Enasidenib in the treatment of relapsed/refractory acute myeloid leukemia: an evidence-based review of its place in therapy

Figures & data

Core Evidence Clinical Impact Summary

Outcome Measure	Evidence	Implications
Disease-Oriented Evidence Relapsed/Refractory IDH-2 mutated AML	Clinicaltrial	The Phase II study of enasidenib showed an overall response rate of 40.3%, including a 19.3% complete remission rate as well as 6.8% complete remission with incomplete count recovery rate. The median overall survival was 9.3 months, and 19.7 months in those with complete remission. Based on the outcome of this Phase II trial, IDH2 inhibitors provide an additional therapeutic option for patients with relapsed/refractory AML with an IDH2 mutation. The Phase III trial (IDHENTIFY) is currently ongoing.
Treatment-naïve IDH-2 mutated AML	Clinical trials ongoing	• A Phase I study examining the use of IDH inhibitors, including enasidenib, in combination with standard cytotoxic therapy is ongoing. • A Phase I study pairing IDH inhibitors, including enaside- nib, with azacitidine for adults unfit for standard induction chemotherapy is ongoing.
Patient-Oriented Evidence	No data	• The drug was generally well tolerated and the maximum tolerated dose was not reached. The most common treatment-related adverse events were hyperbilirubinemia and nausea. One important emergent adverse event was IDH-inhibitor-associated differentiation syndrome, though no patients on the study died due to this entity. • In the Phase II study, 43.1% of red cell transfusion- dependent patients and 40.2% of platelet-dependent patients attained transfusion independence.
Cost-Effectiveness	No data	• No formal analysis has yet been performed.

Figure 1 Hypermethylation phenotype in acute myeloid leukemia (AML). IDH1/2, TET2 and WT1 mutations are often mutually exclusive, but similarly lead to hypermethylation and arrest of differentiation.

Table 1 Hematologic response, time to response and response duration of patients with relapsed/refractory acute myeloid leukemia (AML) in the Phase II trial of Enasidenib

Response	Enasidenib 100 mg (n=109)			Median (range)	All doses (n=176)			Median (range)
	No.	%	95% CI		No.	%	95% CI
ORR	42	38.5	29.4-48.3		71	40.3	33.0-48.0
Best Response
Complete remission (CR)	22	20.2	13.1-28.9		34	19.3	13.8-25.9
CR with incomplete hematologic recovery/CR with incomplete platelet recovery	7	6.4			12	6.8
Partial remission	3	2.8			11	6.3
Morphologic leukemia-free state	10	9.2			14	8.0
Stable disease	58	53.2			85	48.3
Progressive disease	5	4.6			9	5.1
Not evaluable	2	1.8			3	1.7
Time to first reponse, mo				1.9(0.5-9.4)				1.9(0.5-9.4)
Duration of response, mo			3.8-9.7	5.6			3.9-7.4	5.8
Time to CR, mo				3.7(0.7-11.2)				3.8(0.5-11.2)
Duration of response in patients who attained CR, mo			5.3-notreached	8.8			6.4-notreached	8.8

Table 2 Select treatment-related TEAEs from the Phase II trial of Enasidenib

TEAE	Any grade/Enasidenib 100 mg		Any grade/All doses		Grade 3 or 4/Enasidenib 100 mg		Grade 3 or 4/Alldoses
	No.	%	No.	%	No.	%	No.	%
Hyperbilirubinemia	54	35	90	38	13	8	29	12
Nausea	32	21	56	23	2	1	5	2
Decreased appetite	28	18	42	18	3	2	6	3
Fatigue	18	12	33	14	2	1	6	3
IDH differentiation syndrome	15	10	23	10	11	7	15	6
Anemia	12	8	17	7	10	7	12	5
Leukocytosis	8	5	15	6	2	1	6	3

