What the Future Holds in Targeting Cancer Metabolism [0:00] Panelist Eytan Stein, MD Internist Hematologist/Oncologist Leukemia Service Assistant Professor Memorial Sloan Kettering Cancer Center New York, New York Moderator Martin S. Tallman, MD Hematologist/Oncologist Chief Leukemia Service Memorial Sloan Kettering Cancer Center New York, New York

This program will include a discussion of investigational agents not approved by the FDA for use in the United States, and data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal. 00:32 FDA = US Food and Drug Administration

Introduction Targeting Cancer Metabolism The metabolic pathways under investigation represent a heterogeneous collection of targets and pathways[a] Many types of cancers have mutations in the same metabolic enzymes; new therapeutics may be applicable in a variety of malignancies IDH mutations; first described in CRC, found in glioblastomas, astrocytomas, oligodendrogliomas, and more recently, in AML[b] IDH1 mutations present in approximately 10% of adult patients with AML; IDH2 present in approximately 15%[c] IDH = isocitrate dehydrogenase; CRC = colorectal cancer a. Kim SY. Biomol Ther. 2015;23:99-109. b. Walker A, et al. Expert Rev Hematol. 2012;5:547-558. c. Medeiros BC, et al. Leukemia. 2016. doi: 10.1038/leu.2016.275. [Epub ahead of print]

IDH Mutations as a Target in AML acetyl-CoA = acetyl-coenzyme A; AKT = protein kinase B; AML = acute myeloid leukemia; FH = fumarate hydratase; IDH = isocitrate; mTORC1 = mechanistic target of rapamycin complex 1; MYC = proto-oncogene protein; P13K = phosphoinositide 3-kinase; PK-M2 = pyruvate kinase-M2 isoform; SDH = succinate dehydrogenase; succinyl-CoA = succinyl-coenzyme A; TCA = tricarboxylic (cycle)

Targeting Specific Tumor Types IDH mutations are commonly associated with: Older patients Older pts with AML have a greater likelihood of developing IDH mutations IDH mutations are almost never observed in pediatric populations Patients who are in the AML intermediate risk group with normal karyotype Other mutations When IDH2 is found in the R140Q location, patients have more co-occurring mutations vs IDH2 in the R172 location AML = acute myeloid leukemia; IDH = isocitrate dehydrogenase Walker A, et al. Expert Rev Hematol. 2012;5:547-558.

IDH Mutation as a Prognostic Indicator A recent study looked at 5234 driver mutations across 76 genes from 1540 patients with AML (from 3 trials of intensive therapy); 3 heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA splicing regulators, or both (18% of patients); poor outcomes AML with TP53 mutations, chromosomal aneuploidies, or both (13% of patients); poor outcomes Patients with co-occurring mutations in IDH2 and NPM1, without a mutation in FLT3, a FLT3-ITD, appeared to have an excellent prognosis with induction and standard consolidation chemotherapy Other co-occurring driver mutations also had a substantial effect on overall survival These predictions require validation in prospective clinical trials AML = acute myeloid leukemia; FLT3 = receptor-type tyrosine protein kinase 3; IDH = isocitrate dehydrogenase; ITD = internal tandem duplication; NPM1 = nucleophosmin 1 Papaemmaunil E, et al. N Eng J Med. 2016;374:2209-2221.

Should Patients With AML Be Tested for IDH Mutations? In AML, the driver landscape shows diverse molecular subgroups that reveal different pathways in the evolution of AML, thus informing disease classification and prognostic stratification Over the next 3 to 4 years, more and more emerging data will show the prognostic impact of these mutations Currently, there are clinical trials that combine IDH inhibitors with standard of care chemotherapy There is the potential to use mutations analysis to increase the overall survival of patients with AML AML = acute myeloid leukemia; IDH = isocitrate dehydrogenase Papaemmaunil E, et al. N Eng J Med. 2016;374:2209-2221.

