FDA Approval Summary: Olutasidenib for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation

Abstract

On December 1^st, 2022, the FDA approved the new molecular entity olutasidenib (Rezlidhia: Rigel Pharmaceuticals), a small-molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of olutasidenib was established based on complete remission (CR) + CR with partial hematological recovery (CRh) rate, duration of CR + CRh, and conversion of transfusion dependence (TD) to transfusion independence (TI) in Study 2102-HEM-101. In the pivotal trial, 147 adult patients treated with 150 mg twice daily (BID) of olutasidenib were evaluable for efficacy. With a median follow-up of 10.2 months, the CR/CRh rate was 35% (95% CI: 27–43%), with a median duration of response of 25.9 months (95% CI: 13.5 months, not reached [NR]). Of the 86 patients that were TD at baseline, 29 became TI (34%). The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.

Introduction:

Acute myeloid leukemia (AML) can occur in all ages, but it predominantly occurs in older adults with a median age of diagnosis at 68 years (1). Treatment options for patients with relapsed or refractory (R/R) AML is complex and is tailored to the patient’s age, performance status, mutational status, co-morbidities, and previous treatment, including allogeneic stem cell transplantation (2). The National Comprehensive Cancer Network (NCCN) strongly encourages clinical trial enrollment for all patients with R/R AML (3). If a clinical trial is not available, and patients are eligible for intensive therapy, salvage therapy typically consists of an anthracycline and high-dose cytarabine based backbone with CR rates of these regimens ranging from 29–66% (4). For patients who are not eligible for intensive therapy, treatment for R/R AML consists of targeted therapy or supportive care only (5). Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6–16% of patients with AML and leads to a reduction of α-ketoglutarate and over-production of the oncometabolite 2-hydroxyglutarate (2-HG), altering DNA methylation and impairing differentiation (6–8). Ivosidenib, a small molecule inhibitor of IDH1, was first FDA-approved in patients with R/R AML and a susceptible IDH1 mutation on July 20^th, 2018 (9). Approval was based on a complete remission (CR) and CR with partial hematological recovery (CRh) rate of 33%, median duration of response of 8.2 months, and a rate of conversion of transfusion dependence (TD) to transfusion independence (TI) of 37% (9). However, despite the approval of ivosidenib, there remains a clear need for alternative treatments for patients with R/R IDH1- mutated AML, particularly for patients who have cardiac co-morbidities or who are on QTc prolonging medication that may limit the use of ivosidenib.

Olutasidenib, also known as FT-2102, is another small molecule inhibitor of mutant IDH1. This article provides a summary of the FDA’s review of marketing the application of single-agent olutasidenib for the treatment of adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test.

Mechanism of Action:

The nonclinical pharmacology studies included in vitro and in vivo studies to evaluate olutasidenib’s mechanism of action. Olutasidenib inhibited mutated IDH1 and displayed little or no inhibitory activity against wild type IDH1 or mutated IDH2 proteins. The cell lines expressing mutated IDH1 proteins (R132H, R132L, R132S, R132G, and R132C) treated with olutasidenib showed suppressed 2-HG production with IC50 values ranging from 8 to 116 nM. Olutasidenib treatment in primary human AML cells suppressed 2-HG production, increased cell proliferation, and induced granulocytic/monocytic cell differentiation. Overall, the nonclinical pharmacology program demonstrated that olutasidenib inhibited the gain-of-function activity of mutated IDH1.

Clinical Pharmacology:

The recommended dosage of olutasidenib is 150 mg administered orally twice daily (BID). Dose finding was limited; only 11 patients were studied at two dose levels less than 150 mg BID. The pharmacokinetic (PK)/ pharmacodynamic (PD) analysis indicated that 2-HG plasma concentrations were reduced in patients with AML and wild-type IDH1 at all dose levels tested, and 150 mg BID olutasidenib resulted in maximal 2-HG reduction; the mean [% coefficient of variation (%CV)] reduction was 59.1% (122%) by the end of the first cycle and was sustained throughout the treatment period. The safety evaluation showed a positive trend for the probability of increasing rates for Grade 3+ principal investigator-identified differentiation syndrome and Grade ≥ 3 hepatotoxicity with increasing olutasidenib exposures. However, there was no dose-limiting toxicities observed, and preliminary efficacy in the dose escalation/expansion portion at the dose of 150mg BID demonstrated that 5/13 (38%) patients had a CR, CRh, or CR with incomplete hematological recovery (CRi). Thus, based on the maximal 2-HG reduction, relative tolerability, and preliminary efficacy results, this was considered a favorable risk: benefit assessment.

