First Oral Therapy Approved to Treat Relapsed or Refractory AML and IDH2 Mutation

The FDA today granted approval for enasidenib (Idhifa) to treat adults with relapsed or refractory acute myeloid leukemia (R/R AML) with an isocitrate dehydrogenase-2 (IDH2) mutation.

It was approved concurrently with the Abbott RealTime IDH2 diagnostic test, indicated as an aid in identifying patients with AML who are candidates for treatment with enasidenib, according to a press release.

“The FDA approval of IDHIFA provides the first-ever treatment option for patients living with relapsed or refractory AML and an IDH2 mutation. We appreciate the FDA’s efforts to expedite the availability of IDHIFA for patients with this devastating disease weeks ahead of the PDUFA date,” Mark Alles, chief executive officer of Celgene, said in the release. “This milestone further illustrates the value of Celgene’s unique distributed research model. Our partnership with Agios is an exceptional example of how Celgene and its collaborators can positively impact the lives of patients with high unmet needs.”

Enasidenib is an oral inhibitor designed to target the IDH2 enzyme, and is the first and only FDA-approved treatment for patients with R/R AML who have an IDH2 mutation.

The approval was based on data from an open-label, multicenter, single-arm, 2 cohort clinical trial of adult patients with R/R AML and an IDH2 mutation.

The efficacy was evaluated in 199 adult patients with R/R AML, whose IDH2 mutations were identified or confirmed by the Abbott RealTime IDH2 test. Patients had a median age of 68 years and had received a median of 2 prior anticancer regimens, of whom, more than half were refractory to prior therapy.

Enasidenib was administered orally at a starting dose of 100 mg daily until disease progression or unacceptable toxicity, according to the release.

The findings showed enasidenib achieved a complete response or complete response with hematologic improvement (CR/CRh) rate of 23%. The median duration of CR/CRh was 8.2 months.

Among patients who achieved a CR/CRh, the median time to first response was 1.9 months and the median time to best response was 3.7 months.

Eighty-five percent of patients achieving CR/CRh did so within 6 months of treatment with enasidenib.

Of the 157 patients who are dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 34% became independent of RBC and platelet transfusions during any 56-day post-baseline period, according to the release.

Seventy-six percent of the 42 patients who were independent of both RBC and platelet transfusions at baseline remained transfusion independent during any 56-day post-baseline period.

The safety profile of enasidenib was evaluated in 214 patients with R/R AML and an IDH2 mutation, and revealed the median duration of exposure to enasidenib was 4.3 months. The 30-day and 60-day mortality rates were 4.2% and 11.7%, respectively.

The most common adverse events (AEs) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. Serious AEs were reported in 77.1% of patients, with the most frequent being leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome.

“The FDA approval of Idhifa just 4 years after entering the clinic is the first of what we expect to be multiple first-in-class precision medicines for patients with cancer and rare genetic diseases from our productive discovery engine,” David Schenkein, MD, CEO of Agios said in the release. “We look forward to working closely with Celgene to co-commercialize Idhifa and provide access for patients in the US with this devastating disease.”

Martin Tallman, MD, hematologic oncologist and chief, Leukemia Service at Memorial Sloan Kettering Cancer Center, added. “AML is a complex, heterogeneous disease, which is particularly difficult to treat in the relapsed or refractory setting. IDH2 mutations inhibit the normal maturation of myeloid cells, so having a treatment that targets this mechanism is promising for patients and encouraging to us as physicians who have it as our goal to provide options for every patient.”