FDA Approves CPX-351 (Vyxeos™) for Adult Patients with Newly-Diagnosed Therapy-Related AML or AML with Myelodysplasia-Related Changes, Based on an Improvement in Overall Survival in a Phase III Study

Chemotherapy has long been a standard for treatment of acute myeloid leukemia (AML). CPX-351 (brand name Vyxeos™) is a new agent that combines the standard chemotherapies daunorubicin and cytarabine into a fixed-combination agent. This new drug has now been approved to treat adults with two types of AML, newly-diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). Patients with either of these types of AML have a very poor prognosis and very low life expectancies. This chemotherapy combination is the first agent approved specifically for patients with these high-risk forms of AML, and may lengthen survival more than would be likely if patients received daunorubicin and cytarabine separately.1,2

The safety and efficacy of this daunorubicin/cytarabine combination was studied in a cohort of 309 patients with either newly diagnosed t-AML or AML-MRC. Patients were randomized to receive the combination chemotherapy or therapy with daunorubicin and cytarabine administered separately. Patients who received the combination drug had a median overall survival (OS) of 9.56 months vs 5.95 months for those who received the two chemotherapies separately.1,2

This combination agent has been associated with hypersensitivity reactions, along with decreased cardiac function, and serious or fatal bleeding.1 Other common side effects recorded include febrile neutropenia, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.2

FDA Announcement

Prescribing Information

References:

  1. Journal of Clinical Pathways. FDA approval alert: first treatment for two types of AML. (August 3, 2017). Available at: http://www.journalofclinicalpathways.com/news/fda-approval-alert-first-treatment-two-types-aml.
  2. thepharmaletter. FDA approves first treatment for certain types of poor-prognosis AML. (August 4, 2017). Available at: https://www.thepharmaletter.com/article/fda-approves-first-treatment-for-certain-types-of-poor-prognosis-aml.

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FDA Approves Enasidenib for Treatment of Relapsed or Refractory AML

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) are found in approximately 12% of patients who have acute myeloid leukemia (AML). Enasidenib (AG-221/CC-90007) is a first-in-class, oral selective agent that inhibits mutant IDH2 enzymes. The FDA concurrently approved a companion diagnostic, the RealTime IDH2 Assay, used to detect the IDH2 mutation.

Stein, et al., performed a phase 1/2 study that assessed the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. This included clinical effectiveness and safety in the largest patient subgroup, namely patients with relapsed or refractory AML. Following the dose escalation phase, enasidenib at a dose of 100 mg was chosen for the expansion phase due to its PK/PD profiles and efficacy. Among these patients with relapsed/refractory AML disease, the overall response rate (ORR) was 40.3%, and the patients had a median response duration of 5.8 months. Responses were found to be associated with both cellular differentiation and maturation, and they were typically without evidence of cellular aplasia. The median overall survival (OS) for the relapsed/refractory AML subgroup was 9.3 months; 34 patients (19.3%) attained complete remission (CR), with an OS of 19.7 months.

The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. IDH-inhibitor associated differentiation syndrome occurred in 7% who received enasidenib. As differentiation syndrome may be fatal without prompt management, the prescribing information includes a boxed warning and instructions on the risk and need for early intervention.

Overall results demonstrated that continuous daily enasidenib was generally well-tolerated and induced hematologic responses in patients who had failed prior therapy for AML. Inducing differentiation of myeloblasts, not cytotoxicity, appeared to be the driver of clinical efficacy of enasidenib. A multicenter, phase 3 trial of enasidenib vs conventional therapy in older patients with late-stage AML with IDH2 mutation is currently ongoing (IDHENTIFY trial).

FDA Announcement

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Reference:
Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.

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FDA Approves Gemtuzumab Ozogamicin for CD33-positive AML

On September 1, 2017, the United States. Food and Drug Administration granted new approval to gemtuzumab ozogamicin (Mylotarg) for the first-line treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adult patients. The drug was also approved for treatment of relapsed or refractory CD33-positive AML in both adults and pediatric patients ≥2 years of age. This agent may be used in combination with daunorubicin and cytarabine for adult patients, or as a monotherapy for certain adult and pediatric patients.

This approval of gemtuzumab ozogamicin in combination with chemotherapy for adults was based on the ALFA-0701 trial, a multicenter, randomized, phase 3 study of 271 patients between 50 and 70 years of age with newly-diagnosed, previously untreated, de novo AML. Patients were randomized 1:1 to receive standard daunorubicin and cytarabine induction therapy with or without gemtuzumab ozogamicin on days 1, 4, and 7. The primary endpoint was event-free survival. Results demonstrated an estimated median EFS of 17.3 months for patients receiving gemtuzumab ozogamicin vs. 9.5 months for those receiving chemotherapy.