Following oral administration, olutasidenib reaches maximum plasma concentration (Cmax) in approximately 4 hours and the terminal half-life is approximately 67 hours. The Cmax and systemic exposure (the area under the plasma concentration-time curve, AUC) of olutasidenib increased less than proportionally over the dose range of 100 to 300 mg. Olutasidenib accumulation ratios ranging from 7.7 and 9.5 were observed following the approved recommended dosage. Steady-state plasma levels were reached within 14 days. The food effect study reported that the mean (CV%) of olutasidenib Cmax increased by 191% (20.6%) and AUC_inf increased by 83% (18.3%) following administration of a single 150 mg dose of olutasidenib with a high-fat meal (approximately 800 to 1,000 calories, with approximately 50% of total caloric content of the meal from fat) in healthy subjects. As such, olutasidenib is recommended to be taken on an empty stomach at least 1 hour before or 2 hours after a meal.

No clinically significant differences in the PK of olutasidenib were observed based on age (28 to 90 years), sex, body weight (36 to 145 kg), mild to moderate renal impairment (creatinine clearance [CLcr] 30 to < 90mL/min as estimated by Cockcroft-Gault), or mild (total bilirubin > 1 to 1.5 times upper limit of normal [ULN] or any aspartate aminotransferase [AST]) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. The effects of severe renal impairment (CLcr 15 to 29 mL/min, as estimated by Cockcroft-Gault), kidney failure (CLcr <15 mL/min), patients on dialysis, and patients with severe hepatic impairment (total bilirubin > 3 × ULN with any AST) on olutasidenib pharmacokinetics are unknown or not fully characterized.

Olutasidenib is primarily (90%) metabolized by cytochrome P450 (CYP)3A4, with minor contributions from CYP2C8, CYP2C9, CYP1A2, and CYP2C19. Olutasidenib Cmax decreased by 43% and AUC by 80% when used concomitantly with multiple doses of rifampin, a strong CYP3A inducer, which may reduce olutasidenib efficacy. Concomitant use of olutasidenib with strong or moderate CYP3A inducers should be avoided. No clinically significant differences in olutasidenib PK were observed when used concomitantly with multiple doses of itraconazole, a strong CYP3A and P-glycoprotein (P-gp) inhibitor. Based on mechanistic static drug-drug interaction (DDI) risk assessments with in vitro data, olutasidenib may induce CYP3A4, CYP2B6, CYP1A2, CYP2C8 and CYP2C9 and inhibit OATP1B1 at the recommended dosage, which may impact exposure of such substrates when co-administered with olutasidenib. In addition, the potential of olutasidenib to induce CYP2C19 cannot be ruled out based on the hepatocyte induction study. In the current USPI, it was recommended that concomitant use of olutasidenib with sensitive CYP3A substrates should be avoided unless otherwise instructed in the substrates prescribing information. Additionally, one postmarketing requirement and two postmarketing commitments were issued to assess the DDI potential of olutasidenib with moderate CYP3A4 inducers, substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and substrates of OATP1B1.

The largest mean increase in QTc interval was 6.2 msec (upper 90% confidence interval = 9.7 msec) in 33 patients with advanced hematologic malignancies with an IDH1 mutation following both single dose and multiple doses of the recommended olutasidenib dosage under fasted condition. This increase in the QTc interval was concentration dependent. Increased QT prolongation is expected with elevated exposures of olutasidenib under a fed condition (e.g., up to approximately 30 msec) compared to that under fasting conditions.

