Background: Olutasidenib, a potent, selective, oral, small molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), has been previously shown, as a single agent, to be well tolerated and induce durable complete remissions in a subset of patients (pts) with high-risk relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML), with an overall response rate (ORR) of 46% and a CR/CRh rate of 33% (de Botton et al., ASCO/EHA 2021). Azacitidine (AZA) has shown synergistic effects with mIDH1 inhibitors on releasing differentiation block in mIDH leukemia models in vitro. Here, we present results of an ongoing phase 2 trial (NCT02719574) in pts receiving olutasidenib (150 mg twice daily) in combination with AZA (75 mg/m 2) (Olu-AZA).

Methods: Pts were enrolled into 1 of 4 Olu-AZA cohorts: (1) pts with R/R AML/MDS who were naïve to prior hypomethylating agent [HMA] and IDH1 inhibitor therapy, (2) pts with R/R AML/MDS who had inadequately responded to or had progressed on prior HMA, (3) pts with R/R AML/MDS who were previously treated with an IDH1 inhibitor as their last therapy prior to enrollment (including pts who received single-agent olutasidenib), and (4) treatment naïve [TN] mIDH1 AML pts who were candidates for AZA first line treatment. The primary endpoint was CR/CRh (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]) response rate. CRh was defined as bone marrow blasts < 5%, absolute neutrophil count > 0.5×10 9/L, and platelet count > 50×10 9/L. ORR, a secondary endpoint, comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR). Duration of treatment (DOT) time to response, and duration of response were estimated using Kaplan-Meier methodology. Due to the low number of MDS pts, response parameters are presented for AML pts only.

Results: As of 16-June-2021, a total of 72 pts with AML/MDS (n=63/9) received Olu-AZA (R/R w/o prior HMA/IDH1 therapy, n=20; R/R with prior HMA therapy, n=21; R/R with prior IDH1 therapy, n=20; TN AML, n=11) with a median DOT of 4.7 mo (95% CI: 3.6, 5.7). The median age was 72 y (range: 28‒84) with a median number of prior therapies for R/R pts of 2 (1‒5). At the cut-off, 11 (15%) pts remained on treatment and 61 (85%) had discontinued, most commonly (≥10%) due to: disease progression (32%), transplant (11%), and AEs (10%). For pts with AML, the ORR across Olu-AZA cohorts was 40-68% with a median duration of ORR of 3.7-8.5 mo (not reached [NR] for TN AML) and a median time to first response (PR or better) of 1.6-2.8 mo (Table 1). Notably, the CR/CRh rate ranged from 30-47% including 23-45% of pts in CR, with a median duration of CR/CRh of 4.7-16.0 mo (NR for TN AML) and a median time to CR/CRh of 2.8-4.0 mo. For pts who were transfusion-dependent at baseline, 56-day transfusion independence was achieved by 40-100% of pts for platelets and 25-57% of pts for red blood cells (Table 1). Treatment-emergent adverse events (TEAEs) in ≥25% of pts were nausea (49%), constipation (40%), vomiting (35%), thrombocytopenia (32%), diarrhea (28%), and neutropenia (26%). Grade 3/4 all-causality TEAEs in >10% of pts were neutropenia (26%), thrombocytopenia (25%), anemia (19%), and febrile neutropenia (14%). TEAEs of QTc prolongation (all grades) were reported in 5 (7%) pts with grade 3 events in 2 (3%) pts. All pts were receiving concomitant medications associated with QTc prolongation. No events led to olutasidenib dose reduction or discontinuation. Hepatobiliary TEAEs associated with liver enzyme abnormalities (all grades) were reported in 15 (21%) pts, with grade ≥3 events in 6 (8%) pts. Most pts (n=11) required no dose modification or were successfully rechallenged, 3 pts with grade ≥3 events discontinued treatment, two after recurrence of abnormalities with rechallenge, and one pt died with liver function tests abnormal in the setting of AML progression and sepsis. There were no cases of Hy's law. Investigator-assessed IDH1 differentiation syndrome (any grade) was observed in 6 (8%) pts; most cases resolved with treatment interruption, dexamethasone, and/or supportive treatment; 2 pts had concomitant leukocytosis.

Conclusions: Olutasidenib in combination with AZA was well tolerated and induced durable CR/CRh in a subset of high-risk pts with mIDH1 AML. Transfusion independence was achieved in a subset of pts in all cohorts. Additional analyses of safety and efficacy will be presented.

Figure 1
Figure 1.
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Disclosures

Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Esteve: Novartis: Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Jazz: Consultancy; Abbvie: Consultancy. Bajel: Amgen: Speakers Bureau; Abbvie, Amgen, Novartis, Pfizer: Honoraria. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Genentech: Research Funding; Geron: Research Funding; Tolero: Research Funding; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Braun: Servier: Research Funding; Daiichi-Sankyo, Celgene: Consultancy, Honoraria. De Botton: Celgene, Agios, Forma Therapeutics, Astella, Daiichi Sankyo, Syros, Abbvie, Bayer, Seattle Genetics, Janssen: Honoraria; Celgene, Agios, Astellas, Daiichi Sankyo, Syros, Abbvie, Bayer, Janssen, Pierre Fabre, Novartis, Pfizer, Servier: Consultancy; Celgene: Speakers Bureau; Agios, Forma Therapeutics: Research Funding. Recher: Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Watts: Takeda: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Grove: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; AbbVie: Other: Travel reimbursement. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline/Menarini: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Peerview: Honoraria. Prebet: BMS: Research Funding; BMS, Curios, Daichi: Consultancy. Wang: Takeda: Consultancy, Honoraria, Other: Advisory board; Novartis: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Polyanskaya: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Brevard: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Sweeney: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Fenaux: Celgene/BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Wei: Agios: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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2021
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