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

1. Introduction

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of the bone marrow characterized by the clonal expansion of myeloid blasts [1,2]. AML is the most common type of acute adult leukemia, accounting for approximately 80% of all cases and mainly affects older adults (median age at diagnosis: 69 years), men more than women [3–5]. The global incidence of AML has been increasing gradually, with a reported 87.3% increased incidence from 1990 to 2017 [5]. Patients with AML have a poor prognosis, with a 5-year relative survival of only 31.7% (2013–2019) [3]. Survival rates are worse for elderly patients, with an estimated 5-year survival rate of 3%-8% for patients ≥60 years compared with up to 50% for younger patients [6]. Despite significant advances in current treatments, as many as 70% of patients ≥65 years will die within one year of diagnosis; these results are still disappointing and new treatment modalities are needed [4,5].

Advances in genomic research and exploration of the genomic landscape of AML have led to the identification and recognition of many recurring genetic changes. Cytogenetics is the strongest prognostic factor for predicting remission rate, relapse, and overall survival [7–9]. These are incorporated in the classification and risk stratification by the World Health Organization and the European LeukemiaNet (ELN) [10,11]. Recurrent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are some of the most common genetic alterations in acute myeloid leukemia, occurring in approximately 25%-30% of AML cases, with mutations specifically in subtype IDH1 occurring in about 7% to 14% [1,10,12–18]. The discovery of targetable mutations in AML, including IDH mutations, has expanded the therapeutic landscape of AML through development of targeted agents [19]. IDH1-mutated (mIDH1) AML has been associated with older age and possibly a poorer prognosis, although conflicting data exists with some analyses suggesting a neutral effect [1,18,20–24]. The presence or absence of co-occurring mutations may contribute to the impact that IDH1 mutations have on prognosis [1,23,25,26].

IDH enzymes catalyze the conversion of isocitrate to α-ketoglutarate, an important intermediate in the Krebs cycle involved in various metabolic and cellular pathways [1,19,27]. There are three different isozymes: IDH1, located in the cytosol, and IDH2 and IDH3 located in the mitochondria. All three catalyze the same enzymatic reactions. IDH1 mutations are gain of function mutations, which lead to excess production of the oncometabolite 2-hydroxyglutarate (2-HG) [14]. Excess 2-HG ultimately disrupts epigenetic regulation, blocks cellular differentiation, and, thus, contributes to oncogenesis [14,28,29].

Here, we provide a concise review of the pharmacology, clinical efficacy, and tolerability of olutasidenib, an IDH1 inhibitor, including an expert opinion on the current place in therapy for olutasidenib.

1.1. Overview of the therapeutic landscape

Current AML treatment strategies are based largely on the assessment of patient fitness for the determination of whether intensive chemotherapy or non-intensive treatment is appropriate for the patient [30]. The backbone of intensive chemotherapy for fit individuals has remained the same for approximately 40 years and consists of an induction phase with cytarabine combined with an anthracycline; the primary goal of induction is to achieve complete remission (CR) [2,30]. Following induction, post-remission therapy or consolidation is administered to prolong remission duration and ultimately aim for a cure. In many instances, particularly for those at higher risk (as defined per classifications such as the ELN [10]), allogeneic stem cell transplant is performed, which constitutes the best option for cure [2]. Patients who are ineligible for intensive chemotherapy are treated with less intensive agents (e.g. low-dose cytarabine and hypomethylating agents [HMA]) and in combination with venetoclax, which was recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [2]. Cytogenetic abnormalities are a major predictor of response and survival in adult AML [7].

Historically, patients with mIDH1 relapsed/refractory (R/R) AML have had a poor prognosis, with a median overall survival (OS) of 5.9 months after the first salvage treatment, and 4 months after the second salvage and beyond. The introduction of IDH inhibitors offered a promise for safer and more effective treatment options for this patient population [18].

1.2. Available IDH inhibitors

Several agents targeting mutant IDH enzymes have been developed. Enasidenib, an IDH2 inhibitor, was approved in 2017 by the US FDA, and is indicated for R/R IDH2-mutant AML [31]. Ivosidenib, the first oral, targeted small-molecule, IDH1 inhibitor, was approved by the US FDA in 2018 and the EMA in 2023, and is indicated for the treatment of adult patients with R/R mIDH1 AML, and for patients who are ≥75 years old or who are unfit for intensive induction chemotherapy. In R/R mIDH1 AML, ivosidenib demonstrated an overall response rate (ORR; defined as CR + CR with partial hematologic recovery [CRh] + incomplete CR [CRi] + partial response [PR] + morphologic leukemia free survival [MLFS]) of 41.6% and a median duration of response (DOR) of 6.5 months [32]. The combination of ivosidenib (500 mg orally once daily) with azacitidine is also approved by the US FDA and EMA in newly diagnosed adult patients with mIDH1 AML unfit for intensive chemotherapy. In this setting, the combination of ivosidenib plus azacitidine demonstrated an improvement in median OS (24 months) compared to azacitidine alone (7.9 months), and higher rates of CR (47% vs 15%); median duration of remission with the combination was not reached [33–35]. Ivosidenib is also labeled for monotherapy in newly diagnosed patients with mIDH1 AML who are ineligible for intensive chemotherapy [33,35]. Common adverse effects (>20%) reported with ivosidenib include gastrointestinal disturbances, fatigue, leukocytosis, QTc prolongation, and differentiation syndrome (DS) [33,35].