Assessment of Efficacy

Clinical Trial Overview:

Study 2102-HEM-101 is an open-label, nonrandomized, multicenter, multi-arm, dose-escalation and expansion, safety, PK/PD, and clinical activity evaluation of olutasidenib as a single agent or in combination with azacitidine or cytarabine in adult patients with R/R AML or myelodysplastic syndrome (MDS) harboring an IDH1 R132 mutation. Phase 1 included a dose-escalation and dose-expansion portion, which aimed to determine the recommended Phase 2 dose (RP2D) and safety profile of olutasidenib. The Phase 2 portion further evaluated the safety and efficacy of olutasidenib at the RP2D alone or in combination with azacitidine. The primary efficacy endpoint was CR + CRh as determined by the investigator. The number of patients planned for the pivotal analysis was based on a group sequential design with one futility and one efficacy interim analysis at the time of 33% and 67% of patients completing the first response assessments, respectively. If the study did not stop early for efficacy or futility, a total of 173 evaluable patients was needed to provide 90% power on a 1 sided 2.5% significance level to a identify a 25% CR + CRh rate while excluding a 15% CR + CRh rate. Approximately 190 patients were planned to be enrolled to account for the possibility of discordance between local and central testing of the IDH1 mutation.

Treatment Plan:

Olutasidenib was administered at a dose of 150mg BID in continuous 28-day cycles until disease progression/relapse, unacceptable toxicity, or hematopoietic stem cell transplantation (HSCT) in the Phase 2 portion. Dose adjustments were allowed in the case of adverse events (AEs), including differentiation syndrome and hepatotoxicity. Supportive care measures in the event of differentiation syndrome included temporary cessation of olutasidenib, administration of steroids and/or diuretics, and administration of hydroxyurea for management of leukocytosis.

Disposition and Demographics:

Study 2102-HEM-101 accrued and treated 332 patients, including 153 patients with R/R AML treated at the recommended dose of 150mg BID in the pivotal cohort. No patients enrolled in the pivotal cohort had prior exposure to an alternative IDH1 inhibitor. This was an international study with patients from 57 study centers in 9 different countries. At the time of the first interim analysis for efficacy (June 18^th, 2020), 123 patients with R/R AML had been treated at the recommended dose of olutasidenib for at least six months or discontinued treatment earlier. A subsequent efficacy update was submitted which increased the efficacy population to 153 patients. Six patients were excluded for efficacy due to not having received their first dose of olutasidenib at least six months prior to the analysis cutoff date (June 18^th, 2021). The demographics of the 147 patients in the efficacy population are listed in Table 1. Sixteen patients (11%) were able to proceed to allogeneic stem cell transplantation after treatment with olutasidenib.

Table 1:

Demographics of Patients in the Pivotal cohort of Study 2102-HEM-101

Disease Characteristics	Olutasidenib 150mg BID (N=147)
Median Age (range)	71 (32–87)
Age Categories (years)
<65	37 (25)
65–74	65 (44)
>75	45 (31)
Sex at Birth
Female	73 (50)
Male	74 (50)
Race, n (%)
White	67 (46)
Asian	5 (3)
Black	5 (3)
Other/Not Reported	70 (48)
Baseline ECOG
0	45 (31)
1	76 (52)
2	23 (16)
Type of AML
Primary	97 (66)
Secondary	50 (34)
Relapsed/Refractory Category
Primary Refractory	46 (31)
Refractory Relapse	20 (14)
Untreated Relapse	81 (55)
Cytogenetics
Favorable	6 (4)
Intermediate	107 (73)
Poor	25 (17)
Unknown	9 (6)
IDH1 Mutation Type
R132C	85 (58)
R132H	35 (24)
R132G	12 (8)
R132S	11 (7)
R132L	4 (3)
Prior Stem Cell Transplant	17 (12)
Transfusion Dependent at Baseline	86 (59)
Median Number of Prior Therapies (Min, Max)	2 (1,7)

Source: FDA Data

Efficacy Results:

The primary efficacy endpoint was investigator-assessed CR + CRh. At the time of the interim analysis for efficacy, CR + CRh was achieved by 41 out of 123 efficacy evaluable subjects (33%; 95% CI 25.1%−42.4%). Thus, the pre-specified efficacy criterion of the lower bound of the 95% CI being greater than 15% was met. Results of the efficacy update in all 147 patients in the efficacy population revealed a CR+ CRh rate of 35% (95% CI 27%−43%) (Table 2). Efficacy was generally consistent amongst the different baseline demographic and disease characteristics. However, patients with the R132H mutation, previous allogeneic stem cell transplantation (HSCT), or favorable cytogenetics stood out as having a notably lower CR+CRh rate (Supplementary Table S1). Firm conclusions on the efficacy of patients with favorable cytogenetics are limited due to the extremely small sample size (N=6).The lower response rates in patients with the R132H mutation and previous HSCT are consistent with what was seen with ivosidenib (9, 10). The lower response rates seen in patients with R132H mutation warranted a footnote in Section 14 of the United States Prescribing Information (USPI) for olutasidenib.

