FDA News – September 2017

September 2017, Vol 7, No 9 - FDA News


A brief overview of new therapies approved by the FDA between August 1 and August 7, 2017.

In This Article


Enasidenib, a New Targeted Therapy Approved for Relapsed or Refractory AML

On August 1, 2017, the FDA approved enasidenib (Idhifa; Celgene), an isocitrate dehydrogenase-2 inhibitor, for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML) who have the IDH2 genetic mutation.

The FDA approved enasidenib for use based on results of a companion diagnostic—the RealTime IDH2 Assay (by Abbott Laboratories)—which was approved by the FDA on the same day and is specifically designed to detect mutations in the IDH2 gene in patients with AML. If the RealTime IDH2 Assay detects the IDH2 mutation in the patient’s blood or bone marrow, that patient may be eligible for treatment with enasidenib. The FDA granted enasidenib a priority review and an orphan drug designation.

“Idhifa is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH2 mutation,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “The use of Idhifa was associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.” Enasidenib works by blocking several enzymes that promote cell growth.

The FDA approval of enasidenib was based on a single-arm clinical trial that enrolled 199 patients with relapsed or refractory AML and had an IDH2 mutation that was detected by the RealTime IDH2 Assay. The study’s primary end points were complete remission (CR) and CR with partial hematologic recovery (CRh).

Patients received at least 6 months of treatment with enasidenib; of the 199 patients in the study, 19% had CR lasting for a median duration of 8.2 months, and 4% of patients had CRh lasting for a median duration of 9.6 months.

Furthermore, at the start of the study, 157 patients required transfusions of blood or platelets because of AML; of these patients, 34% stopped the transfusions after initiating treatment with enasidenib.

The common side effects reported with enasidenib were nausea, vomiting, diarrhea, increased bilirubin levels, and decreased appetite. Women who are pregnant or are breastfeeding should not take enasidenib, which may cause harm to the fetus or the newborn baby.

The prescribing information of enasidenib includes a boxed warning about the risk for differentiation syndrome with this drug, which can be fatal if not properly treated. When this syndrome is suspected, patients should receive corticosteroids and be monitored closely.

The National Cancer Institute estimates that approximately 21,380 Americans will be diagnosed with AML and 10,590 patients will die of the disease in 2017.

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Ibrutinib First Treatment Approved by the FDA for Chronic Graft-versus-Host Disease

On August 2, 2017, the FDA approved a new in­dication for ibrutinib (Im­bruvica; Pharmacyclics) for the treatment of adults with chronic graft-versus-host disease (GVHD) after ≥1 lines of systemic therapy.

This is the first drug approved specifically by the FDA for the treatment of patients with chronic GVHD. The FDA used its priority review process, and granted ibrutinib a breakthrough therapy designation and an orphan drug designation for this new indication.

The FDA approval of this new indication for ibrutinib was based on an open-label, multicenter, single-arm clinical trial that included 42 patients with chronic GVHD who did not respond to first-line therapy with a corticosteroid. The majority (88%) of patients had ≥2 organs involved at baseline, including the mouth (86%), skin (81%), and gastrointestinal (GI) tract (33%).

The overall response rate, as assessed by the investigators, was 67%, or 28 patients (95% confidence interval, 51%-80%). The responses were seen in all the involved organs, including skin, mouth, GI tract, and liver. Furthermore, in 20 (48%) patients, the responses lasted for ≥5 months.

The most common (≥20%) adverse events observed in the study were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. A grade 3 atrial fibrillation was reported in 1 patient. Ibrutinib therapy was discontinued because of adverse events in 24% of the patients; fatigue and pneumonia were the most common events leading to treatment discontinuation.

Ibrutinib was previously approved by the FDA for the treatment of patients with different types of cancer, including patients with chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma (SLL); patients with CLL or SLL that is associated with 17p deletion; and patients with Waldenström’s macroglobulinemia, marginal-zone lymphoma, or mantle-cell lymphoma.

The recommended dose of ibrutinib for patients with chronic GVHD is 420 mg (three 140-mg oral capsules once daily).

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Vyxeos First Treatment Approved Specifically for 2 Types of High-Risk AML

On August 3, 2017, the FDA approved a fixed combination of cytarabine plus daunorubicin (Vyxeos; Jazz Pharmaceuticals) injection for the treatment of adults with 2 types of acute myeloid leukemia (AML)—newly diagnosed, therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). This is the first drug approved by the FDA specifically for t-AML or AML-MRC.

“This is the first approved treatment specifically for patients with certain types of high-risk AML,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Vyxeos combines two commonly used chemotherapies into a single formulation that may help some patients live longer than if they were to receive the two therapies separately,” he added.

t-AML occurs as a complication of chemotherapy or radiation in approximately 8% to 10% of all patients who receive treatment for any type of cancer, during an average of 5 years after treatment. AML-MRC is a type of AML that results from certain blood disorders that are associated with significant mutations in cancer cells. The prognosis for patients with t-AML or AML-MRC is very short.

This new combination was evaluated in 309 patients with newly diagnosed t-AML or AML-MRC who were randomized to the daunorubicin plus cytarabine combination or to monotherapy with either of the components of the combination. The primary end point was overall survival (OS). The median OS was 9.56 months with the combination of both drugs versus 5.95 months with monotherapy with either drug.

The most common side effects seen with the combination include hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

This new combination chemotherapy has been associated with serious or fatal bleeding events. Daunorubicin has been associated with localized necrosis. Women who are pregnant or breastfeeding should not use this combination.

The FDA used its priority review process for this indication and granted the new drug a breakthrough therapy designation.

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First CAR T-Cell Therapy Unanimously Recommended by FDA Advisory Committee for Treatment of B-Cell Acute Lymphoblastic Leukemia in Young Patients

On July 12, 2017, the FDA’s Oncologic Drugs Advisory Committee unanimously recommended the approval of CTL019 (tisagenlecleucel; Novartis)—the first ever chimeric antigen receptor (CAR) T-cell therapy to be presented to the FDA for approval. The manufacturer’s application for CTL019 is for the treatment of pediatric patients and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The committee’s recommendation was based on a review of ELIANA, the first pediatric global CAR T-cell therapy clinical trial. The results from a multicenter trial and a single-center trial that assessed the drug’s safety and efficacy in pediatric patients and young adults with relapsed or refractory B-cell ALL also supported the recommendation.

Among the 63 patients who received CTL019 between April 2015 and August 2016, 63 (82.5%) patients experienced diseased remission, and 11 patients died.

“It’s a new world, an exciting therapy,” said Gwen Nichols, MD, Chief Medical Officer of the Leukemia & Lymphoma Society, which funded some of the research related to this treatment.

The FDA agreed to review the Bio­logics License Application for this agent under its priority review status; if approved, CTL019 would become the first CAR T-cell therapy in the United States.

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