Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial
Authors: Stein Eytan M. , Shoben Abigail , Borate Uma , Baer Maria R. , Stock Wendy , Patel Prapti A. , Kovacsovics Tibor , Blum William , Vergilio Jo-Anne , Heerema Nyla A. , Rosenberg Leonard , Marcus Sonja , Stefanos Mona , Chervin Jordan , Druker Brian J. , Burd Amy , Byrd John C. , Levine Ross L. , Mims Alice S. 
Published: October 2019

Abstract
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: Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Borate:Novartis: Consultancy; Agios: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Patel:France Foundation: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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. Levine:Celgene: Consultancy, Research Funding; C4 Therapeutics: Equity Ownership; Isoplexis: Equity Ownership; Epizyme: Patents & Royalties; Gilead: Honoraria; Roche: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership; Imago: Equity Ownership; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Prelude: Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria. Mims:Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.