1.3. Other IDH1 inhibitors under development

BAY1436032, an IDH1 inhibitor under investigation, demonstrated activity in preclinical models, and recently completed a phase 1 trial (NCT03127735) in which modest clinical benefit was seen in patients with advanced mIDH1 AML [36]. This agent is also being investigated in a phase 1 trial (NCT02746081) for advanced solid tumors. DS1001 is also an IDH1 inhibitor and is currently being studied for the treatment of glioma in a phase 1 (NCT03030066) and a phase 2 (NCT04458272) trial. LY3410738, a dual IDH1/2 inhibitor, is being evaluated in phase 1 trials for advanced solid tumors (NCT04521686) and advanced hematologic malignancies (NCT04603001). IDH305, an IDH1 inhibitor, is being examined for advanced malignancies in a phase 1 trial (NCT02381886). Finally, preclinical models recently suggest that 2-HG enhances mIDH cancer cell sensitivity to PARP inhibitors [37]. Thus, a phase 2 trial is currently ongoing to evaluate the PARP inhibitor olaparib in refractory, mIDH solid tumors (NCT03212274).

2. Introduction to olutasidenib

Olutasidenib (150 mg twice daily) was approved by the US FDA on 1 December 2022, for the treatment of adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test [33].

2.1. Olutasidenib mechanism of action

Olutasidenib is a small, allosteric, selective inhibitor of mIDH1. Olutasidenib binds to each monomer of IDH1 in an allosteric pocket near the dimer interface, which prevents structural changes necessary for catalytic activity, reduces 2-HG levels in leukemia cells, and ultimately restores cell differentiation (Figure 1) [14,28,29,38,39]. While both olutasidenib and ivosidenib are allosteric inhibitors of mIDH1, olutasidenib has a unique quinolinone-based structure with a distinct binding stoichiometry of two inhibitor molecules for each IDH1 dimer, compared to one inhibitor molecule for each IDH1 dimer for ivosidenib [40]. In addition, olutasidenib selectively binds to mIDH1, while ivosidenib inhibits both wildtype and mIDH1 [41]. Non-clinical studies have also shown that olutasidenib maintains its binding affinity and high level of activity against double variants that confer resistance to ivosidenib such as R132C/S280F and R132H/S280F [40].

Figure 1. Diagram showing the position where mIDH1 increases conversion of a-KG to 2-HG (left) and the mIDH1 binding pocket where olutasidenib binds (right) [38,39]. a-KG, alpha-ketoglutarate; 2-HG, 2-hydroxyglutarate; AML, acute myeloid leukemia; H1F1α, hypoxia inducible factor 1 subunit alpha; IDH1, isocitrate dehydrogenase 1; KDM2a, lysine-specific demethylase 2a; TET1/2, 10-11 translocation 1/2.

Adapted with permission from Medeiros BC, Fathi AT, DiNardo CD, et al: Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 31:272-281, 2017. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. To view a copy of this license, visit: http://creativecommons.org/licenses/by-nc-sa/4.0/.

Reprinted with permission from Caravella JA, Lin J, Diebold RB, et al. Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor. J Med Chem 63:1612-1623, 2020. Copyright 2020 American Chemical Society.

2.2. Pharmacology of olutasidenib

After administration of a single oral dose of 150 mg, olutasidenib is orally absorbed and reaches the median time to maximum plasma concentration at approximately 4 hours (range 2–24 hours) [33]. The maximum drug concentration (Cmax) of olutasidenib increased significantly (191%) with a high fat meal, and, thus, olutasidenib is recommended to be taken 1 hour before or 2 hours after meals [33]. Once steady state was achieved, typically around day 15 of cycle 1, a 59.1% reduction of 2-HG levels was consistently observed. Steady-state concentrations were significantly lower than those predicted to induce QTc prolongation in monkey models. The PK parameters of olutasidenib were not affected by the addition of azacitidine.

Olutasidenib has an apparent volume of distribution of 319 L with 93% plasma protein binding [33]. The mean terminal elimination half-life of olutasidenib is approximately 67 hours, and the main pathway involved in metabolism includes N-dealkylation, demethylation, oxidation deamination followed by oxidation, and mono-oxidation with secondary glucuronidation, with extensive (90%) biotransformation by the cytochrome P450 3A4 (CYP3A4) isozyme [33]. After the administration of one dose in healthy subjects, 75% of olutasidenib was excreted in feces (35% unchanged) and 17% in urine (1% unchanged) [30]. No clinically significant differences in the pharmacokinetics of olutasidenib were observed based on age, sex, body weight, or mild to moderate renal or hepatic impairment [33].

