2020.38.15_suppl.7513
5. Roboz GJ, Dohner H, Pocock C, et al. Health-related quality of life (HRQoL) in the phase III QUAZAR-AML-001 trial of CC-486 as maintenance therapy for patients with acute myeloid leukemia (AML) in first remission following induction chemotherapy (IC). J Clin Oncol. 2020;38(suppl 15):7533. doi:10.1200/JCO.2020.38.15_suppl.7533

This article was originally published on OncLive as, "FDA Approves Oral Azacitidine for Acute Myeloid Leukemia."
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