Table 3 Active and recently completed studies of Enasidenib

Study Name	Description	Phase	Status	ID
Acute myeloid leukemia (AML) A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG- 221 (CC-90,007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation (IDHENTIFY)	An international, multicenter, open-label, randomized trial comparing enasidenib versus conventional care in adults >60. Intervention arm will receive AG-221 plus best supportive care. Comparator arms will be treated with best supportive care, azacitidine, low-dose cytarabine or intermediate-dose cytarabine.Targets: AML in unfit adults	III	Recruiting	NCT02577406
A Phase 1, Multicenter, Open-Label, Safety Study of AG-120 or AG-221 in Combination With Induction Therapy and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation	This study combines IDH inhibitors with standard chemotherapy regimens (cytarabine, idarubicin or daunorubicin, mitoxantrone and etoposide) in a total of 6 arms.Targets: Treatment-naive AML	I	Active, not recruiting	NCT02632708
A Phase 1b/2 Open-label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy	Treatment-naïve subjects who have an IDH-1 or IDH-2 mutation ineligible for standard induction who will receive azacitidine, azacitidine + AG-120, or azacitidine +AG-221.Targets: Treatment-naive AML in unfit adults	I/II	Active, not recruiting	NCT02677922
Phase II Study of the Targeted Mutant IDH2 Inhibitor Enasidenib in Combination With Azacitidine for Relapsed/Refractory AML	Open-label trial examining enasidenib with azaci- tidine for R/R AML. One treatment arm that will receive both azacitidine and enasidenib.Targets: R/R AML	II	Not Yet Recruiting	NCT03683433
HSCT A Phase I Study of IDH2 Inhibition Using Enasidenib as Maintenance Therapy for IDH2- mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation	Open-label trial studying enasidenib as maintenance therapy in IDH-2 mutant AML or CMML undergoing allogeneic hematopoetic stem cell transplantation.Targets: AML/CMML w/IDH-2 mutation undergoing HSCT	I	Recruiting	NCT03515512
Phase IB Trial of Enasidenib (AG-221) Maintenance Post Allogeneic Hematopoietic Cell Transplantation in Patients With IDH2 Mutation	Open-label trial studying enasidenib as maintenance therapy in IDH-2 mutant AML undergoing allogeneic hematopoetic stem cell transplantation. Targets: AML w/IDH-2 mutations undergoing HSCT	I	Not Yet Recruiting	NCT03728335
Myelodysplastic Syndrome (MDS) Targeted Therapy with the IDH2-Inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome	Non-randomized, open-label trial of Enasidenib (AG-221) alone or in combination with azacitidine in MDS.Arm A: Participants who have never received a hypomethylating agent who will receive Azacitidine and Enasidenib.Arm B: Participants who have received a hypomethylating drug and have relapsed or refractory MDS who will receive Enasidenib alone.Targets: MDS w/IDH-2 mutation	II	Recruiting	NCT03383575
A Single-arm Phase II Multicenter Study of IDH2 (AG-221) Inhibitor in Patients With IDH2 Mutated Myelodysplastic Syndrome	An open-label trial examining the overall hematologic response of MDS patients treated with enasidenib.Targets: MDS w/IDH-2 mutation	II	Not Yet Recruiting	NCT03744390
Broad Molecular-based Studies European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART)	Non-randomized, open-label trial with arms A-J examining different targeted therapies, including Enasidenib (arm I).	I/II	Recruiting	NCT02813135
A Master Protocol for Biomarker-Based Treatment of AML (The Beat AML Trial)	Non-randomized, open-label trial with 8 treatments arms based on molecular markers. The study also includes a marker negative sub-study which will include all screened patients not eligible for any of the biomarker-driven sub-studies.	I/II	Recruiting	NCT03013998