Additional Mutation Testing Mutations Risk Status Normal cytogenetics: FLT3-ITD TP53 mutations Poor risk NPM1 mutations in the absence of FLT3-ITD or isolated biallelic CEBPα Favorable risk Validated assays are commercially available Risk stratification should be modified accordingly given the rapid pace of emerging research Patients with FLT3-ITD mutations should be considered for clinical trial where possible CEBPα = CCAAT/enhancer binding protein alpha; FLT3 = receptor-type tyrosine protein kinase 1; ITD = internal tandem duplication; NPM1 = nucleophosmin 1; TP53 = tumor protein 53 https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf NCCN website.

Ongoing Clinical Trials Agent Clinical Trial Information Enasidenib (AG-221)[a] Recently reported phase 1 and 2 data (N = 16) ORR was 53% (8/15), including 1 patient who achieved CR Half of evaluable MDS pts who had failed prior HMA therapy had a response NCT02577406 (IDHENTIFY) AG-120[b] Has shown evidence in patients with relapsed AML, efficacy is similar to that of the IDH2 inhibitor, with an ORR of 31% and a true CR rate of 15% NCT02632708 (newly diagnosed AML with IDH1 and/or IDH2) NCT02677922 plus sc azacitidine NCT02074839 in advanced heme malignancies with IDH1 mutation IDH305[c] Phase 1 data reported: Objective responses were reported in 7 (33%) patients with AML; CR in 2 (9.5%), CR with incomplete recovery in 1 (4.8%), and PR in 4 (19.0%) patients. Responses appear durable NCT02381886 (in advanced malignancies including rel/ref AML and MDS with IDH1R132 mutations) NCT02826642 (efficacy of IDH305 with standard care) AG-881[d] Orally administered Phase 1 trials in patients with IDH1 and IDH2 mutations NCT02492737 (advanced heme malignancies) NCT02481154 (advanced solid tumors) AML = acute myeloid leukemia; CR = complete response; HMA = hypomethylating agent; IDH = isocitrate dehydrogenase; MDS = myelodysplastic syndrome; ORR = overall response rate; PR = partial remission; Sc = subcutaneous a. Stein EM, et al. ASH 2016. Abstract 343. b. Stein EM, et al. Blood. 2016;127:71-78. c. DiNardo CD, et al. ASH 2016. Abstract 1073. d. ClinicalTrials.gov website.

Differentiation Syndrome in Patients Treated With IDH Inhibitors Neutrophil recovery within the setting of clinical differentiation syndrome has been described in the clinic in patients with AML treated with targeted mutant IDH inhibitor therapy Patients might present with nonspecific clinical manifestations such as leukocytosis related to exuberant neutrophil recovery Quick identification of this syndrome is needed Noncardiogenic pulmonary edema, sometimes fevers, pericardial effusions, pleural effusions Prompt initiation of treatment interventions including hydroxyurea, corticosteroids, and/or temporary treatment discontinuation are important to facilitate prompt resolution AML = acute myeloid leukemia; IDH = isocitrate dehydrogenase Birendra KC, et al. Clin Lymphoma Myeloma Leuk. 2016;16:460-465.

Concluding Remarks Multiple new drugs are being developed to treat AML, other hematological malignancies, and solid tumors utilizing novel formulations of traditional chemotherapy-antibody drug conjugates and agents that target specific mutant enzymes Next-generation sequencing has allowed the discovery of genetic mutations that lead to the development and clinical progression of AML Exciting data is emerging on targeted therapy against mutant driver proteins that improve the overall survival of patients AML = acute myeloid leukemia

Abbreviations acetyl-CoA = acetyl-coenzyme A AML = acute myeloid leukemia CEBPα = CCAAT/enhancer binding protein alpha CR = complete response CRC = colorectal cancer FDA = US Food and Drug Administration FH = fumarate hydratase FLT3 = receptor-type tyrosine protein kinase 3 HMA = hypomethylating agent IDH = isocitrate dehydrogenase ITD = internal tandem duplication MYC = proto-oncogene protein NPM1 = nucleophosmin 1 ORR = overall response rate P13K = phosphoinositide 3-kinase PK-M2 = pyruvate kinase-M2 isoform PR = partial remission AML = acute myeloid leukemia

Abbreviations (cont) Sc = subcutaneous SDH = succinate dehydrogenase succinyl-CoA = succinyl-coenzyme A TCA = tricarboxylic (cycle) TP53 = tumor protein 53 AML = acute myeloid leukemia