Co-administration of olutasidenib with strong CYP3A4 inducers significantly reduces systemic exposure of olutasidenib; therefore, co-administration is not recommended with strong or moderate CYP3A4 inducers [33]. In vitro, olutasidenib exhibited CYP3A4 induction potential, and thus medications that are sensitive CYP3A4 substrates should not be used while taking olutasidenib [33]. There are no clinically significant differences in olutasidenib pharmacokinetics when used with multiple doses of a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor (itraconazole).

3. Clinical safety and efficacy of olutasidenib

3.1. Phase 1 evaluation of olutasidenib

The goals of the phase 1 portion of an open-label, multicenter, phase 1/2 clinical trial (NCT02719574) were to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of olutasidenib as monotherapy or in combination with azacitidine in patients with mIDH1 AML or intermediate, high, or very high-risk myelodysplastic syndrome (MDS) (according to revised International Prognostic Scoring System) (Table 1) [42].

Table 1. Summary of clinical trials.

Study name, (ID), phase, and participant number (n)	Study design and key eligibility criteria	Interventions	Objectives	Source
2102-HEM-101, NCT02719574, Phase 1/2 Phase 1: n = 78 Monotherapy: n = 32 Combination: n = 46	Phase 1, multicenter, open-label, non-randomized Phase 1: Key eligibility criteria: ≥18 years with AML or intermediate, high, or very high-risk MDS with mutant-IDH1 ECOG PS 0–2 with adequate liver and renal function, QTc ≤450 ms Patients eligible for olutasidenib monotherapy: R/R to standard therapy, or inappropriate for standard therapy Prior IDH1 inhibitor (ivosidenib) or HMA allowed No exclusions for concomitant medications	Phase 1: Olutasidenib monotherapy: 150 mg daily 300 mg daily 150 mg BID Combination therapy with azacitidine 75 mg/m^2 IV or SQ on days 1–7 of each 28-day cycle: Olutasidenib 150 mg daily Olutasidenib 150 mg BID	Phase 1: Primary Determine dose-limiting toxicities, maximum tolerated dose, maximum evaluated dose, and recommended phase 2 dose of olutasidenibSecondary Determine PK profile of olutasidenib as monotherapy and with azacitidine Determine preliminary evidence of clinical response^a Exploratory Assess changes in in plasma 2-HG levels Determine frequency of cancer-associated mutations and genetic alterations in responders and non-responders Evaluate the PK/PD, and clinical response relationships	Watts JM, et al. Lancet Haematol 2023; 10: e46–58 [42] de botton S, et al. Blood Advances 2023; 7(13): 3117–3127 [43]
2102-HEM-101, NCT02719574, Phase 1/2 Phase 2: Pivotal registrational cohort Monotherapy n = 153 (147 efficacy evaluable)	Phase 2 ≥18 years with mutant-IDH1, R/R AML ECOG PS 0–2 with adequate liver and renal function, QTc ≤450 ms Patients excluded: symptomatic central nervous system leukemia, uncontrolled infections, metabolic disorder, and/or prior IDH inhibitor therapy	Phase 2 Olutasidenib 150 mg BID in continuous 28-day cycles	Phase 2 Primary Rate of CR + CRh Secondary ORR Duration of CR/CRh, DOR, rate of TI, and OS
2102-HEM-101, NCT02719574, Phase 1/2 Multiple Cohorts (not the pivotal cohort)	Newly diagnosed or R/R	Monotherapy or combination

^aDetermination of clinical response based on investigator’s assessment using the International Working Group (IWG) and modified IWG criteria for AML (2003) and MDS (2006); for AML, ORR (defined as complete remission, complete remission with partial hematological recovery, complete remission with incomplete blood count recovery, morphological leukemia-free state, or partial response), complete remission or complete remission with partial hematological recovery, and complete remission were assessed. For MDS, overall response was defined as complete remission plus marrow complete remission plus partial response.

2-HG, 2-hydroxyglutarate; AML, acute myeloid leukemia; BID, twice daily; CR, complete response; CRh, CR with partial hematologic recovery; CRi, CR with incomplete blood count recovery; DOR, duration of overall response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HMA, hypomethylating agents; IV, intravenous; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia-free state; ORR, overall response rate; OS, overall survival; PD, pharmacodynamic; PK, pharmacokinetic; PR, partial response; R/R, relapsed/refractory; SQ, subcutaneous; TI, transfusion independence.

Olutasidenib monotherapy was evaluated in patients with R/R mIDH1 AML or MDS who were R/R or unfit for standard therapy [42]. Combination treatment with azacitidine and olutasidenb was evaluated in treatment naïve patients and those with R/R disease. Starting with 150 mg once daily, olutasidenib monotherapy was evaluated using escalating doses, with or without azacitidine, utilizing a 3 + 3 design; combination therapy with olutasidenib plus azacitidine was evaluated after monotherapy, with 150 mg BID considered safe and chosen as the treatment dose.

