Clinical Activity and Safety of IDH2 Inhibitor Enasidenib (AG-221) in IDH2-Mutant Relapsed/Refractory AML CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals AML, acute myeloid leukemia. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Enasidenib in IDH2-Mutant R/R AML: Background Mutated IDH2 (mIDH2): produces oncometabolite 2-HG which can alter DNA methylation and lead to blocked myeloid differentiation[1] mIDH2 observed in 10%[2] to 13%[3] of pts with AML 2-HG can be synthesized from mutated IDH2 (mitochondrial form) or mutated IDH1 (cytoplasmic) Enasidenib (AG-221): investigational, selective, potent oral inhibitor of mutated IDH2 enzyme[4] Induced leukemic cell differentiation in preclinical models[4] and in pts with R/R AML[5] Current report assessed MTD, PK/PD, safety, clinical activity of enasidenib in IDH2-mutant R/R AML cohort in first phase of phase I/II trial[6,7] AML, acute myeloid leukemia; MTD, maximum tolerated dose; PD, pharmacodynamics; PK, pharmacokinetics; R/R, relapsed/refractory. 1. Stein EM, et al. Blood. 2016;127:71-78. 2. Green CL, et al. Blood. 2011;118:409-412. 3. DiNardo CD, et al. Am J Hematol. 2015;90:732-736. 4. Yen K, et al. Cancer Discov. 2017;7:478-493. 5. Amatangelo MD, et al. Blood. 2017;[Epub ahead of print]. 6. Stein EM, et al. ASCO 2017. Abstract 7004. 7. Stein EM, et al. Blood. 2017;[Epub ahead of print]. Slide credit: clinicaloptions.com

Enasidenib in IDH2-Mutant R/R AML: Study Design Multicenter, open-label phase I/II study Current analysis of dose-escalation and dose-expansion data from pts with IDH2-mutant R/R AML Dose Escalation Dose Expansion Phase II Pts with R/R AML, age ≥ 60 yrs or any age if relapsed after BMT (Arm 1) and age < 60 yrs with no relapse after BMT (Arm 2)* Enasidenib 50-650 mg QD in cont. 28-d cycles (n = 113) Enasidenib 100 mg QD (n = 126) Enasidenib 100 mg QD (n = 91†) Pts with IDH2-mutant advanced heme malignancies Pts with R/R AML *Also includes pts with untreated AML, age ≥ 60 yrs, who declined SoC (Arm 3) and with any heme malignancy ineligible for other arms (Arm 4). †To April 15, 2016. AML, acute myeloid leukemia; BMT, bone marrow transplantation; DLT, dose-limiting toxicity; IWG, International Working Group; MTD, maximum tolerated dose; PD, pharmacodynamics; PK, pharmacokinetics; R/R, relapsed/refractory; SoC, standard of care. Endpoints: MTD, safety, tolerability, DLTs, response in R/R AML pts (investigator assessed per IWG criteria), clinical activity MTD not reached in dose escalation Enasidenib 100 mg QD selected for expansion phase based on efficacy, PK/PD Slide credit: clinicaloptions.com Stein EM, et al. ASCO 2017. Abstract 7004. ClinicalTrials.gov. NCT01915498.

Enasidenib in IDH2-Mutant R/R AML: Baseline Characteristics Characteristic, n (%) R/R AML All Pts in Phase I (N = 239) 100 mg/day (n = 109) All Doses (n = 176) Median age, yrs (range) 67 (19-100) 70 (19-100) Female, % 58 49 43 IDH2 mutation site R140 R172 83 (76) 25 (23) 130 (74) 45 (26) 179 (75) 57 (24) ECOG PS 0-1 2 93 (85) 16 (15) 145 (82) 31 (18) 194 (81) 45 (19) Median prior tx, n (range) 1 (1-14) 2 (1-14) -- Cytogenetic risk status Intermediate Poor n = 80 51 (64) 29 (36) n = 128 85 (66) 43 (34) n = 175 117 (67) 58 (33) Outcome With Prior AML Tx,* n (%) R/R AML 100 mg/day (n = 109) All Doses (n = 176) Refractory to initial induction/reinduction tx 35 (32) 57 (32) R/R to ≥ 2 cycles with first-line lower-intensity tx† 25 (23) 43 (24) Relapsed ≤ 1 yr after initial tx 27 (25) 41 (23) Relapsed > 1 yr after initial tx 8 (7) 15 (9) Relapsed after transplant 12 (11) 24 (14) ≥ 2 relapses 13 (12) 22 (13) AML, acute myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; PS, performance status; R/R, relapsed/refractory; Tx, treatment. *A single pt could be in multiple categories. †Also includes low-dose cytarabine, hypomethylating agents. IDH2 R140 mutation associated with higher comutation burden than R172 (~ 4 vs < 3 co- occurring mutations; P = .020) Slide credit: clinicaloptions.com Stein EM, et al. ASCO 2017. Abstract 7004.

