Ivosidenib Approved for IDH1-Mutant Relapsed or Refractory Myelodysplastic Syndromes

Myelodysplastic disorder.

The FDA has approved ivosidenib (Tibsovo®, Servier Pharmaceuticals LLC) for adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. In addition, the FDA approved a companion diagnostic device, Abbott RealTime IDH1 Assay, to select patients for ivosidenib.  

Why it matters: “Mutations in IDH1 occur in ~3% of patients with MDS and are associated with increased transformation to acute myeloid leukemia (AML),” wrote David Sallman, MD, an Assistant Member in the Department of Malignant Hematology at Moffitt Cancer Center, and colleagues, in their published abstract of the AG120-C-001 trial (NCT02074839), on which approval was based. “Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to ivosidenib in metastatic IDH1 relapsed or refractory MDS.”

What they studied: Efficacy of ivosidenib was studied in the phase 1, open-label, single-arm trial in which 18 patients with relapsed or refractory MDS with an IDH1 mutation were administered 500 mg ivosidenib daily, continuously for 28-day cycles until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation.

The efficacy end points measured were complete remission and partial remission, duration of complete and partial remission, and the conversion rate from transfusion dependence to independence.

What they found: The median treatment duration was 9.3 months. All observed responses were complete remission at a rate of 38.9%. The median time to complete remission was 1.9 months, and the median duration of complete remission was not estimable.

Six of the nine patients who were dependent on red blood cell and/or platelet transfusions at baseline achieved red blood cell and platelet transfusion independence during any 56-day post-baseline period. Of the remaining nine patients who were already independent of both red blood cell and platelet transfusions at baseline, seven remained transfusion-independent during any 56-day post-baseline period.

Adverse events: The most common adverse events experienced, which were similar to common adverse events observed with ivosidenib monotherapy for AML, included gastrointestinal (GI) toxicities—diarrhea, constipation, mucositis, and nausea—arthralgia, fatigue, cough, myalgia, and rash. It is noted that ivosidenib may also cause QTc prolongation.

What to know: A Boxed Warning is listed in the prescribing information alerting health care professionals and patients about the risk of differentiation syndrome which may be life-threatening or fatal.

Conclusion: “In patients with metastatic IDH1 relapsed or refractory MDS, ivosidenib monotherapy was tolerable and induced durable remissions and transfusion independence,” concluded Dr. Sallman and colleagues. “These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with metastatic IDH1 relapsed or refractory MDS.”

Instructions: The recommended dosage of ivosidenib is 500 mg daily with or without food until disease progression or unacceptable toxicity. Patients should avoid taking with a high-fat meal.

For More Information

Sallman DA, Foran JM, Watts JM, et al (2022). Ivosidenib in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy. J Clin Oncol (ASCO Annual Meeting Abstracts), 40(suppl_16). Abstract 7053. DOI:10.1200/JCO.2022.40.16_suppl.7053

Clinicaltrials.gov (2023). Study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation. NLM identifier: NCT02074839.

Tibsovo® (ivosidenib) prescribing information (2023). Servier Pharmaceuticals LLC. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211192s011lbl.pdf

US Food and Drug Administration (2023). FDA approves ivosidenib for myelodysplastic syndromes. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-myelodysplastic-syndromes

Image credit: Ed Uthman. Licensed under CC BY-SA 2.0 DEED


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