In the dose escalation phase, sequential monotherapy cohorts received olutasidenib 300 mg once daily or 150 mg twice per day (in continous 28 day cycles), while combination patients received olutasidenib 150 mg once or twice daily plus azacitidine 75 mg/m² (subcutaneous or intravenously) daily for 7 days on, 21 days off. The dose expansion phase evaluated monotherapy or combination therapy at doses up to the maximum tolerated dose, or maximum evaluated dose; the recommended phase 2 dose (RP2D) was determined based on the safety and PK profile.

No dose-limiting toxicities were reported in the dose escalation cohorts. The most common (≥20%) grade 3–4 treatment-emergent adverse events (TEAEs) with monotherapy were thrombocytopenia (28%; 9/32 patients), febrile neutropenia (22%; 7/32 patients), and anemia (22%; 7/32 patients). Similarly, with combination therapy the most common grade 3–4 TEAEs were thrombocytopenia (41%; 19/46 patients), febrile neutropenia (28%; 13/46 patients), neutropenia (28%; 13/46 patients), and anemia (20%; 9/46 patients) (Table 2). Common (≥25%) grade 1–2 non-hematologic TEAEs with monotherapy were nausea (47%; 15/32 patients), fatigue (41%; 13/32 patients), pyrexia (31%; 10/32 patients), and vomiting (25%; 8/32 patients); with combination therapy, common events included nausea (65%; 30/46 patients), constipation (59%; 27/46 patients), diarrhea (43%; 20/46 patients), coughing and vomiting (37% each; 17/46 patients), and fatigue and headache (30% each; 14/46 patients).

Table 2. Summary of treatment-emergent adverse events from phase 1 and pivotal registrational cohort of phase 2 trial [42, 43].

Phase 1 Trial			Source: Watts, et al., 2023 [42]
	Olutasidenib (n = 32)		Olutasidenib + azacitidine* (n = 46)
Adverse Event (AE)	Grade 1–2, n (%)	Grade 3 or 4, n (%)	Grade 1–2, n (%)	Grade 3 or 4, n (%)
Patients with any AE	31 (97)	32 (100)	46 (100)	43 (93)
Febrile neutropenia	0	7 (22)	2 (4)	13 (28)
Neutropenia	1 (3)	2 (6)	3 (7)	13 (28)
Leukocytosis	4 (13)	4 (13)	7 (15)	7 (15)
Anemia	3 (9)	7 (22)	5 (11)	9 (20)
Thrombocytopenia	3 (9)	9 (28)	8 (17)	19 (41)
Abdominal pain	1 (3)	0	9 (20)	1 (2)
Constipation	6 (19)	1 (3)	27 (59)	1 (2)
Diarrhea	7 (22)	1 (3)	20 (44)	2 (4)
Nausea	15 (47)	0	30 (65)	4 (9)
Vomiting	8 (25)	0	17 (37)	1 (2)
Asthenia	1 (3)	0	10 (22)	2 (4)
Fatigue	13 (41)	2 (6)	14 (30)	8 (17)
Pyrexia	10 (31)	2 (6)	11 (24)	0
Peripheral edema	2 (6)	0	10 (22)	0
Hypokalemia	5 (16)	2 (6)	13 (28)	3 (7)
Decreased appetite	7 (22)	0	11 (24)	1 (2)
Arthralgia	3 (9)	2 (6)	9 (20)	0
Dizziness	7 (22)	1 (3)	11 (24)	1 (2)
Headache	6 (19)	0	14 (30)	1 (2)
Cough	5 (16)	0	17 (37)	1 (2)
Dyspnea	7 (22)	0	13 (28)	1 (2)
Pruritus	4 (13)	0	9 (20)	0
Pivotal Registrational Cohort of Phase 2 Trial (n = 153)			Source: de Botton, et al., 2023 [43]
	All treatment-emergent adverse events (TEAE)
Adverse event (AE)	All grades, n (%)		Grade 3 or 4, n (%)
Patients with any AE	153 (100)		129 (84)
Nausea	58 (38)		0 (0)
Anemia	40 (26)		31 (20)
Constipation	40 (26)		0 (0)
Leukocytosis	38 (25)		14 (9)
Pyrexia	36 (24)		1 (1)
Fatigue	35 (23)		2 (1)
Febrile neutropenia	33 (22)		31 (20)
Dyspnea	31 (20)		5 (3)
Diarrhea	31 (20)		2 (1)
Thrombocytopenia	31 (20)		25 (16)
Hypokalemia	30 (20)		9 (6)
Neutropenia	20 (13)		20 (13)
Decreased appetite	25 (16)		3 (2)
Differentiation syndrome	22 (14)		13 (8)
Patients with at least 1 hepatic TEAE^a	38 (25)		23 (15)

Events occurring in 20% or more patients in any group. Adverse events were coded using the Medical Dictionary for Drug Regulatory Affairs, version 19.1. *Dose of azacitidine 75 mg/m². TEAE, treatment emergent adverse event. ^aThe most frequent grade 3 or 4 hepatic events were increases in laboratory liver function parameters.