Table 2:

Efficacy Results in Patients with IDH1-Mutated R/R AML on Study 2102-HEM-101

Endpoint	Olutasidenib (150mg BID), N=147
CR + CRh, n (%)	51 (35)
95% CI	(27,43)
Median DOCR + CRh (months)	25.9
95% CI	(13.5, NR)
CR, n (%)	47 (32)
95% CI	(25,40)
Median DOCR (months)	28.1
95% CI	(13.8, NR)
CRh, n (%)	4 (2.7)
95% CI	(4.5,13.1)
Median DOCRh (months)	3.6
95% CI	(1,5.5)
Conversion from TD to TI, n (%)	29/86 (34%)
Maintenance of TI, n (%)	39/61 (64%)

Source: FDA Data

Key secondary endpoints included duration of response (DOR) and time to response (TTR). For patients with a CR +CRh response, the median duration of response was 25.9 months (Table 2). The TTR for patients with CR + CRh was 1.9 months. Thus, it was concluded the responses were reasonably quick and durable.

Assessment of Safety

Nonclinical Toxicology:

Nonclinical safety assessments included general, reproductive, and genetic toxicology studies. General toxicological assessment of olutasidenib was conducted in rats and cynomolgus monkeys for the duration of 13-weeks with a 4-week recovery period. The toxicology studies in both species identified altered glucose and lipid metabolism, inflammation, and the GI tract, liver, kidney, and cardiovascular system as the main organs of toxicity. Distribution studies showed binding of olutasidenib to melanin-containing tissues and a follow up phototoxicity study in rats showed erythema in the skin of animals after 48 hours of exposure to UV light. In embryo-fetal development studies, olutasidenib resulted in embryo-fetal death and altered fetal growth when administered to pregnant rats and rabbits. Olutasidenib was not genotoxic.

Safety Events in the Intended Population:

Safety was assessed in 153 patients with R/R AML treated with at least one dose of olutasidenib at 150mg BID in the pivotal cohort. All patients experienced at least one treatment-emergent adverse event (TEAE) and 129 (84%) patients experienced a Grade 3 or 4 TEAE. The most common (≥20%) adverse reactions (ARs) that occurred on or within 28 days of treatment of olutasidenib are listed in Table 3. The most common Grade 3 or higher adverse reactions (ARs) were transaminitis (12%), leukocytosis (9%), differentiation syndrome (8%), dyspnea (5%), and hypertension (5%).

Table 3:

Treatment-Emergent Adverse Reactions in Safety Population

Preferred Term	Any Grade	Grade ≥3
Nausea	57 (38)	0
Fatigue/Malaise	55 (36)	2 (1)
Arthralgia*	43 (28)	4 (3)
Constipation	39 (26)	0
Leukocytosis	38 (25)	14 (9)
Dyspnea*	37 (24)	4 (3)
Rash*	36 (24)	2 (1)
Pyrexia	36 (24)	1 (1)
Mucositis	35 (23)	5 (3)
Diarrhea	31 (20)	2 (1)
Transaminitis*	31 (20)	18 (12)
Abdominal Pain	28 (18)	1 (1)
Edema*	27 (18)	4 (3)
Cough*	26 (17)	1 (1)
Differentiation Syndrome	25 (16)	13 (8)
Vomiting	25 (16)	1 (1)
Headache	19 (13)	0
Hypertension*	16 (10)	7 (5)

Source: FDA Data

^*Includes Grouped Terms. See Supplementary Table S1 for more information.

