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287 Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Targeted Therapy For Adults Diagnosed With Acute Myeloid Leukemia
Hematology Disease Topics & Pathways:
AML, Biological, Diseases, Adult, Therapies, enzyme inhibitors, Study Population, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018: 8:30 AM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Eytan M. Stein, MD1, Abigail Shoben2*, Uma Borate, MD3, Maria R. Baer, MD4, Wendy Stock, MD5, Prapti A. Patel, MD6, Tibor Kovacsovics, MD7, William Blum, MD8, Jo-Anne Vergilio, MD9*, Nyla A. Heerema, PhD10, Leonard Rosenberg11*, Sonja Marcus, MPH12*, Mona Stefanos, MBChB13*, Jordan Chervin14*, Brian J. Druker, MD3, Amy Burd, PhD15, John C. Byrd, MD16, Ross L. Levine, MD17 and Alice S. Mims, MD18

1Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2The Ohio State University Comprehensive Cancer Center, Columbus, OH
3Knight Cancer Institute, Oregon Health & Science University, Portland, OR
4University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
5Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
6University of Texas Southwestern, Dallas, TX
7Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT
8Department of Hematology and Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
9Foundation Medicine Inc, Cambridge, MA
10Ohio State University, Columbus, OH
11Leukemia & Lymphoma Society, Mount Laurel, NJ
12Leukemia & Lymphoma Society, Rye Brook, NY
13Ohio State, Ohio State, Columbus, OH
14Memorial Sloan Kettering Cancer Center, New York, NY
15Leukemia and Lymphoma Society, White Plains, NY
16The Ohio State University, Columbus, OH
17Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
18Comprehensive Cancer Center, The Ohio State University, Columbus, OH

The majority of patients with acute myeloid leukemia (AML), including nearly all patients older than age 60, present with multiple, sequentially acquired, somatic mutations. The 5-year overall survival (OS) for AML patients ≥ 60 with the current standard-of-care is less than 10 percent and the median OS in most genetically defined subtypes is < 1 year. The Leukemia & Lymphoma Society (LLS) Beat AML Master Trial is a precision medicine trial for previously untreated AML pts age ≥ 60. Eligible patients are assigned to an interventional sub-study based upon an algorithm incorporating cytogenetic and mutational analysis, all within 7 days of enrollment. The primary objective of this phase 1B/II sub-study is to assess the efficacy of the oral IDH2 inhibitor enasidenib, as measured by overall response rate, in newly diagnosed AML patients, ≥ 60, with IDH2 mutant AML.

Pt eligibility included ECOG performance status of 0-2, AST/ALT < 5 x the upper limit of normal (ULN), bilirubin ≤ 2.0 x ULN, creatinine ≤ 1.5 x ULN, cardiac ejection fraction of 40%, and no prior chemotherapy for AML or MDS. Exclusion criteria included symptomatic disseminated intravascular coagulation, leukostasis requiring urgent therapy, active hepatitis, or active second malignancy. Patients were treated with enasidenib 100 mg/day in continuous 28-day cycles. Azacitidine (75 mg/m2 days 1-7) was added to enasidenib for patients not achieving a complete remission or complete remission with incomplete hematologic recovery (CR/CRi) by cycle 5, or those with earlier progression as part of a delayed phase 1b study using a standard 3 + 3 design.

At data cut off (April 30, 2018), 24 patients were consented to the trial and 23 received therapy. Of these, 18 (78%) had an IDH2 R140 and 5 (22%) had an IDH2 R172 mutation. The median age was 76 (range 62 -84) and 57% were female. Median WBC was 6.0 x 109/L (range .69-30.1), hemoglobin 8.2 g/dl (range 6.8-12.8) and platelets of 66 x 1012/L (range 6-517). 44% of patients had abnormal cytogenetics, including 17 % which were high risk according to CALGB criteria. Of the 23 patients enrolled, there were no deaths within the first 28 days of treatment. A total of 13 pts experienced one or more serious adverse events on enasidenib monotherapy, the most common being differentiation syndrome (n=4), sepsis (n=4), bleeding (n=3, 1 grade 5), elevated liver tests (n=3), and respiratory failure (n=2). Other common adverse events grade ≥3 occurring in 20% or more patients included fatigue, fever, edema, anorexia, low albumin, low electrolytes, nausea, diarrhea, constipation, insomnia and depression. For the 23 patients receiving enasidenib monotherapy, the median time on any treatment (including combination) is 138 days (min=43, max=312), and the median time on enasidenib monotherapy is 110 days (min=43, max=312). CR/CRi was achieved in 43% (7 CR/2CRi) of patients. Of the 6 pts with RAS or PTPN11 mutations, 1 responded. Reasons for discontinuing monotherapy include proceeding to allogeneic stem cell transplant after attaining CR (2), failure to respond to monotherapy (9), CR or CRi with discontinuation (2) or progression after CR/CRi (1). At the time of data cutoff, five pts have died. Five pts with inadequate response to monotherapy proceeded to the phase 1b portion of the study with enasidenib in combination with azacitidine. The combination was generally well tolerated with one DLT (nausea) and no other safety concerns. One patient attained a CRi and four pts have discontinued combined therapy without response. This trial demonstrates the significant clinical activity of enasidenib in previously untreated IDH2 mutated AML patients who do not choose to receive intensive chemotherapy. Enasidenib in this trial was associated with a low early death rate and an acceptable toxicity profile. These results justify further exploration of single agent enasidenib in newly diagnosed AML and of novel combination strategies building upon the efficacy of enasidenib in newly diagnosed AML patients ≥ 60.

Disclosures: Stein: Bayer: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Borate: Novartis: Consultancy; Agios: Consultancy. Stock: Jazz Pharmaceuticals: Consultancy. Patel: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; France Foundation: Honoraria; Dava Oncology: Honoraria. Kovacsovics: Abbvie: Research Funding; Amgen: Honoraria, Research Funding. Blum: Pfizer: Consultancy; Boehringer Ingelheim: Research Funding; Forma: Research Funding; Tolero: Research Funding; Astellas: Consultancy; Xencor: Research Funding. Vergilio: Foundation Medicine Inc: Employment. Druker: Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; McGraw Hill: Patents & Royalties; Aileron Therapeutics: Consultancy; Novartis Pharmaceuticals: Research Funding; Fred Hutchinson Cancer Research Center: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Oregon Health & Science University: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Celgene: Consultancy. Byrd: Jazz: Honoraria; Pharmacyclics: Research Funding; Acerta: Honoraria, Research Funding. Levine: C4 Therapeutics: Equity Ownership; Isoplexis: Equity Ownership; Epizyme: Patents & Royalties; Imago: Equity Ownership; Novartis: Consultancy; Prelude: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Honoraria; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership. Mims: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH