Final Phase III Data Uphold CPX-351 Survival Benefit in AML

Jeffrey E. Lancet, MD

CPX-351 (Vyxeos) reduced the risk of death by 31% compared with cytarabine and daunorubicin (7+3) for older patients with high-risk, secondary AML, according to the final results of a phase III trial presented at the 2016 ASCO Annual Meeting.

The study showed a median overall survival (OS) of 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 (HR, 0.69; P = .005). Based on these data, the FDA previously granted CPX-351 a breakthrough therapy designation as a treatment for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

“CPX-351 should be considered standard first-line treatment for older patients with high-risk AML,” the principal investigator for the study, Jeffrey E. Lancet, MD, senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center, said when presenting the data at ASCO.

CPX-351 is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin in a 5:1 molar ratio that was developed using a system known as “CombiPlex,” which was developed by Celator. This platform is meant to improve upon existing therapies through in vitro studies that illuminate an optimal molar ratio for combinations.

The randomized, controlled phase III trial consisted of 309 patients across 39 sites throughout both the United States and Canada who were between the ages of 60 and 75. Patients enrolled in the study were split into either an age group consisting of patients between the ages of 60 to 69 or from 70 to 75.

Those enrolled were further stratified based on AML type. Patients had either therapy-related AML, AML with a history of MDS with and without prior HMA therapy, AML with a history of CMML, or de novo AML with MDS karyotype.

Patient characteristics were well-balanced between the 2 arms. Approximately 62% of patients in each arm were male. In the CPX-351 arm, 90.2% of patients had an ECOG PS of 0 or 1, with 85.9% of patients in the 7+3 arm having an ECOG PS of 0 or 1. The rate of patients with an ECOG PS of 2 were 9.8% and 14.1%, respectively.

Patients were randomized in a 1:1 ratio to receive either CPX-351 (n = 153) or 7+3 (n = 156). Those receiving CPX-351 were given a first induction of 100u/m² on days 1, 3, and 5. Patients in the control arm received daily cytarabine 100 mg/m² for 7 days, followed by daunorubicin 60 mg/m2 on days 1, 2, and 3. Second induction for patients enrolled in the CPX-351 arm was 100u/m2 on days 1 and 3, while patients receiving conventional cytarabine and daunorubicin were given cytarabine 100mg/m² daily for 5 days with daunorubicin 60 mg/m² on days 1 and 2.

At 12 months, 41.5% of patients enrolled in the CPX-351 arm remained alive versus 27.6% in the 7+3 arm. 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 versus 1.31 months (1.08-1.64) with 7+3 (HR, 0.74; P = .021).

Induction response rates (complete remission [CR] plus CR with incomplete hematologic recovery [CRi]) were 47.7% for CPX-351 versus 33.3% for 7+3, yielding a relative benefit of 43.2% with the investigational treatment (P = .016). For CR alone, the rates were 37.3% and 25.6%, between CPX-351 and 7+3, respectively (P = .04).

Patients who achieved a CR or CRi were eligible to receive consolidation chemotherapy. In the investigation arm, consolidation CPX-351 was administered at 65 u/m² on days 1 and 3. In the control arm, consolidation therapy consisted of daily cytarabine at 100 mg/m² for 5 days and daunorubicin at 60mg/m² on days 1 and 2 (5+2).

“We dose-reduced patients during the consolidation phase due to concerns that were raised during the phase II study that delayed count recovery may occur, and we didn’t want to run into problems of harming patients during remission,” said Lancet.

As a primary measurement of toxicity and safety, the researchers analyzed the early mortality rate. “What we determined was that there appeared to be a moderately decreased risk of early mortality at both 30 days and 60 days favoring CPX-351 compared to 7+3,” said Lancet.

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).

As a measure of hematologic toxicity, the researchers assessed blood count recovery in patients achieving a CR or CRi. Patients who received either 1 or 2 inductions of CPX-351 had an approximately 7-day delay in count recovery of neutrophils and platelets compared with the 7+3 group. “We did not observe any increased incidence of early death as a function of delayed count recovery,” Lancet noted.

The researchers also assessed outcomes specifically among patients who underwent hematopoietic stem cell transplantation (HSCT). About one-third of patients underwent HSCT during the study and these patients were well-balanced in baseline characteristics between the 2 arms.

A sensitivity analysis at the time of transplant showed that there was a trend toward improved OS in patients who received CPX-351 compared with 7+3. The median OS was 7.75 months versus 5.55 months, respectively (HR, 0.81; P = 0.165)

In January 2015 the FDA granted Fast Track status to CPX-351 for the treatment of elderly patients with secondary AML. The designation was based on the results of 2 phase II studies. In these studies, CPX-351 showed promising results for patients with newly diagnosed and relapsed AML.

Celator, which was recently acquired by Jazz Pharmaceuticals, reported in a press release that it intends to submit a new drug application to the FDA for CPX-351 by the end of the third quarter of 2016.

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).

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