Myeloma-Developing Regimens Using Genomics (MyDRUG) (Genomics Guided Multi-arm Trial of Targeted Agents Alone or in Combination With a Backbone Regimen)	Non-randomized, open label trial with 6 treatment arms based on molecular markers for relapsed refractory multiple myeloma. Patients will receive a standard myeloma regimen plus a targeted therapy like enasidenib.		Not Yet Recruiting	NCT03732703
Pharmacokinetics/Pharmacodynamics A Phase 1, Open-Label Single-Dose Study to Assess the Pharmacokinetics of Enasidenib (AG 221, CC 90,007) in Subjects With Moderate and Severe Hepatic Impairment.	Multi-center, open-label study to assess the pharmacokinetics of a single 100 mg oral dose of enasidenib in subjects with moderate and severe hepatic impairment, and in matched healthy control subjects with normal hepatic function.	I	Recruiting	NCT03290443
A Phase 1, 2-Part, Multicenter, Open-label, 3-Arm Study to Determine the Effect of Enasidenib (CC- 90,007) on the Pharmacokinetics of Single Doses of Caffeine, Dextromethorphan, Flurbiprofen, Midazolam, Omeprazole, Digoxin, Rosuvastatin and Pioglitazone in Subjects With Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation	Multi-center, open label study to assess the effect of enasidenib on pharmacokinetics of common drugs and substances in patients receiving enasi- denib for AML. Arm 1 will receive caffeine, dextromethorphan, flubiprofen, midazolam and omeprazole. Arm 2 will receive digoxin and rosuvastatin. Arm 3 will receive pioglitazone.	I	Not Yet Recruiting	NCT03720366
A Phase 1, Open-Label, Two-Part Study to Evaluate the Metabolism, Excretion and Absolute Bioavailability of AG-221 in Healthy Adult Male Subjects	An open-label study with two experimental arms examining the absorption, metabolism and excretion ofenasidenib in healthy patients. This arm will receive 100 mg enasidenib and a microtracer and be monitored through urine, fecal and blood samples. Second arm to determine bioavailability will receive oral enasidenib, followed by IV solution of enasidenib and be monitored via serial blood draws.	I	Completed	NCT02443168
A Phase 1, Single Ascending Dose, Open-label Study to Evaluate the Pharmacokinetics and Safety of AG-221 in Healthy Male Japanese Subjects Relative to Healthy Male Caucasian Subjects	An open-label study to examine pharmacokinetics and safety. There will be three cohorts with 10 healthy Japanese and 10 healthy Caucasian patients each. Cohort A will receive 100 mg of enasidenib. Cohort B will receive 50 mg of enasi- denib. Cohort C will receive 300 mg of enasidenib.	I	Completed	NCT02387866
A Phase 1, Two-Way Crossover Study to Assess the Pharmacokinetics and Safety of a Single Dose of AG-221 in Healthy Male Subjects When Administered Under Fed and Fasted Conditions	An open-label study to examine pharmacokinetics and safety of enasidenib under fed and fasted conditions in healthy patients. First arm will receive 100 mg of enasidenib after a 10 hrs fast. The second group will receive 100 mg of enasi- denib 30 mins after the start of a high-fat breakfast.	I	Completed	NCT02218346
Solid Tumors A Phase 1/2, Multicenter, Open-Label, Dose- Escalation Study of AG-221 in Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, That Harbor an IDH2 Mutation	Multi-center, open-label study to examine the safety/tolerability of enasidenib in advanced gliomas and angioimmunoblastic T-cell lymphoma with IDH-2 mutations.Targets: Advanced solid tumors	I/II	Completed	NCT02273739
Other Prospective Analysis of Frailty Phenotype Assessments to Optimize Treatment Strategies for Older Patients With Hematologic Malignancies	Non-randomized, open-label trial assessing whether frailty assessments can be used to predict outcomes of patients 60 years and older who undergo chemotherapy or allogeneic stem cell transplant. Enasidenib will be evaluated as a part of Arm A, assessing different cancer directed therapies, including targeted therapies in combination or alone.	N/A	Not Yet Recruiting	NCT03680677