Differentiation syndrome (DS), a potentially fatal clinical syndrome characterized by shortness of breath, fever, weight gain, hypotension, acute kidney injury, and pulmonary infiltrates or pleuropericardial effusion is a known complication of IDH inhibitors (11, 12). DS occurred in 16% (25 patients) of patients in the safety population, with 8% being Grade 3 or higher. Of the 25 patients that experienced DS, the median time to onset was 14 days (range: 1–561 days) and 11 patients (44%) had olutasidenib held due to the AR. Nineteen (76%) recovered after treatment or dosage interruption of olutasidenib. Two patients died of DS or complications from DS on day 4 and day 33, respectively, of treatment with olutasidenib. Both patients that died from DS had treatment with olutasidenib interrupted. One patient was treated with steroids, hydroxyurea, and other supportive care measures, while no information was available for the treatment of the second patient.

Hepatobiliary toxicity was another serious toxicity associated with olutasidenib. Hepatotoxicity primarily consisted of transaminitis, which was a grouped term that consisted of several AE terms with similar clinical meaning (Supplementary Table S2). The biliary events included the AE terms of blood bilirubin increase, biliary colic, biliary tract disorder, cholangitis, and cholestasis. The FDA determined that 35 patients (23%) had a hepatotoxicity TEAE, with 20 patients (13%) having a Grade 3 or 4 TEAE. The median time to onset of transaminitis for patients in the pivotal cohort was 1.2 months (range: 2 days to 17.5 months) after the first dose of olutasidenib. The median time to resolution was 12 days (range: 1 day to 17 months). There were no confirmed Hy’s Law cases (defined as 1. alanine aminotransferase [ALT] or AST levels ≥3 times ULN, 2. total bilirubin ≥2 times ULN without elevated serum alkaline phosphatase and 3. no other reason found to explain the findings). Most of the hepatobiliary ARs were reversible with dose interruption, however 9 (6%) and 7 (5%) patients had olutasidenib therapy reduced or discontinued, respectively, due to a hepatobiliary AR.

QTc prolongation is a serious toxicity that has been associated with other small molecule targeted inhibitors (13–15). Twelve (8%) patients in the pivotal trial had any grade TEAE of QTc prolongation, with only 1 (1%) being Grade 3 or higher. Two (1%) patients had their dose of olutasidenib held due to QTc prolongation, and no patients had their dose reduced or discontinued due to QTc prolongation.

Overall, olutasidenib treatment was interrupted in 49 patients (32%) and 12 patients (8%) discontinued therapy with olutasidenib due to an AR. The most frequent ARs that led to treatment interruption were transaminitis (10%) and DS (7%). The most frequent ARs that led to treatment discontinuation were transaminitis (3%), DS (3%), and gallbladder disorders (1%).

There were 101 (66%) total deaths, with 45 deaths (29%) occurring on treatment (defined as on or within 28 days of the last olutasidenib dose). Thirty-seven (82%) on treatment deaths were due to underlying AML or complications from AML. There were 2 deaths (4%) that were due to complications from DS and were felt to have resulted from a direct toxicity of olutasidenib. Overall, the 30-day mortality with olutasidenib was 8% (13 patients).

Regulatory Insights:

The efficacy of single-agent olutasidenib in study 2102-HEM-101 demonstrated substantial evidence of efficacy and an acceptable safety profile to support traditional approval of olutasidenib in adult patients with R/R AML with a susceptible IDH1 mutation as detected by an FDA-approved test. The statistical analysis plan of Study 2102-HEM-101 set CR + CRh as the primary endpoint and conversion to and maintenance of TI as a secondary endpoint. The FDA has previously accepted CR + CRh as a clinical benefit for patients with R/R AML as it represents a direct palliative clinical benefit as temporary control of AML (9, 16, 17). CR + CRh was achieved in 51 patients (35%), with most of the responses being a CR (47 patients). Additionally, the median duration of CR + CRh of 25.9 months suggests that responses were durable.

The data on achievement and maintenance of TI for a period of at least 56 days postbaseline added support for the meaningfulness of CR + CRh as a palliative benefit for patients. Nearly all patients that achieved a CR + CRh and were TD at baseline converted to TI (16/18 patients; 89%). Likewise, nearly all patients that had a CR + CRh maintained their TI (32/34; 94%). In total, approximately one-third of patients who were TD at baseline became TI (29/86, 34%) and over 60% of patients that were TI at baseline maintained their TI (39/61, 64%).

