EMA Committee Recommends CPX-351 Approval for 2 AML Types

Allen Yang, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of 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).

The recommendation is based on findings from 5 studies, including a pivotal phase III trial. The phase III study compared CPX-351 with traditional cytarabine and daunorubicin (7+3) for patients with newly diagnosed t-AML or AML-MRC. In the study, the median overall survival (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).

The European Commission will now review the CHMP recommendation and make a final decision on whether to approve CPX-351 for use in the European Union.

"Jazz is committed to bringing new and clinically meaningful treatment options to patients on a global basis, and we now look forward to bringing Vyxeos to adults with AML in the European Union," Allen Yang, MD, PhD, vice president, hematology/oncology therapeutic area head, and acting chief medical officer at Jazz Pharmaceuticals, the manufacturer of CPX-351, said in a statement.

"If approved by the European Commission, Vyxeos will become the first chemotherapy treatment option specifically for European patients with therapy-related AML or AML with myelodysplasia-related changes," added Yang.

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).

In the United States, the FDA approved CPX-351 in August 2017 for adult patients with newly diagnosed t-AML or AML-MRC. The approval came 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).