A fixed combination of two chemotherapies, daunorubicin and cytarabine, in a liposome formulation, known as Vyxeos (from Jazz Pharmaceuticals), has been approved by the US Food and Drug Administration (FDA) for use in adults with two types of acute myeloid leukemia (AML).
One of the indications is for adults with newly diagnosed therapy-related AML (t-AML). This occurs as a complication of previous cancer treatment and is seen in 8% to 10% of patients who undergo chemotherapy or radiotherapy. It occurs within an average of 5 years after therapy.
The other indication is for AML with myelodysplasia-related changes (AML-MRC).
With both of these types of AML, life expectancies are very low, the agency notes.
“This is the first approved treatment specifically for patients with certain types of high-risk AML,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
“Vyxeos combines two commonly used chemotherapies into a single formulation that may help some patients live longer than if they were to receive the two therapies separately,” Dr Pazdur added in a statement.
“Vyxeos is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes,” said Jeffrey E. Lancet, MD, chair of the Department of Malignant Hematology at Moffitt Cancer Center, Tampa, Florida.
“The prognosis for these patients is poor, so the FDA approval of this new drug provides a welcome therapeutic advance,” he added in a statement.
Fixed Combination
The product, formerly known as CPX-351, is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin in a 5:1 molar ratio that maximizes synergy, according to the manufacturer.
In the pivotal phase 3 trial that was the basis for FDA approval, the product was compared to the standard version of this combination, the 7+3 regimen of cytarabine and daunorubicin.
This trial was conducted in 309 patients (aged 60 – 75 years) with newly diagnosed t-AML or AML-MRC.
In the Vyxeos arm, patients received 44 mg/100 mg/m2 (daunorubicin and cytarabine) liposome intravenously via a 90-minute infusion on days 1, 3, and 5 of induction (days 1 and 3 if a second induction was needed) and 29 mg/65 mg per m2 (daunorubicin and cytarabine) liposome on days 1 and 3 for consolidation.
Patients in the 7+3 arm received induction with cytarabine 100 mg/m2/day on days 1 to 7 by continuous infusion and daunorubicin 60 mg/m2/day on days 1 to 3.
For consolidation, cytarabine was administered on days 1 to 5, and daunorubicin on days 1 and 2.
The primary endpoint was overall survival (OS). Vyxeos was shown to be significantly superior: median OS was 9.6 months compared with 5.9 months for the 7+3 treatment group (P = .005; hazard ratio = 0.69; 95% confidence interval, 0.52 – 0.90).
There was a statistically significant improvement in complete response rate of 38% vs 26% (P = .036). The overall, all-cause 30-day mortality was 6% vs 11% in the control arm.
In addition, more patients in the Vyxeos arm (34%) went on to receive a hematopoietic stem cell transplant than in the control arm (25%).
Results from this study were reported at the 2016 annual meeting of the American Society of Clinical Oncology and were reported at the time by Medscape Medical News. “Based on these data, CPX-351 should be considered as the new standard for first-line treatment of older patients with high-risk or secondary AML who are fit for intensive chemotherapy,” said Joseph G. Jurcic, MD, professor of medicine at Columbia University Medical Center, in New York City.
Overall, AML is a “daunting disease” to treat, he noted, especially for older patients, in whom the median survival is typically about 6 months.
Details of Adverse Reactions
In this phase 3 study, the most common adverse reactions (incidence ≥25%) were bleeding events, fever, rash, swelling, nausea, sores in the mouth or throat, diarrhea, constipation, muscle pain, tiredness, stomach pain, difficulty breathing, headache, cough, decreased appetite, irregular heartbeat, pneumonia, blood infection, chills, sleep disorders, and vomiting.
Fatal adverse reactions were reported in 6% of patients in both treatment arms.
During the first 60 days of the study, 14% of patients died in the Vyxeos arm compared with 21% of patients in the 7+3 arm
The FDA notes that patients who have a history of serious hypersensitivity to daunorubicin, cytarabine, or any component of the formulation should not use Vyxeos. Patients taking the new formulation should be monitored for hypersensitivity reactions and decreased cardiac function. The product has been associated with serious or fatal bleeding events, the FDA adds.
In addition, the agency warns that daunorubicin has been associated with severe damage (necrosis) caused by the drug leaking into the skin and subcutaneous tissue from the intravenous infusion (extravasation).
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