Safety was assessed in all 153 patients that were enrolled and treated in the pivotal cohort in study 2102-HEM-101. Olutasidenib is a small-molecule inhibitor that induces cellular differentiation and, as such, DS was an expected complication of olutasidenib. Given the fatal and serious adverse reactions of DS, as well as the prompt need for diagnosis and treatment, this has resulted in a boxed warning in the USPI. Hepatoxicity is another potentially life-threatening complication of olutasidenib identified by the FDA that resulted in Warnings and Precautions in the USPI. Other than these notable toxicities, tolerability was generally favorable, with dose reductions due to adverse reactions in 11% and permanent discontinuations due to adverse reactions in 8%. There is a post-marketing requirement for long-term safety follow-up from the ongoing Study 2102-HEM-101.

Of note, olutasidenib is the second IDH1 inhibitor to be approved for the treatment of patients with R/R IDH1-mutated AML; ivosidenib was approved for this indication in 2018 (9). The overall efficacy results appeared similar, although no firm conclusions can be made on cross trial comparisons. Duration of response should not be compared across studies due to differences in both measured and unmeasured confounders, as well as differences in median duration of follow-up. There also appeared to be a similar safety profile between ivosidenib and olutasidenib, with some notable differences. The rates of all grades DS (16% vs. 19%) and grade 3 (8% vs 13%) or higher DS were similar between olutasidenib and ivosidenib, respectively (9). However, the rate of all grade QTc prolongation was lower with olutasidenib (8%) than ivosidenib (26%) in patients with R/R AML, but the rates of AST/ALT elevation were higher with olutasidenib (47%/46%) than ivosidenib (27%/15%). Clinicians will have to carefully assess a patient’s comorbidities and concomitant medications when deciding whether to prescribe olutasidenib or ivosidenib for patients with R/R AML and an IDH1 mutation.

It should be noted that ivosidenib is also FDA-approved for patients with newly-diagnosed AML and a susceptible IDH1 mutation both as monotherapy and in combination with azacitidine (14). Patients that had received previous IDH1 inhibitors were excluded from study 2102-HEM-101, therefore uncertainty remains if olutasidenib would be beneficial in patients with prior exposure to IDH1 inhibitors. Future studies would be needed to evaluate mechanisms of resistance to the IDH1 inhibitors and discern biomarkers predictive of response.

Similar to ivosidenib and other nonmyelosuppressive targeted therapies in patients with R/R AML, olutasidenib was approved on the basis of a single arm trial that demonstrated durable CR + CRh, an endpoint that conveys clinical benefit and temporary control of AML (9, 17, 18). This development strategy has allowed expedited access to novel therapies, but it is important to note that randomized controlled trials (RCTs) remain the preferred approach for oncology drug approvals (19). Ultimately, gilteritinib and enasidenib are the only approved targeted inhibitors for the treatment of R/R AML that were evaluated on randomized controlled trials (RCTs); gilteritinib demonstrated a survival advantage whereas enasidenib did not (16, 20, 21). It is unclear how olutasidenib or ivosidenib compare to other agents for the treatment of patients with R/R IDH1-mutated AML (or to one another). As the therapeutic armamentarium for patients with R/R AML continues to expand, it will be important to perform RCTs to adequately evaluate comparative efficacy and safety. This will be particularly important for myelosuppressive, toxic therapies, and combination strategies.

Conclusions:

In study 2102-HEM-101, olutasidenib 150mg orally BID lead to a CR + CRh rate of 35% (95% CI: 27%−43%), with a median DOR of 25.9 months (95% CI: 13.5-NR) in adult patients with R/R IDH1-mutated AML. Likewise, a transfusion benefit was also observed with 34% of patients going from TI to TD. The median duration of treatment currently was relatively short at 4.7 months, so long-term benefits of olutasidenib are unclear at this time. However, olutasidenib provided clinically meaningful, short-term benefit in patients with R/R IDH1-mutated AML. The AEs of olutasidenib were comparable to other small molecule targeted inhibitors, with DS and hepatoxicity being the most serious AEs. Most AEs were manageable with temporary cessation and treatment of the AE. Long-term safety data, particularly with DS and hepatoxicity, will be provided with a postmarketing requirement.