May 2, 2019—Ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) for newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

July 20, 2018—Ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.


May 2, 2019

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211192s001lbl.pdf

On May 2, 2019, the Food and Drug Administration approved ivosidenib (TIBSOVO, Agios Pharmaceuticals, Inc.) for newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

Approval was based on an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of single-agent ivosidenib for newly-diagnosed AML with an IDH1 mutation detected by the Abbott RealTimeTM IDH1 Assay. Patients enrolled were at least 75 years old or met at least one of the following criteria: baseline Eastern Cooperative Oncology Group performance status of ≥ 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin > 1.5 times the upper limit of normal, or creatinine clearance < 45 mL/min. The 28 patients treated had a median age of 77 years (range, 64-87 years), and 22 (79%) had therapy-related AML or AML with myelodysplasia-related changes. Ivosidenib was administered orally at a dose of 500 mg daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation. Two of the 28 patients underwent stem cell transplantation following ivosidenib.

Efficacy was based on the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the conversion rate from transfusion dependence to transfusion independence. Twelve (42.9%) of the 28 achieved CR+CRh (95% CI: 24.5, 62.8), and 7 (41.2%) of the 17 transfusion-dependent patients achieved transfusion independence lasting at least 8 weeks.

The adverse reactions that occurred in at least 25% of patients were diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome and myalgia. Prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome which may be life-threatening or fatal.

The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response.

View full prescribing information for TIBSOVO.

This application used the Real-Time Oncology Review pilot program. FDA granted this application priority review and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA granted this application priority review, fast track, and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.


July 20, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211192s000lbl.pdf

On July 20, 2018, the Food and Drug Administration approved ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.

Approval was based on an open-label, single-arm, multicenter clinical trial (AG120-C-001, NCT02074839) that included 174 adult patients with relapsed or refractory AML with an IDH1 mutation confirmed using the Abbott RealTime IDH1 Assay, the FDA-approved test for selection of patients with AML for treatment with ivosidenib. Ivosidenib was given orally at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 4.1 months (range, 0.1 to 39.5 months). Twenty-one of the 174 patients (12%) received a stem cell transplant following ivosidenib treatment.

Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), CR+CRh duration, and the rate of conversion from transfusion dependence to independence. The CR+CRh rate was 32.8% (95% CI: 25.8%-40.3%). The median time-to-response was 2 months (range, 0.9-5.6 months), and the median response duration was 8.2 months (95% CI: 5.6 -12 months). The CR and CRh rates were 24.7% (95% CI: 18.5%, 31.8%) and 8.0% (95% CI: 4.5%, 13.1%), respectively.

Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.

The most common adverse reactions (≥20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation.

The FDA today also approved the Abbott RealTime IDH1 Assay for use in selecting patients for treatment with ivosidenib.

The recommended ivosidenib dose is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow time for clinical response.

View full prescribing Information for Tibsovo.

FDA granted this application priority review, fast track, and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia

Author: Matthew Chui, PharmD
PGY-2 Oncology Pharmacy Resident
University of Minnesota Health Cancer Center
Minneapolis, MN

What is the potential role for ivosidenib in the treatment of relapsed or refractory acute myeloid leukemia (AML)?

  • Ivosidenib is currently the only drug indicated for patients with relapsed or refractory AML (r-r AML) who have an isocitrate dehydrogenase 1 (IDH1) mutation.1
  • In a phase-1 trial of 179 patients with r-r AML and IDH1 mutation:
    • Complete remission (CR) or complete remission with partial hematologic recovery (CRh) was demonstrated in 30.4% of patients.1
    • In patients who achieved CR or CRh, median duration of response was 6.5 months.1
    • Median overall survival of the r-r AML group was 10.2 or 14.5 months, depending on clearance of the IDH1 mutation.
    • 177 out of 179 (98.9%) patients experienced an adverse event. The most commonly reported (>20%) were diarrhea (30.7%), leukocytosis (29.6%), febrile neutropenia (28.5%), nausea (27.9%), fatigue (25.7%), dyspnea (24.6%), QT prolongation (24.6%), peripheral edema (21.8%), anemia (21.8%), pyrexia (21.2%), and cough (20.7%).
  • Prior to the approval of ivosidenib, patients with relapsed or refractory IDH1 mutation–positive AML had limited therapeutic options and often had to rely on systemic chemotherapy, which had limited efficacy.2

What role can the pharmacist play in the management of patients on ivosidenib?

  • Pharmacists can ensure monitoring of appropriate laboratory values including, but not limited to, the following:3
    • Comprehensive metabolic panel and complete blood count: at baseline, weekly for the first month, every other week for the second month, and then monthly thereafter
    • Creatine phosphokinase: weekly for the first month of therapy
    • Electrocardiogram: weekly for the first 3 weeks and then once monthly thereafter
  • Pharmacists can screen for drug-drug interactions because ivosidenib is a major cytochrome P450 3A4 (CYP3A4) substrate.
  • Pharmacists can provide recommendations for dose adjustments or interruptions in therapy for patients who experience differentiation syndrome, leukocytosis, and treatment-related adverse events.3
  • A patient assistance program is available through myAgios patient support services at https://www.myagios.com/hcp/index.html. Eligible patients are able to receive the drug for no more than $25.

Clinical Pearls

  • Time to response was 1.9 months (0.8–4.7 months). It is recommended that patients without disease progression or unacceptable toxicity be treated for a minimum of 6 months to allow sufficient time for clinical response.
  • IDH differentiation syndrome was reported in 10.6% of patients and is potentially lethal.1 Management of IDH differentiation syndrome in the study protocol was as follows:
    • Ivosidenib should be temporarily withheld if clinical symptoms cannot be medically managed with one of the following:
      • Initiation of hydroxyurea 2–3 g by mouth twice or three times daily
      • Initiation of dexamethasone 10 mg IV every 12 hours until symptoms resolve and for a minimum of 3 days
      • Initiation of furosemide and leukapheresis if clinically indicated.
  • Although 24.6% of patients experienced QTc prolongation, it’s important to note that 59.2% of patients in this study were receiving concomitant mediations known to prolong the QT interval, which included fluoroquinolones, ondansetron, and azole antifungal agents.1

References

  1. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378:2386-2398.
  2. Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016;27:599-608.
  3. Tibsovo (ivosidenib) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals, Inc.; July 2018.