1. Phase I Study: Ivosidenib or Enasidenib + Induction Chemotherapy in Newly Diagnosed AML With IDH1/IDH2 Mutations
Integrating New Hematology Findings Into Practice: Independent Conference Coverage of ASH 2017,* December 9-12, Atlanta, Georgia
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
AML, acute myeloid leukemia.
This activity is supported by educational grants from AbbVie; AstraZeneca; Celgene Corporation; Genentech; Janssen Biotech, Inc administered by Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals; Novartis Pharmaceuticals Corporation; Pharmacyclics Inc; Seattle Genetics; and Takeda Oncology.

2. mIDH Inhibition in AML: Background
Mutations in IDH1 or IDH2 observed in ~ 15% to 20% of pts with AML
mIDH results in metabolic dysregulation within cells
2-hydroxyglutarate accumulates, leading to DNA and histone hypermethylation and, ultimately, impaired cellular differentiation
Ivosidenib (AG-120) and enasidenib (AG-221): oral inhibitors of mIDH1 and mIDH2, respectively
Both have demonstrated single-agent activity in relapsed/refractory AML
Use in earlier lines of therapy of interest
Current study explored safety and efficacy of ivosidenib or enasidenib in combination with standard induction chemotherapy and consolidation
AML, acute myeloid leukemia.; mIDH, mutated IDH.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

3. mIDH Inhibition in AML: Study Design
Open-label, phase I dose-escalation and -expansion trial
Induction (1-2 cycles)
Consolidation
Maintenance
Ivosidenib 500 mg QD + ARA-C 200 mg/m2/day x 7 days + DNR 60 mg/m2/day x 3 days
Ivosidenib 500 mg QD + ARA-C up to 4 cycles
CR CRi CRp
Adults with previously untreated AML (de novo or secondary) with documented IDH1 and/or IDH2 mutations
mIDH1
Ivosidenib 500 mg QD + ARA-C 200 mg/m2/day x 7 days + IDR 12 mg/m2/day x 3 days
Single-agent ivosidenib or enasidenib QD for up to 2 yrs from induction Day 1
CR CRi CRp
Enasidenib 100 mg QD + ARA-C 200 mg/m2/day x 7 days + DNR 60 mg/m2/day x 3 days
Enasidenib 100 mg QD + ARA-C up to 4 cycles
CR CRi CRp
AML, acute myeloid leukemia; ARA-C, cytarabine; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; DNR, daunorubicin; HSCT, hematopoietic stem cell transplant; IDR, idarubicin; mIDH, mutated IDH; QD, once a day.
mIDH2
Enasidenib 100 mg QD + ARA-C 200 mg/m2/day x 7 days + IDR 12 mg/m2/day x 3 days
Pts who discontinue to go to transplant may not restart study treatment
Primary objectives: safety and tolerability of ivosidenib and enasidenib
Stein EM, et al. ASH Abstract 726.

4. mIDH Inhibition in AML: Baseline Characteristics
Ivosidenib + CT (n = 32)
Enasidenib + CT (n = 56)
Median age, yrs (range)
≥ 60 yrs, n (%)
60.5 (24-76) 17 (53)
63 (32-76) 35 (62)
Male, n (%)
18 (56)
31 (55)
de novo AML
Secondary AML, n (%)
Receipt of prior hypomethylating agent
22 (69) 10 (31) 4 (13)
32 (57) 24 (43) 15 (27)
IDH1 mutation: R132/other, n (%)
30 (94)/2 (6) NA
IDH2 mutation: R140/R172, n (%)
39 (70)/17 (30)
Risk status, n (%)
Favorable
Intermediate
Poor
Unknown
8 (25) 13 (41) 11(34) 0
4 (7) 25 (45) 20 (36) 7 (13)
Co-mutations, n (%)
FLT3-ITD
FLT3-TKD
NPM1
CEBPA
3 (9) 1 (3) 13 (41) 1 (3)
7 (13) 1 (2) 7 (13) 3 (5)
AML, acute myeloid leukemia; CT, chemotherapy; mIDH, mutated IDH; NA, not applicable.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

5. mIDH Inhibition in AML: Safety
1 DLT in enasidenib + daunorubicin/cytarabine cohort
Persistent grade 4 thrombocytopenia on Day 42 of induction; no residual leukemia
No DLTs in ivosidenib induction cohorts
No deaths related to ivosidenib or enasidenib by investigator assessment
Mortality, %
Ivosidenib + CT (n = 32)
Enasidenib + CT (n = 56)
At 30 days 6 5
At 60 days 7
AML, acute myeloid leukemia; CT, chemotherapy; DLT, dose-limiting toxicity; mIDH, mutated IDH.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

