EMA Committee Recommends CPX-351 Approval for 2 AML Types

Allen Yang, MD, PhD, associate professor of oncology and urology at Johns Hopkins Medicine

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).