Adapted from Watts JM, Baer MR, Yang J, et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol 10:e46–e58, 2023, with permission from Elsevier. Copyright 2022 Elsevier.

Adapted from de Botton S, Fenaux P, Yee KWL, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv 7:3117–3127, 2023, with permission from The American Society of Hematology. Copyright 2023 The American Society of Hematology.

In the monotherapy cohort, AEs of special interest, which are considered IDH inhibitor-class effects, included DS, liver function test abnormalities, and QT prolongation. DS was reported in 13% of patients in both the monotherapy (4/32 patients) and combination therapy groups (6/46 patients). DS was most often reported in cycle 1 (seven of the 10 instances of DS), and all cases resolved with treatment interruption or dose reduction, dexamethasone, and/or supportive treatment, without recurrences. A leukemia response was achieved in 50% (2/4) of the monotherapy patients and 83% (5/6) of the combination therapy patients who developed DS.

Grade 3 or higher abnormal liver function tests were reported in 16% (5/32 patients) in the monotherapy group and 11% (5/46 patients) in the combination group. Two patients discontinued olutasidenib (1 in the monotherapy group, 1 in the combination group) due to grade 3 abnormal liver function tests, which then resolved. All other cases resolved with temporary interruptions or dose adjustments. QTc prolongation was not reported in any patients in the monotherapy group, and occurred transiently in 7% (3/46 patients, grades 2–3) in the combination therapy group; treatment resumed after interruption (n = 1), or continued without any therapy modification (n = 2), without recurrences.

Signs of clinical activity were demonstrated in the R/R AML monotherapy group with an ORR (defined as CR, CRh, CRi, MLFS, or PR) of 41% (9/22 patients), and an ORR of 46% (12/26 patients) in the combination group (Table 3) [42]. CR + CRh rates were 32% and 15%, respectively. Of the treatment naïve patients with AML, 25% (1/4) of patients receiving monotherapy and 77% (10/13; CR 54%) of patients receiving combination therapy had an overall response. Of the 59 patients with AML who were transfusion-dependent at baseline, 36% (21) achieved 56-day transfusion independence. Olutasidenib 150 mg twice daily was chosen as the recommended phase 2 dose based on the acceptable safety profile, PK/PD data demonstrating consistent exposure at twice daily dosing and activity at all investigated doses, and early signs of clinical activity. It is noteworthy that during the dose escalation part of the study, 15 patients received an assigned olutasidenib monotherapy dose that was lower than the US FDA approved dose of 150 mg twice daily and 7 patients receiving the combination of olutasidenib and azacitidine received less than 150 mg twice daily of olutasidenib along with a standard dose of azacitidine.

Table 3. Summary of efficacy outcomes from phase 1 trial in R/R or treatment-naïve patients with AML and MDS [42].

AML			Source: Watts, et al., 2023 [42]
	Olutasidenib monotherapy		Olutasidenib + azacitidine combination therapy^b
Responses^a	Relapsed or Refractory (n = 22)	Treatment-naïve (n = 4)	Relapsed or Refractory (n = 26)	Treatment-naïve (n = 13)
Best response, n (%)
CR	4 (18)^d	0	3 (12)^d	7 (54)
CRh	3 (14)	0	1 (4)	0
CRi	2 (9)	1 (25)	6 (23)	3 (23)
MLFS	0	0	2 (8)	0
SD	2 (9)	2 (50)	9 (35)	2 (15)
Rates of response, n (%; 95% CI)^c
ORR	9 (41; 21–64)	1 (25; 1–81)	12 (46; 27–67)	10 (77; 46–95)
MDS			Source: Watts, et al., 2023 [42]
Responses	Olutasidenib (n = 6)		Olutasidenib + azacitidine (n = 7)
Best response, n (%)
CR	1 (17)		4 (57)
Marrow CR	1 (17)		2 (29)
SD and clinical benefit	2 (33)		1 (14)
Rates of response, n (%, 95% CI)
ORR (CR, marrow CR, PR)	2 (33; 4–78)		6 (86; 42–100)
CR	1 (17; <1–64)		4 (57; 18–90)

^aInvestigators assessed clinical responses using the modified International Working Group criteria for AML; ^b Standard dose of Azacitidine (75 mg/m²); ^c95% CI estimates calculated using Brookmeyer Crowley method; ^dTwo R/R patients had CR with molecular clearance (1 monotherapy and 1 combination therapy) by standard next-generation sequencing with a detection limit of 5%.

AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; CRh, complete remission with partial hematological recovery; CRi, complete remission with incomplete blood count recovery; MDS, myelodysplastic syndrome; MLFS, morphological leukemia-free state; ORR, overall response rate (CR, CRh, CRi, MLFS, or PR); PR, partial remission; R/R, relapsed/refractory; SD, stable disease.

