On December 7, 2020 Bristol Myers Squibb (NYSE: BMY) reported new results from the QUAZAR AML-001 study presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, evaluating Onureg (azacitidine tablets; CC-486), an oral hypomethylating agent, as a treatment for adult patients with acute myeloid leukemia (AML) who achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy (Press release, Bristol-Myers Squibb, DEC 7, 2020, View Source [SID1234572374]). Results demonstrated treatment with Onureg improved overall survival (OS), the primary endpoint of the study, as well as showed clinical benefit across other key secondary endpoints, compared to placebo, in patients with AML in first remission.

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A longitudinal assessment of measurable residual disease (MRD) status from QUAZAR AML-001 evaluated treatment with Onureg in patients with both MRD positive (MRD+) and MRD negative (MRD-) status at baseline. The MRD evaluable cohort comprised 463/472 randomized patients (Onureg, N=236; placebo, N=227).

Median OS was prolonged with Onureg compared with placebo in patients who were either MRD+ (median 14.6 vs. 10.4 months, respectively; HR: 0.69 [95% CI: 0.51, 0.93]) or MRD- (median 30.1 vs. 24.3 months; HR: 0.81 [0.59, 1.12]) at baseline.
The median duration of MRD negativity was extended with Onureg vs. placebo (11.0 vs. 5.0 months, respectively; HR: 0.62 [95% CI: 0.48, 0.78]). Treatment with Onureg also resulted in a higher rate of MRD response (MRD+ to MRD-) vs. placebo: 37% vs. 19%, respectively.
Median relapse-free survival (RFS) was extended with Onureg for both MRD+ (7.1 vs. 2.7 months, respectively; HR: 0.58 [95% CI: 0.43, 0.78]) and MRD- patients (13.4 vs. 7.8 months; HR: 0.71 [0.52, 0.98]).
The MRD assay used in the QUAZAR AML-001 study is not part of the label recently approved by the U.S. Food and Drug Administration (FDA) for Onureg as a continued treatment for adult patients with AML who achieved first CR or CRi following intensive induction chemotherapy and who are not able to complete intensive curative therapy.
Results from a separate post-hoc analysis evaluated treatment with Onureg in patients from the QUAZAR AML-001 study who had a range of prior consolidation chemotherapy cycles.

472 patients were randomized to Onureg (N=238) or placebo (N=234) and most patients (80%) received consolidation before study entry. Common agents used for consolidation were cytarabine, idarubicin and daunorubicin.
In the cohort where no prior consolidation was administered, median OS with Onureg (N=52) vs. placebo (N=42) was 23.3 vs. 10.9 months, respectively (HR: 0.55 [95% CI: 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 months (0.55 [0.34, 0.88]).
In the cohort of patients who received one cycle of consolidation treatment, median OS was 21.0 vs. 14.3 months with Onureg (N=110) vs. placebo (N=102), respectively (HR: 0.75 [95% CI: 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 months (0.72 [0.53, 0.99]).
In the ≥2 consolidations cohort, median OS was 28.6 months with Onureg (N=76) vs. 17.6 months with placebo (N=90) (HR: 0.75 [95% CI: 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 months (0.59 [0.41, 0.87]).
"These analyses from the QUAZAR AML-001 study provide further insight into the clinical activity of Onureg and its potential role in the treatment paradigm of patients with acute myeloid leukemia in first remission following intensive chemotherapy," said Andrew Wei, MBBS, Ph.D., QUAZAR AML-001 lead investigator, Alfred Hospital and Monash University, Melbourne, Australia. "Persistence of acute myeloid leukemia is frequently measurable after intensive chemotherapy, and these new analyses from the pivotal trial demonstrate that Onureg can improve survival in patients with or without measurable residual disease, and across a range of consolidation cycles."

An additional post-hoc analysis showed treatment with Onureg was associated with reduced risk of hospitalization events and days in hospital, as well as estimated cost savings associated with hospitalizations, compared with placebo. Hospitalization events in the study were collected starting from informed consent signature through 28 days after the last intraperitoneal (IP) dose. Rates of hospitalization and days in hospital were adjusted for duration of Onureg and placebo exposure. 469 patients received Onureg (N=236) or placebo (N=233). In all, 108 patients (45.8%) in the Onureg arm and 118 (50.6%) in the placebo arm were hospitalized. The analysis showed that Onureg reduced exposure-related rate of hospitalization and days in hospital compared to placebo in the QUAZAR AML-001 study. Additionally, the analysis showed that extended remission periods with Onureg compared to placebo may translate into hospitalization-related cost reductions due to reduced rates of hospitalization and days in the hospital.

"New data we’re presenting for Onureg at ASH (Free ASH Whitepaper) highlight its potential to improve long-term outcomes for people living with this aggressive blood cancer," said Samit Hirawat, M.D., executive vice president, chief medical officer, global drug development, Bristol Myers Squibb. "Moreover, oral treatment options like Onureg that can be taken at home are even more important than ever before for patients."

About QUAZAR AML-001

QUAZAR AML-001, is a Phase 3, international, randomized, double-blind study. Eligible patients were ages 55 years or older, had newly diagnosed AML, intermediate or poor cytogenetics, had achieved first CR or CRi following intensive induction chemotherapy with or without consolidation treatment (per investigator preference prior to study entry) within four months before randomization, and were not candidates for hematopoietic stem cell transplant (HSCT) at the time of screening. The study enrolled 472 patients, randomized 1:1 to receive either Onureg 300 mg (N=238) or placebo (N=234) orally, once daily, for 14 days of a 28-day cycle, plus best supportive care.1

About AML

There will be nearly 20,000 new cases of acute myeloid leukemia (AML) in the United States this year, accounting for 1.1% of all cancer cases, with an estimated 11,180 deaths resulting from the disease. There were an estimated 64,500 people living with AML in the United States in 2017.2 AML is one of the most common acute leukemias in adults. AML is characterized by the rapid growth of abnormal cells in the bone marrow and as such interferes with normal blood cell production and function. Because of the impaired production of red blood cells, platelets and white blood cells, it can present with signs of anemia, bleeding and infections.3 AML is a heterogeneous disease associated with diverse genetic mutations, and can rapidly progress and lead to death if not promptly treated.4 AML response to treatment may be of short duration, meaning following patients’ initial response to chemotherapy, there is still a very high risk of relapse, thus representing a significant unmet need for continued treatment options that prolong overall survival.5

About Onureg

Onureg, the first and only FDA-approved continued AML treatment for patients in first remission, is an oral hypomethylating agent that incorporates into DNA and RNA. The main mechanism of action is thought to be hypomethylation of DNA, as well as direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore normal function to genes that are critical for cell differentiation and proliferation.6,7

INDICATION

ONUREG is indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.
IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS

Risks of Substitution with Other Azacitidine Products: Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in a fatal adverse reaction. Treatment with ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG for intravenous or subcutaneous azacitidine.
Myelosuppression: New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS): In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG or placebo. 107 received a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG for MDS have not been established. Treatment of MDS with ONUREG is not recommended outside of controlled trials.
Embryo-Fetal Toxicity: ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose.
ADVERSE REACTIONS

Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG.
Most common (≥10%) adverse reactions with ONUREG vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION

There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose.
Please see full Prescribing Information for ONUREG.

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