6. mIDH Inhibition in AML: Grade ≥ 3 Nonhematologic AEs
Grade ≥ 3 Nonhematologic AEs* During Induction in ≥ 3 Pts, n (%)
Ivosidenib + CT (n = 32)
Enasidenib + CT (n = 56)
> 1 grade 3 or higher TEAE
30 (94)
51 (91)
Febrile neutropenia
19 (60)
35 (63)
Blood bilirubin increased
3 (9)
5 (9)
Hypertension
Colitis
3 (5)
ALT increased
1 (2)
AST increased
Bacteremia
1 (3)
Diarrhea
4 (7)
AEs, adverse events; ALT, alanine aminotransferase; AML, acute myeloid leukemia; AST, aspartate aminotransferase; CT, chemotherapy; mIDH, mutated IDH; TEAE, treatment-emergent adverse event.
*AEs from any cause. Other grade ≥ 3 AEs in ivosidenib (all 2 cases each) included lung infection (3 in enasidenib), sepsis (2 in enasidenib), multiple organ dysfunction syndrome, acute kidney injury (1 in enasidenib), abdominal infection.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

7. mIDH Inhibition in AML: Hematologic Recovery and PK/PD
PK/PD profiles for enasidenib and ivosidenib similar across daunorubicin and idarubicin induction cohorts
By Day 14 of induction cycle 1, plasma trough concentrations for both agents reached steady-state and plasma 2-HG concentrations decreased by up to 99%
Hematologic Recovery Following Induction*
Ivosidenib + CT
Enasidenib + CT n
Days (95% CI)
Median time to ANC recovery > 500/mm3
De novo AML
Secondary AML
28.5 (27-34) 28 (26-32) 35 (23-63)
34 (29-35) 32.5 (29-42) 34 (28-35)
Median time to platelet recovery > 50,000/mm3
28 (26-34) 27 (25-32) 38 (27-NE)
33 (29-50) 29 (25-35) 50 (29-74)
*Only pts who achieved CR, CRi, CRp, or MLFS by Day 28 (± 7 days) of first cycle of induction therapy included.
2-HG, 2-hydroxyglutarate; AML, acute myeloid leukemia; ANC, absolute neutrophil count; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; CT, chemotherapy; mIDH, mutated IDH; MLFS, morphologic leukemia-free state; NE, not estimable; PD, pharmacodynamics; PK, pharmacokinetics.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

8. mIDH Inhibition in AML: Response Rate
Best Response, n (%)
Ivosidenib + CT
Enasidenib + CT
All (n = 30)
de novo (n = 21)
Secondary (n = 9)
All (n = 50)
de novo (n = 27)
Secondary (n = 23)
CR + CRi/CRp CR
CRi/CRp
23 (77) 19 (63) 4 (13)
19 (91) 15 (71) 4 (19)
4 (44) 4 (44) 0
31 (62) 25 (50) 6 (12)
18 (67) 16 (59) 2 (7)
13 (57) 9 (39) 4 (17)
MLFS
1 (3)
1 (11)
10 (20)
4 (15)
6 (26) PR
2 (7)
1 (5)
Persistent disease
5 (10)
3 (13) NE
2 (22)
4 (8)
3 (11)
1 (4)
AML, acute myeloid leukemia; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; CT, chemotherapy; mIDH, mutated IDH; MLFS, morphologic leukemia-free state; NE, not estimable.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

9. mIDH Inhibition in AML: Conclusions
Investigators conclude that ivosidenib or enasidenib safe, well tolerated when combined with standard induction therapy in pts with AML and mIDH, including pts with secondary AML with prior HMA therapy
Febrile neutropenia most common grade ≥ 3 AE
Platelet recovery delayed in some patients with secondary AML who received enasidenib; alternative dosing schedule being explored
Response data consistent with that observed with induction chemotherapy in newly diagnosed pts with AML and mIDH
CR + CRi/CRp rates 67% (enasidenib) to 91% (ivosidenib) in pts with de novo AML and 44% (ivosidenib) to 57% (enasidenib) in pts with secondary AML
Randomized phase III trial planned to assess ivosidenib or enasidenib + standard induction therapy in pts newly diagnosed with AML and mIDH
AE, adverse event; AML, acute myeloid leukemia; CRi, CR with incomplete hematologic recovery; CRp, CR with incomplete platelet recovery; HMA, hypomethylating agents; mIDH, mutated IDH.
Slide credit: clinicaloptions.com
Stein EM, et al. ASH Abstract 726.

10. Go Online for More CCO Coverage of ASH 2017!
Short slideset summaries of all the key data
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Myeloma
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