Adapted from Watts JM, Baer MR, Yang J, et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol 10:e46-e58, 2023, with permission from Elsevier. Copyright 2022 Elsevier.

3.2. Phase 2 evaluation of olutasidenib

The phase 2 portion of the phase 1/2 trial is ongoing and includes multiple cohorts of patients with AML and MDS [43]. In the preplanned interim analysis of the pivotal registrational cohort (data cutoff: 18 June 2021), 153 adults with R/R mIDH1 AML were treated with 150 mg of olutasidenib, as monotherapy, twice daily, in continuous 28-day cycles until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. Enrolled patients had failed prior standard treatment and had a baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2, with adequate liver, renal, and cardiac function; patients with symptomatic central nervous system leukemia, uncontrolled infections or metabolic disorders, and/or prior IDH inhibitor therapy were excluded. The primary efficacy endpoint was CR plus CRh (per investigator assessment) using modified response criteria of the International Working Group in AML.

A group sequential design was used with a planned futility interim analysis when about 33% (n = 58) evaluable patients were enrolled and an efficacy interim analysis when about 67% (n = 115) of patients completed the first response assessment.

Of the 153 enrolled patients in the pivotal cohort, 147 were efficacy evaluable (i.e. had central laboratory confirmation of mIDH1 and had received olutasidenib for at least six months prior to data cutoff), with most patients (65%; n = 96) having relapsed disease and 35% (n = 51) with primary refractory disease (Table 4). The median number of prior treatment regimens was 2; 97% (n = 143) of patients had received prior induction chemotherapy, 39% (n = 58) prior HMA-based therapy, 12% (n = 17) prior allogeneic hematopoietic stem cell transplant (HSCT), and 8% (n = 12) had received prior therapy with venetoclax.

Table 4. Summary of baseline characteristics and efficacy outcomes in the phase 2 registrational pivotal cohort [43].

Baseline Characteristics	Source: de Botton, et al., 2023 [43]
Parameter	Efficacy-evaluable population (n = 147)
Men, n (%)	74 (50)
Median age (range)	71.0 years (32–87)
ECOG PS, n (%)
0	45 (31)
1	76 (52)
2	23 (16)
AML: Primary/Secondary, n (%)	97 (66)/50 (34)
Cytogenetics, n (%) (NCCN/ELN) Favorable Intermediate Poor Unknown	6 (4) 107 (73) 25 (17) 9 (6)
Refractory/Relapsed, n (%)	51 (35)/96 (65)
Median no. of prior treatments	2.0 (range 1–7)
Prior Induction Therapy, n (%)	143 (97)
Prior HSCT, n (%)	17 (12)
Summary of Efficacy Outcomes
CR^a or CRh
n (%) [95% CI]	51 (35) [27–43]
Median time to CR/CRh, mo (range)	1.9 (0.9–5.6)
CR^a
n (%) [95% CI]	47 (32) [24.5–40.2]
Median time to CR/CRh, mo (range)	2.8 (0.9–7.4)
Overall response
n (%) [95% CI]	71 (48) [40–56.7]
Median time to CR/CRh, mo (range)	1.9 (0.9–10.2)
Best overall response, n (%)
CR^a	47 (32)
CRh	4 (3)
CRi	15 (10)
PR	3 (2)
MLFS	2 (1)
SD^b	42 (29)
PD	10 (7)
Not evaluable/not done	6 (4)/18 (12)

^aIncludes patients with CR, complete cytogenetic remission, and complete molecular remission.

^bIncludes 3 patients considered to have clinical benefit by the treating physician and 2 patients considered to have resistant by stable disease.

CR, complete remission; CRh, complete remission with partial hematological recovery; CRi, CR with incomplete blood count recovery; PD, progressive disease; MLFS, morphologic leukemia-free state; PR, partial remission; SD, stable disease (failure to achieve at least a PR but not meeting criteria for progressive disease. SD for a period of ≥8 weeks indicates clinical benefit).

Adapted from de Botton S, Fenaux P, Yee KWL, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv 7:3117–27, 2023, with permission from The American Society of Hematology. Copyright 2023 The American Society of Hematology.

The primary endpoint, CR + CRh, was 35% (95% CI, 27–43) for the efficacy evaluable patients (Table 4). The median time to response was 1.9 months (range, 0.9–5.6 months), and the median duration of CR/CRh was 25.9 months (95% CI, 13.5-not evaluable [NE]). The ORR was 48% (n = 71; 95% CI, 40–56.7) with a median DOR of 11.7 months (95% CI, 6.9–25.9). The composite CR (CRc [CR+CRh+CRi]) was 45%. Of the 12 patients with previous venetoclax treatment, the ORR was 50% (n = 6; 95% CI, 21.1–78.9) with a CR+CRh rate of 33% (n = 4; 95% CI, 9.9–65.1) and a CR rate of 25% (n = 4; 95% CI, 9.9–65.1), and 2 patients with CRi and 2 with stable disease (SD).

