SEPTEMBER 1, 2020: BMS announced that the U.S.FDA has approved Onureg® (azacitidine 300 mg tablets, CC-486) for the continued treatment of 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 and who are not able to complete intensive curative therapy.
AML is one of the most common acute leukemias in adults.
The approval is based on results from the pivotal Phase 3 QUAZAR® AML-001 study in which treatment with Onureg resulted in a statistically significant and clinically meaningful improvement in overall survival (OS), the study’s primary endpoint, of nearly 10 months compared to placebo.
Median OS from time of randomization was greater than two years (24.7 months; 95% Confidence Interval [CI]: 18.7 to 30.5) among patients who received Onureg compared to 14.8 months (95% CI: 11.7 to 17.6) among patients receiving placebo (Hazard Ratio [HR]: 0.69, 95% CI: 0.55 to 0.86; p=0.0009).
Onureg was continued until disease progression or unacceptable toxicity. Onureg has warnings and precautions for risks of substitution with other azacitidine products, myelosuppression, increased early mortality in patients with myelodysplastic syndromes (MDS) and embryo-fetal toxicity.
Due to substantial differences in the pharmacokinetic parameters, Onureg should not be substituted for intravenous or subcutaneous azacitidine as it may result in a fatal adverse reaction. New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received Onureg, respectively.
Febrile neutropenia occurred in 12% of patients. Complete blood counts should be monitored, dosing should be modified as recommended and standard supportive care should be provided if myelosuppression occurs.
Enrollment was discontinued early in the study AZA-MDS-003 due to a higher incidence of early fatal and/or serious adverse reactions in the Onureg arm compared with the placebo arm.
Treatment of MDS with Onureg is not recommended outside of controlled trials. Onureg can cause fetal harm when administered to a pregnant woman.
“Continued treatment with Onureg demonstrated an overall survival benefit in adults with AML who had achieved first complete remission in the QUAZAR® AML-001 study and, notably, it has the potential to do this in a convenient manner, given its once daily oral formulation,” said Andrew Wei, MBBS, Ph.D., QUAZAR® AML-001 lead investigator, Alfred Hospital and Monash University, Melbourne, Australia.
“This approval should help establish continued treatment with Onureg as a standard component of AML therapy for adults who achieved first complete remission following chemotherapy and who cannot proceed to intensive curative therapy, like hematopoietic stem cell transplant.”
“The FDA approval of Onureg is the culmination of over a decade of research and 13 pre-clinical and clinical trials. We are grateful to the patients, families and caregivers who participated in and supported these trials, and who ultimately made today’s advancement possible,” said Giovanni Caforio, M.D., chairman and chief executive officer, Bristol Myers Squibb.
“This milestone is representative of our commitment to helping patients with hard-to-treat cancers live longer, and the approval of Onureg as an oral therapy option for patients is more relevant now than ever as the world continues to navigate the COVID-19 pandemic.”
The New Drug Application was granted Priority Review Designation by the FDA, and a Marketing Authorization Application (MAA) for this indication was validated by the European Medicines Agency in May 2020.
QUAZAR ® AML-001 Pivotal Trial Results
The FDA approval of Onureg is based on data from QUAZAR® AML-001, a Phase 3, international, randomized, double-blind study.
Eligible patients were ages 55 years or older, had AML, were within four months of achieving first CR or CRi following intensive induction chemotherapy with or without consolidation treatment (per investigator preference prior to study entry), 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.
Results showed continued treatment with Onureg significantly improved OS in patients with AML in remission compared to placebo, establishing Onureg as a new continued therapy option for patients who are not able to complete intensive curative therapy, including HSCT.
Median OS, the primary endpoint, from time of randomization was greater than two years (24.7 months; 95% CI: 18.7 to 30.5) in the Onureg arm compared to 14.8 months for placebo (HR: 0.69, 95% CI: 0.55 to 0.86; p=0.0009). A subgroup analysis showed consistency in the OS benefit for patients in either CR or CRi.
The median duration of treatment was 12 cycles (1 to 82) for Onureg and 6 cycles with placebo (1 to 76).
Serious adverse reactions occurred in 15% of patients who received Onureg. Serious adverse reactions in ≥2% of patients who received Onureg included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received Onureg.
The most common adverse reactions with Onureg versus 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%) and pain in extremity (11%, 5%). Of patients who received Onureg, permanent discontinuation due to an adverse reaction occurred in 8% of patients.
Results from the QUAZAR® AML-001 trial were first presented at the American Society of Hematology (ASH) Annual Meeting in December 2019.
About Onureg ®
Onureg, the first and only FDA-approved continued AML therapy for patients in 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.”
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