Olutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia

ABSTRACT

Introduction

Recurrent mutations in isocitrate dehydrogenase 1 (mIDH1) occur in about 7% to 14% of all cases of acute myeloid leukemia (AML). The discovery of targetable mutations in AML, including IDH mutations, expanded the therapeutic landscape of AML and led to the development of targeted agents. Despite significant advances in current treatment options, remission and overall survival rates remain suboptimal. The IDH1 inhibitor, olutasidenib, demonstrated encouraging safety and clinical benefits as monotherapy in patients with relapsed or refractory (R/R) mIDH1 AML.

Areas covered

This review outlines the olutasidenib drug profile and summarizes key safety and efficacy data, focusing on the 150 mg twice daily dose from the pivotal registrational cohort of the phase 2 trial that formed the basis for the US Food and Drug Administration approval of olutasidenib in patients with R/R AML with a susceptible IDH1 mutation.

Expert opinion

Olutasidenib offers patients with R/R mIDH1 AML a new treatment option, with improved complete remission and a longer duration of response than other targeted mIDH1 treatment options. Olutasidenib provided clinical benefit with a manageable safety profile. Additional analyses to further characterize the safety and efficacy of olutasidenib in frontline and R/R settings as monotherapy and as combination therapy are ongoing.

Plain Language Summary

Olutasidenib is an oral prescription medication for patients diagnosed with acute myeloid leukemia (AML) with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene. The US FDA approved olutasidenib at a dose of 150 mg twice a day for use as stand-alone (monotherapy) treatment in patients with IDH1-mutated AML whose disease has come back or has not improved after previous treatment(s). Olutasidenib is not traditional chemotherapy; it is a targeted treatment called an IDH1 inhibitor, which blocks IDH1 when it has been altered (mutated). These alterations happen in some patients, and when they do, the products of these alterations can lead to leukemia. By blocking mutated IDH1, the body can resume normal blood cell production and functioning. In studies, response to olutasidenib was measured by the number of people who went into remission. Complete remission (CR) means there is no sign of cancer and laboratory values are normal. Complete remission with partial hematologic recovery (CRh) means there is no sign of cancer, but some lab values do not reach normal levels. Thirty-five percent of people taking olutasidenib achieved CR or CRh and stayed in remission for 25.9 months. About 14% of patients who did not achieve remission also experienced some improvement in symptoms. The most common side effects in studies were nausea, feeling tired, fever, constipation, diarrhea, abnormal liver function tests, and changes in certain blood tests. Serious side effects included liver problems and differentiation syndrome, which is a potentially life-threatening situation that can occur when blood cells mature too quickly. Olutasidenib is also being studied in patients with IDH1 mutated AML who have never been treated before and in combination with a chemotherapy medication called azacitidine.

KEYWORDS:

• Olutasidenib
• 2-hydroxyglutarate
• acute myeloid leukemia
• IDH1 mutation
• differentiation syndrome

Article highlights

• Mutated isocitrate dehydrogenase 1 (mIDH1) is present in 7%-14% of patients with acute myeloid leukemia (AML). Inhibition of mIDH1 can restore normal cellular differentiation and provide therapeutic benefit in mIDH1 AML, a patient population with a poor prognosis and limited treatment options.

• Olutasidenib is a potent, selective, oral, small-molecule inhibitor of mIDH1. In a phase 1 trial, the safety of olutasidenib as monotherapy and in combination with hypomethylating agent azacitidine was established in patients with treatment-naïve or relapsed or refractory (R/R) AML or myelodysplastic syndrome harboring mIDH1.

• Olutasidenib was US FDA approved for the treatment of R/R AML based on results from the pivotal registrational cohort of an ongoing phase 2 trial in which patients achieved a 35% rate of complete remission (CR) + complete remission with partial hematologic recovery (CRh) and a duration of response (DOR) of 25.9 months. Clinical benefit was also seen in responders who did not achieve CR/CRh.

• Olutasidenib also demonstrated clinical benefit in patients with prior exposure to venetoclax or ivosidenib as well as in patients with a prior hematopoietic stem cell transplant (HSCT).

• Side effects from olutasidenib are manageable, however, patients should be monitored for signs and symptoms of differentiation syndrome (DS) and liver abnormalities; DS should be promptly treated with treatment interruption, with corticosteroids and in some instances administration of hydroxyurea.

• A clinical trial is currently ongoing to evaluate olutasidenib monotherapy in frontline and R/R settings and as combination therapy with azacitidine.

• Olutasidenib as monotherapy appears to have notable differences from ivosidenib, including duration of CR/CRh (25.9 months v 8.2 months, respectively), 18-month survival in CR/CRh responders (78% v 50%), and median OS (11.6 months v 8.8 months) in patients with R/R AML.

Declaration of interest

J Cortes has received research funding for his current or former institution from, and is a consultant to, Astellas, Amphivena, BMS, Novartis, Pfizer, Takeda, Daiichi, Jazz Pharmaceuticals, Merus, and Forma Therapeutics; and is a consultant to Rigel, BiolineRx, Bioptah, Novartis, Pfizer, Sun Pharma, Tern, and Jazz Pharmaceuticals.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The author would like to thank the patients and their families for participating in the study as well as the study site investigators and staff. The author would also like to thank CD Gioiello, of PharmaWrite, LLC, for medical writing and editorial assistance, which was funded by Rigel Pharmaceuticals, Inc.

Data availability statement

For deidentified data, requests may be sent to [email protected] at least 24 months after clinical trial completion, provided a scientifically valid research proposal is made by qualified, academic researchers for data associated with interventions that have received regulatory approval in the US and Europe.

Additional information

Funding

This paper was funded by Rigel Pharmaceuticals, Inc., and Forma Therapeutics, Inc.