CC-486 Constitutes Standard of Care for Subset of Patients with AML

Older patients with acute myeloid leukemia are traditionally treated with intensive induction chemotherapy and derive benefit, but responses are not durable, and the overall survival (OS) with this treatment in short. It was hypothesized by Guillermo Garcia-Manero, MD et al, that maintenance therapy for post-remission AML might improve upon survival in the patient population, and the phase 3 QUAZAR AML-001 clinical trial was designed to investigate the hypothesis.

The oral hypomethylating agent, CC-486 induced a statistically significant improvement in OS compared with placebo in patients with AML, according to results from QUAZAR AML-001 (NCT0175753). These study findings recently drove the FDA’s decision to approve the drug as a maintenance treatment for adult patients with AML who achieved a first complete remission or with incomplete blood count recovery after intensive induction chemotherapy and who are unable to complete intensive curative therapy.

The OS observed with CC-486 in QUAZAR AML-001 was 24.7 months compared with 14.8 months with placebo (HR, 0.69; 95% CI, 0.55-0.86; P = .0009). In addition to the OS benefit, relapse-free survival (RFS) was improved with CC-486 at 10.2 months compared to only 4.8 months with placebo (HR, 0.65; 95% CI, 0.52-0.81; P = .0001). During the presentation of these findings at the 2019 American Society of Hematology (ASH) Annual Meeting, the investigators concluded that CC-482 is the first agent used in the maintenance setting to show statistically significant and clinically meaningful improvements in both OS and RFS in post-remission patients with AML.

In an interview with Targeted Oncology following the FDA approval of CC-486, Dr. Garcia-Manero, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the key findings from the QUAZAR AML-001 study and the importance of the FDA approval of CC-486 in post-remission AML.

TARGETED ONCOLOGY: It is known that azacitidine injection is effective for the treatment of AML, but why was is necessary to develop a new form of this drug?

Garcia-Manero: We refer to these drugs as hypomethylating agents. The issue with them is that if the patient responds to them, this requires therapy that could last for multiple months or years. We have 2 hypomethylating agents now, which are decitabine and azacitidine. The agents are usually given for five days a month or sometimes seven consecutive days a month.

This means some patients have to take IV or subcutaneous injections every week for the rest of their life.Because of this, we’ve been trying to develop an oral hypomethylating agent for about 50 years, and it’s exciting that we finally have it.

TARGETED ONCOLOGY: What was the rationale for the QUAZAR AML-001 clinical trial?

Garcia-Manero: This was a very interesting study where patients with AML that were in remission were treated in a randomized fashion with azacitadine tablets or a control. The problem with AML is relapse and there have been multiple trying this concept of maintenance therapies to see if some type of low-dose intensive chemotherapy approach would improve survival.

TARGETED ONCOLOGY: What were the key findings of the QUAZAR AML-001 study? What was the safety profile observed with CC-486 in this study?

Garcia-Manero: This is the first study where we see a survival benefit that is quite significant with the hypomethylating agent CC-486, which is a consolidation therapy approach rather than doing nothing.

The data are highly significant in terms of improvement in OS. It is close to 10 months which we have not seen in the past with almost no intervention. The only intervention performed was stem cell transplantation.

The toxicity profile of the compound was well tolerated. That said, these kinds of drugs are mild forms of chemotherapy and therefore can induce cytopenia or mild gastrointestinal toxicities.

TARGETED ONCOLOGY: Now that CC-486 is FDA approved, what will be the overall impact of this drug in the AML treatment landscape?

Garcia-Manero: There’s an interesting shift in the landscape because another oral hypomethylating agent (decitabine) was approved by the FDA last month. For CC-486, in particular, I think we’re going to have to decide what the role of the drug is outside its current indication of post-consolidation maintenance therapy because this CC-486 is not exactly like azacitadine, it has a different pharmacokinetic and pharmacodynamic profile. We are going to have to design new studies in AML and myelodysplastic syndrome. Right now, the role of CC-486 is clearly post-consolidation maintenance therapy.

TARGETED ONCOLOGY: How would you advise oncologists to use CC-486 in practice, now that is available?

Garcia-Manero: In my opinion, using for CC-486 in patients that have completed consolidation therapy, or who are not candidates for stem cell transplantation or had significant toxicity from consolidation, the data from QUAZAR constitute using CC-486 as the standard of care. I would advise using this maintenance approach for this patient population.

If a patient can undergo stem cell transplantation, that should be considered over CC-486. I think the future, we should also pay attention to particular genetic alterations of the patients because there may be a specific subset of patient mutated disease that may be candidates for other targeted agents instead of CC-486.

_Reference:

_{Wei A, Dohner 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 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia (AML) in First Remission. Blood. 2019;134(suppl 2): LBA3. doi:10.1182/blood-2019-132405.}