The median OS was 11.6 months (95% CI, 8.9–15.5) for the overall study population, but was not reached for those who achieved CR/CRh (95% CI, 22.8-NE). Responders who did not achieve CR/CRh had a median OS of 13.7 months (95% CI, 6-NE), while non-responders had a median survival of only 4 months (95% CI, 3.2–5.8). Transfusion independence (TI) was achieved for ≥56 days across patients in all response groups (34%; 29/86) who were red blood cell and/or platelet transfusion dependent at baseline. RBC and platelet TI was acheived in 88% and 100% of responders with a CR/CRh. Responders who did not achieve CR/CRh also demonstrated RBC (53%) and platelet (58%) TI.

Of the 153 safety-evaluable patients, the most common grade 3 or 4 TEAEs included febrile neutropenia and anemia (20%; n = 31 patients each), thrombocytopenia (16%; n = 25), and neutropenia (13%; n = 20) (Table 2). DS, an adverse event (AE) of special interest, occurred in 14% (n = 22) of patients, with 9% (n = 14) grade ≥ 3, and 1 fatality reported. DS most often occurred within the first 2 cycles of treatment, with a median time to first event of 17.5 days (range, 1–561 days); IV or oral dexamethasone was used to treat most patients with DS. Hepatic AEs occurred in 25% (n = 38) of patients, with 12% (n = 19) reported as grade 3 and 3% (n = 4) grade 4 events, which were mostly reversible laboratory liver test abnormalities, with no reports of liver failure. Hepatic AEs often occurred within the first two months of treatment and resolved within 2 to 4 weeks, with or without dose alterations. QT prolongation was reported in 8% (n = 12) of patients, which were all transient in nature. All cases of QT prolongation were grade 1 or 2 events, except for one report of a grade 3 event; none of the cases required dose reduction or discontinuation.

4. Conclusion

Olutasidenib is a very welcome new treatment option for patients with R/R mIDH1 AML, a patient population with a poor prognosis and limited treatment modalities. In the pivotal cohort of the phase 2 study, olutasidenib produced encouraging efficacy results with durable CR/CRh and transfusion independence achieved in all response groups. Clinical benefit was also observed in responders who did not achieve CR/CRh, as demonstrated by DOR and OS. Olutasidenib was well tolerated with a manageable side effect profile; patients should be monitored for signs and symptoms of DS and liver abnormalities. A phase 2 clinical trial is currently ongoing to evaluate olutasidenib monotherapy in frontline and R/R settings and as combination therapy with azacitidine (NCT02719574).

5. Expert opinion

Olutasidenib was US FDA-approved for adult patients with R/R AML with an IDH1 mutation based on the safety and efficacy results of the pivotal cohort of the registrational phase 2 trial. Currently, the only other US FDA approved single agent for patients with R/R mIDH1 AML is ivosidenib (Table 5). While superiority claims cannot be made for either ivosidenib or olutasidenib without the availability of data from head-to-head studies, there are differences between olutasidenib and ivosidenib. For example, in patients with R/R AML treated with monotherapy, the median duration of CR/CRh with olutasidenib and ivosidenib was 25.9 months and 8.2 months, respectively [32,43]. The 18 month-survival in CR/CRh responders was 78% with olutasidenib and 50% with ivosidenib [32,43]. The median OS in all patients with olutasidenib and ivosidenib was 11.6 months and 8.8 months, respectively [32,43]. The rate of CR/CRh for olutasidenib and ivosidenib was 35% and 30%, respectively, the CR rate was 32% and 22%, and the rate of composite CR was 45% and 34% [32,43]. A post-hoc analysis of 9 patients previously treated with ivosidenib showed a complete remission to olutasidenib combined with azacitidine in 2 (22%) during the phase 1/2 study [44]. It is not surprising that some of the clinical results differ between the two molecules as they are structurally quite different, with unique binding kinetics and pharmacodynamic properties.

Table 5. Summary of baseline demographics and efficacy outcomes for patients with R/R mIDH1 AML treated with olutasidenib and ivosidenib in Registrational Trials [32,43].

