The FDA has approved CPX-351 (Vyxeos), a fixed-combination of daunorubicin and cytarabine, for adult patients with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC), based on an improvement in overall survival (OS) in a phase III study.
The approval, which arrived several months ahead of an FDA deadline, was based on findings from a phase III study comparing CPX-351 with the traditional cytarabine and daunorubicin (7+3) for patients with newly diagnosed t-AML or AML-MRC. In the study, the median OS was 9.56 months (95% CI, 6.60-11.86) with CPX-351 versus 5.95 months (95% CI, 4.99-7.75) with 7+3, representing a 31% reduction in the risk of death (HR, 0.69; P = .005).
“This is the first approved treatment specifically for patients with certain types of high-risk AML,” 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, said in a statement. “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.”
CPX-351 is a liposomal bound coformulation of cytarabine and daunorubicin that delivers the two medications in a 5:1 molar ratio. The phase III trial consisted of 309 patients aged 60 to 75 who were stratified evenly between each arm into groups aged 60 to 69 (n = 198) or from 70 to 75 (n = 111). Patient characteristics were well-balanced between the 2 arms and groups.
Patients were randomized to receive CPX-351 (n = 153) or 7+3 (n = 156). In the first induction phase, CPX-351 was administered at a first induction dose of 100 u/m2 on days 1, 3, and 5. In the 7+3 arm, cytarabine was given at 100 mg/m2 daily for 7 days, followed by 60 mg/m2 of daunorubicin on days 1, 2, and 3. In the second induction portion, CPX-351 was given at 100 u/m2 on days 1 and 3 and in the 7+3 group cytarabine was given at 100 mg/m2 daily for 5 days with 60 mg/m2 of daunorubicin on days 1 and 2.
The complete response (CR) or CR with incomplete platelet or neutrophil recovery (CRi) rate was 47.7% versus 33.3% for CPX-351 and 7+3, respectively (odds ratio [OR], 1.77; 95% CI, 1.11-2.81; P = .016). For CR alone, the rates were 37.3% for CPX-351 and 25.6% for 7+3 (P = .04).
At 12 months, the OS rate was 41.5% in the CPX-351 arm versus 27.6% in the 7+3 group. At 24 months, 31.1% of patients enrolled in the CPX-351 arm of the study remained alive compared with 12.3% with 7+3. The median event-free survival was 2.53 months (95% CI, 2.07-4.99) with CPX-351 compared with 1.31 months (95% CI, 1.08-1.64) with 7+3 (HR, 0.74; P = .021).
In an exploratory analysis of the phase III study for those with secondary, untreated AML, 34 of the 52 patients (65%) in the CPX-351 arm who proceeded to transplant remained alive after a median follow-up of 521 days. In the 7+3 arm, after 442 days of follow-up, 13 of 39 patients remained alive (33%).
From the time of transplant, the median OS was not reached in the CPX-351 arm versus 10.25 months for 7+3, representing a 54% reduction in the risk of death (HR, 0.46; P = .0046). Furthermore, 100 days after transplant, the rate of mortality from any cause was 53% lower in the CPX-351 arm versus 7+3.
The rates of grade 3 to 5 nonhematologic adverse events (AEs) were similar between the 2 arms. Common grade 3 to 5 AEs occurring in the 2 arms included febrile neutropenia (68% with CPX-351 vs 71% with 7+3), pneumonia (20% vs 15%), hypoxia (13% vs 15%), sepsis (9% vs 7%), hypertension (10% vs 5%), respiratory failure (7% each), fatigue (7% vs 6%), bacteremia (10% vs 2%), and ejection fraction decreased (5% each).
CPX-351, which is being marketing by Jazz Pharmaceuticals, was approved with a boxed warning advising against interchanging the medication with other daunorubicin- and/or cytarabine-containing products. The FDA also advised against using CPX-351 in patients with a history of serious hypersensitivity to daunorubicin, cytarabine, or any component of the formulation.
Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. 34, 2016 (suppl; abstr 7000).