Enasidenib in IDH2-Mutant R/R AML: Most Frequent TEAEs 8% of pts experienced serious treatment-related IDH inhibitor–associated differentiation syndrome TEAE in ≥ 20% of All Pts All Pts (N = 239) Any Grade Grade 3/4 All Tx Related Nausea 46 5 2 Hyperbilirubinemia 45 18 12 Diarrhea 40 4 < 1 Fatigue 8 3 Decreased appetite 38 Vomiting 32 Dyspnea 31 1 Cough 29 Pyrexia 28 TEAE in ≥ 20% of All Pts All Pts (N = 239) Any Grade Grade 3/4 All Tx Related Febrile neutropenia 28 27 1 Thrombocytopenia 23 6 Anemia 19 5 Constipation < 1 Hypokalemia 8 Peripheral edema 2 Pneumonia 21 18 Hyperuricemia 20 3 AML, acute myeloid leukemia; R/R, relapsed/refractory; TEAE, treatment-emergent adverse event; Tx, treatment. Slide credit: clinicaloptions.com Stein EM, et al. ASCO 2017. Abstract 7004.

Enasidenib in IDH2-Mutant R/R AML: Response ORR: 100 mg/day, 38.5%; all doses, 40.3% Platelets, hemoglobin, ANC generally increased with enasidenib cycle number Bone marrow blasts decreased over time FISH and morphological evidence from individual pts suggested myeloblast differentiation with enasidenib Responders and nonresponders had similar BL 2-HG levels, BL mIDH2 VAF Post-BL transfusion independence rates (per RBC, platelet parameters): ~ 36% in overall pts, ~ 53% with non-CR responders, > 94% in pts with CR Endpoint R/R AML 100 mg/d (n = 109) All Doses (n = 176) Best response, n (%) CR CRi/CRp PR MLFS SD PD NE 22 (20.2) 7 (6.4) 3 (2.8) 10 (9.2) 58 (53.2) 5 (4.6) 2 (1.8) 34 (19.3) 12 (6.8) 11 (6.3) 14 (8.0) 85 (48.3) 9 (5.1) 3 (1.7) Median time to first response, mos (range) 1.0 (0.5-9.4) 1.9 (0.5-9.4) Median DoR, mos (95% CI) 5.6 (3.8-9.7) 5.8 (3.9-7.4) Median time to CR, mos (range) 3.7 (0.7-11.2) 3.8 (0.5-11.2) Median DoR with CR, mos (95% CI) 8.8 (5.3-NR) 8.8 (6.4-NR) AML, acute myeloid leukemia; ANC, absolute neutrophil count; BL, baseline; CRi, incomplete CR; CRp, pathologic CR; DoR, duration of response; MLFS, morphologic leukemia-free state; NE, not estimable; PD, progressive disease; RBC, red blood cell; R/R, relapsed/refractory; SD, stable disease. Slide credit: clinicaloptions.com Stein EM, et al. ASCO 2017. Abstract 7004.

Enasidenib in IDH2-Mutant R/R AML: Overall Survival OS in R/R AML Pts (n = 176) OS by Best Response in R/R AML Pts (n = 176) 1 Survival Probability 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median OS, Mos (95% CI) 19.7 (11.6-NE) 13.8 (8.3-17.0) 7.0 (5.0-8.3) CR Non-CR response No response Median OS: 9.3 mos (95% CI: 8.2-10.9) 0.9 Censored 0.8 0.7 Censored 0.6 Survival Probability 0.5 0.4 0.3 0.2 AML, acute myeloid leukemia; NE, not estimable; R/R, relapsed/refractory. 0.1 3 6 9 12 15 18 21 24 27 Pts at Risk, n Mos 3 6 9 12 15 18 21 24 27 CR Non-CR response No response 34 34 31 25 15 11 6 2 Mos Pts at Risk, n 37 34 30 17 11 7 3 1 1 176 138 105 63 37 21 10 3 1 97 68 43 20 10 3 1 Slide credit: clinicaloptions.com Stein EM, et al. ASCO 2017. Abstract 7004. Reproduced with permission.

Enasidenib in IDH2-Mutant R/R AML: Investigator Conclusions Enasidenib generally well tolerated with most AEs being low grade and unrelated to treatment Most common treatment-related grade 3/4 AEs: hyperbilirubinemia (12%), thrombocytopenia (6%), anemia (5%) MTD not reached up to 650 mg/d; 100 mg/day selected for phase II Clinical activity appears related to myeloblast differentiation rather than cytotoxicity Investigators concluded that enasidenib associated with durable CRs, median OS of 9.3 mos in heavily pretreated R/R AML population with IDH2-mutant disease 100 mg/day: CR in 22% after median of 3.7 mos Responses may require multiple enasidenib cycles and can improve with continued treatment Enasidenib currently being compared vs conventional care in phase III IDHENTIFY study (NCT02577406) AE, adverse event; AML, acute myeloid leukemia; MTD, maximum tolerated dose; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Stein EM, et al. ASCO 2017. Abstract 7004.

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