Efficacy evaluable population	Olutasidenib (efficacy population n = 147)	Source: de Botton, et al., 2023 [43]	Ivosidenib (efficacy population n = 125)	Source: DiNardo, et al., 2018 [32]
Study design	Multicenter, open-label, phase 2 study; (R/R) monotherapy		Multicenter, open-label, phase 1 study; (R/R) monotherapy
Age, median (range)	71 (32–87)		67 (18–87)
Male, n (%)	74 (50)		65 (52)
AML type, n (%)
De novo	97 (66)		83 (66)
Secondary	50 (34)		42 (34)
MDS	39 (78)		18 (14)
Therapy-related	4 (8)		14 (11)
Other	7 (14)		10 (8)
Cytogenetic risk, n (%)
Favorable	6 (4)		-
Intermediate	107 (73)		66 (53)
Poor	25 (17)		38 (30)
Missing/unknown	9 (6)		21 (17)
IDH1 mutation, n (%)
R132C	90 (61)		76 (61)
R132H	34 (23)		27 (22)
R132G/S/L	23 (16)		19 (15)
Wild-type/other	0		3 (2)
Co-mutations, n (%)
NPM1	31 (21)		24 (20)
FLT3	15 (10)		9 (8)
CEBPA	4 (3)		3 (3)
Prior regimens, median (range or IQR)	2 (1–7)		2 (1–6)
Venetoclax, n (%)	12 (8)		-
HSCT, n (%)	17 (12)		36 (29)
ECOG PS, n (%)
0	45 (31)		27 (22)
1	76 (52)		64 (51)
2	23 (16)		32 (26)
3	0		2 (1)
Bone marrow blast %, median (range)	42 (4–98)		56 (0–98)
Response Rates
Response outcomes n (%)
CR rate	47 (32)		27 (22)
CRh	4 (3)		11 (9)
CR or CRh rate	51 (35)		38 (30)
CRi^a	15 (10)		5 (4)
Composite CR (CR+CRh+CRi)	66 (45)		43 (34)
Overall response rate (CR+CRh+CRi+PR+MLFS)	71 (48)		52 (41)
Duration of responses (months)
Median time to CR/CRh	1.9		2.7
Median duration of CR/CRh	25.9		8.2
Median duration of CR	28.1		9.3
Median duration of overall response	11.7		6.5
Survival outcomes^b
18-month survival rate for patients with CR/CRh	78%		50%
Median overall survival	11.6 months^a		8.8 months

^aCRi rate was based on patients who were not already counted in the CRh rate.

^bOverall survival was based on the 153-patient safety population (which included the 147-patient efficacy evaluable population plus 6 patients with lack of centrally confirmed IDH1 mutation.

AML, acute myeloid leukemia; CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete count recovery; ECOG PS, Eastern cooperative group performance status; HSCT, hematopoietic stem cell transplantation; IQR, interquartile range; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia-free state; PR, partial response.

Adapted from de Botton S, Fenaux P, Yee KWL, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv 7:3117–3127, 2023, with permission from The American Society of Hematology. Copyright 2023 The American Society of Hematology.

Adapted from DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 378:2386–2398, 2018, with permission from the Massachusetts Medical Society. Copyright 2018 Massachusetts Medical Society.

A post-hoc analysis demonstrated appreciable response rates (50% composite CR) with olutasidenib in patients with AML previously treated with venetoclax regimens, further demonstrating the utility of this drug in the R/R setting [43]. This report is valuable as there is minimal information on patients with mIDH1 AML following failure of a venetoclax regimen. In fact, only eight patients across two case series with mIDH1 AML have been reported to be treated with an IDH1 inhibitor (ivosidenib in 7 and olutasidenib in 1) after venetoclax-based therapy [45,46]. One (14%) of seven responded to ivosidenib with a CR; the one patient treated with olutasidenib had stable disease (SD) [45,46]. These patients are becoming increasingly common due to the logistics and time involved with obtaining molecular profiling of patients with newly diagnosed AML [44]. Results from individual molecular profiling may take several days or weeks, and patients and/or physicians may not always consider the wait prudent or appropriate for an individual patient. An additional group of R/R patients who may benefit from olutasidenib include post-transplant patients; of 31 patients with a prior HSCT, 6 (19%) had a CR and 3 (10%) had a CRi to olutasidenib alone or in combination with azacitidine in the phase 1/2 study [44].

In general, olutasidenib has been well tolerated. The rates and severity of DS with olutasidenib are consistent with rates reported in the literature for IDH inhibitors. The incidence of QTc prolongation has been very low, in agreement with the PK data, suggesting plasma concentrations are well below the level required to induce this complication in animal models. Olutasidenib carries a warning for hepatotoxicity, which also requires monitoring with a potential for dose interruption and/or reduction. Most instances of olutasidenib-induced hepatotoxicity can be managed by dose adjustments, but some instances may require treatment discontinuation. These safety profile differences may be important considerations when selecting a treatment option for an individual patient. Also important is the data from the combination cohorts that has demonstrated efficacy of olutasidenib in combination with azacitidine in patients with AML who were R/R as well as in newly diagnosed patients [42]. Combination therapy might be a more appropriate approach in many instances for AML. Additional data is required to better understand its role in the treatment of this patient population. Future studies can also explore combinations of olutasidenib with other agents. The treatment landscape for AML is rapidly evolving with additional targeted therapies on the horizon, and 66 interventional studies for AML are currently enrolling patients. Final data from the ongoing phase 2 study will further elucidate the overall efficacy and safety profile of olutasidenib in combination with azacitidine and provide insight into its utility in patients with newly diagnosed and R/R AML and MDS.

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.