Regulatory Decision Summary for Vyxeos

Vyxeos, a dual-drug combination of liposomal encapsulated cytarabine and daunorubicin, conferred a clinically meaningful benefit on the outcome of survival in adult patients with newly diagnosed, high-risk AML. The pivotal Phase 3 study (Study 301) randomized 309 newly diagnosed adults to receive Vyxeos or conventional cytarabine plus daunorubicin (referred to as the 7+3 regimen, a cycle of 7 days cytarabine + 3 days daunorubicin). The study met its primary overall survival (OS) endpoint, demonstrating significantly improved survival with Vyxeos over the 7+3 regimen of care. The median OS for Vyxeos was 9.56 months versus 5.95 months for the 7+3 regimen (p = 0.005). Vyxeos showed a 30% reduction in the risk of death, reaffirmed in 5-year follow-up data. A 5-year OS rate was higher with Vyxeos (18% vs 8%). The complete remission (CR) rate was also higher with Vyxeos (37%) as compared to 26% for the 7+3 regimen (p = 0.040). The overall rate of hematopoietic stem cell transplantation (HSCT) was 34 % with Vyxeos versus 25% in the control arm, and the 5-year survival outcome among the HSCT recipients was superior for Vyxeos-treated patients.

In the adult population, the safety profile of Vyxeos at the proposed dose of 100 units/m² (44 mg/m² daunorubicin and 100 mg/m² cytarabine) is similar to that of the 7+3 regimen of care. Notably, the cardiotoxicity of Vyxeos was not lower as compared to the conventional use of cytarabine and daunorubicin in the 7+3 regimen. The safety profile of Vyxeos is well-characterized by the pooled analysis of 375 patients treated with Vyxeos in adult clinical trials. The risks associated with Vyxeos are managed with adequate labeling and considered acceptable for the treatment of adults with newly diagnosed t-AML and AML-MRC.

In the adult population, Vyxeos demonstrated significant improvement in overall survival and an acceptable safety profile when compared to conventional treatment with the same drugs in the 7+3 regimen. Therefore, benefits of Vyxeos outweigh its risks in adults with untreated t-AML or AML-MRC. Based on the evaluation of the submitted data, Vyxeos can be recommended for use in adults for treatment of newly diagnosed t-AML or AML-MRC.

The second indication proposed in this NDS was for treatment of relapsed or refractory AML (R/R AML) in pediatric and young adult patients aged 1 to 21 years old. However, the safe and effective dose was not established in the two single arm pediatric studies, AAML1421 (Phase 1/2 pivotal pediatric study in 38 anthracycline pre-treated patients with relapsed AML aged 1 to 21 years) and CPX-MA 2101 (Phase 1 dose-finding study in 27 patients aged 1 to 19 years with relapsed/refractory hematologic malignancies. The maximum tolerated doses (which were 135 and 100 units/m², respectively) were discordant between the two single arm pediatric studies.

In the treatment of pediatric patients with R/R AML, no long-term data was provided regarding the cardiotoxicity of the cumulative doses of anthracycline used (for both prior anthracycline treatment, and for daunorubicin from Vyxeos). In study CPX-MA 2101, the higher Vyxeos dose produced a higher complete remission (CR) rate (40% versus 17%) compared to a lower dose, but was associated with important increased toxicities. In the pivotal study AAML1421, the rate of cardiotoxicity in children with relapsed AML (21%) was twice as high as in older adults with newly diagnosed AML (11%). No laboratory data were available from either pediatric study; therefore, no conclusions could be drawn regarding the effects of Vyxeos on hematologic toxicities and other serious risk of AEs including prolonged myelosuppression in the pediatric population.

Given the absence of an active comparator and long-term safety data, the clinical benefit of Vyxeos in relapsed AML in the pediatric population remains inconclusive, while the risks of anthracycline-related cardiotoxicity are significant and were not adequately addressed. Based on the evaluation of submitted data, there is insufficient evidence of clinical safety and efficacy at this time to support the Vyxeos indication for treatment of R/R AML in pediatric and young adult patients aged 1 to 21 years old. It should be noted that this proposed indication for the use of Vyxeos in pediatric patients with relapsed or refractory AML is not currently approved by the Food and Drug Administration or European Medical Association.