Gemtuzumab ozogamicin was evaluated in 2 clinical trials for use as monotherapy. AML-19 was a multicenter, randomized, open-label phase 3 study where 237 patients were randomized 1:1 to gemtuzumab ozogamicin monotherapy vx best supportive care (BSC). Patients had newly-diagnosed AML, and were either older than 75 years of age or were between 61 to 75 years of age with a WHO performance status greater than 2 (or who were unwilling to receive intensive chemotherapy). Patients with no evidence of disease progression or significant toxicities after initial induction received continuation therapy for up to 8 courses of treatment, including gemtuzumab ozogamicin every 4 weeks. BSC included standard supportive care measures along with hydroxyurea or other anti-metabolites for palliative purposes. Results demonstrated an estimated median overall survival (OS) of 4.9 months for patients who received gemtuzumab ozogamicin vs. 3.6 months for those in the BSC-only group.

The MyloFrance-1 study, a phase 2, single-arm, open-label trial, assessed 57 patients with CD33-positive AML who had an initial disease relapse. Patients received a single course of gemtuzumab ozogamicin along with cytarabine consolidation therapy. Results showed that 26% of patients achieved complete response (CR) following the single administered course of gemtuzumab ozogamicin. Median relapse-free survival was 11.6 months, measured from first-noted CR to the date of either relapse or death.

In 2000 this drug received approval in older AML patients in the first relapse setting but the agent was voluntarily withdrawn after trials failed to confirm benefit and safety concerns arose surrounding a high number of early patient deaths. This new approval includes a lower recommended dose and treatment schedule along with a different indicated patient population than when originally approved. with use.

The FDA has included a boxed warning for hepatotoxicity, including severe or fatal hepatic veno-occlusive disease, which has been reported in 5% of patients treated with either gemtuzumab ozogamicin alone or with chemotherapy.

FDA Announcement

Prescribing Information

Reference:

United States Food and Drug Administration. FDA Approves Gentuzumab Ozogamicin for CD33-positive AML. (September 1, 2017). Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm574518.htm.

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FDA Approves Midostaurin for Treatment of Adult Patients with Newly-Diagnosed AML (FTL3+ Disease) in Combination with Standard Cytarabine and Daunorubicin Induction and Cytarabine Consolidation

Acute myeloid leukemia (AML) remains a challenging disease to treat for many reasons, including intrinsic biologic factors impacting therapy. Mutations in the fms-related tyrosine kinase 3 gene (FLT3) have been identified in 30% of adults with newly-diagnosed AML, and about 75% of these patients have a FLT3 internal tandem duplication mutation (ITD subtype), which is associated with a poor prognosis owing to a high disease relapse rate.

Midostaurin is a multitargeted kinase inhibitor that was originally assessed to be administered safely at a dose of 50 mg twice daily for 14 days to patients with newly-diagnosed AML, in an early phase 1 study. This agent would be administered beginning on the eighth day after the start of treatment during standard courses of induction and consolidation chemotherapy used for patients with early-stage disease. Stone, et al., conducted a phase 3 trial to determine if midostaurin added to chemotherapy would impact overall survival (OS) in this patient population. A total of 779 patients were randomized to either midostaurin (360 patients) or placebo (357 patients) on the basis of their subtype of FLT3 mutation (ITD-high or ITD-low). Results demonstrated that among the 359 patients who survived (median follow-up of 59 months), median OS was 74.7 months for those who received midostaurin vs 25.6 months for those who received placebo. The 4-year survival rate was 51.4% in the midostaurin group and 44.3% for patients who received placebo. Median event-free survival was 8.2 months in the midostaurin group and 3.0 months for those who received placebo. The benefit of midostaurin was consistent across all FLT3 subtypes, including in patients who underwent allogeneic transplantation. The rate of severe adverse events (AEs) was similar in the two groups, with the most common serious AE being febrile neutropenia in both treatment groups. The researchers concluded that the addition of midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with FT3+ AML.1

It must be noted that the approval for clinical use of midostaurin for AML requires the use of a companion diagnostic test, the LeukoStrat® CDx FLT3 Mutation Assay, also now approved for detecting FLT3 mutations.2

FDA Announcement

Prescribing Information

References:

  1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FTL3 mutation. N Eng J Med. 2017;377(5):454-464.
  2. National Cancer Institute. (June 1, 2017). Midostaurin approved by FDA for acute myeloid leukemia. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-midostaurin-aml.

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