Background Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib has previously demonstrated a favorable tolerability profile and clinical activity in high-risk mIDH1 AML patients (pts) in the completed Phase 1 portion of a Phase 1/2 trial (Watts, Blood 2019; NCT02719574). Here, we report results in pts with relapsed/refractory (R/R) mIDH1 AML from the pivotal Phase 2 cohort of the trial. Enrollment was stopped early at this planned interim analysis when efficacy stopping criteria of at least 28 responses in 115 evaluable pts were met.

Methods The primary endpoint was CR+CRh rate (complete remission [CR] according to modified IWG 2003 criteria, plus CR with partial hematologic recovery [CRh]). CRh was defined as bone marrow blasts <5%, absolute neutrophil count >0.5×109/L and platelet count >50×109/L. Overall response rate (ORR) comprised CR, CRh, CR with incomplete blood count recovery (CRi), partial response (PR) and morphologic leukemia-free state (MLFS). Time to response, duration of CR/CRh, duration of response (DOR) and overall survival (OS) were estimated using Kaplan-Meier methodology. Data cut-off for the analysis was 18 June 2021.

Results In total, 153 IDH1 inhibitor-naïve pts with R/R mIDH1R132 AML received olutasidenib monotherapy 150 mg twice daily. The Efficacy Evaluable cohort comprised 147 pts with centrally confirmed mIDH1 who received the first dose of olutasidenib ≥6 months prior to data cut-off. Median age (range) was 71 years (32-87) and the median number of prior regimens was 2 (1-7).

The CR+CRh rate was 35% (n=51; 95% CI, 27.0-43.0); median time to CR/CRh was 1.9 months (0.9-5.6). The ORR was 48% (n=71; 95% CI, 40.0-56.7). Response rates were similar for 12 pts who had received prior venetoclax. Median duration of CR/CRh was 25.9 months (95% CI, 10.6-NE), with 28 (55%) pts censored, all of whom were on treatment at data cut-off. Median DOR was 11.7 months (95% CI, 6.9-25.9). Median OS was 11.6 months (95% CI, 8.9-15.5). Sixteen (11%) pts received allogeneic transplant. Among 64 pts who were red blood cell and/or platelet transfusion dependent at baseline, a 56-day transfusion independence was achieved in 22 (34%), including pts in all response groups.

The most frequently reported TEAEs (≥20%) were nausea (n=58; 38%), constipation and anemia (n=40; 26% each), leukocytosis (n=38; 25%), pyrexia (n=36; 24%), fatigue (n=35, 22%), febrile neutropenia (n=33; 22%), dyspnea and diarrhea (n=31; 20% each) and thrombocytopenia and hypokalemia (n=30, 20% each). Grade 3/4 TEAEs (≥10%) were febrile neutropenia and anemia (n=31; 20% each), thrombocytopenia (n=25; 16%) and neutropenia (n=20; 13%). Differentiation syndrome (DS) and hepatic effects were AEs of special interest. DS occurred in 22 (14%) pts, with 14 (9%) grade ≥3. Most cases of DS resolved with treatment interruption, dexamethasone and/or supportive care; 1 fatal case was reported. Hepatic AEs occurred in 38 (25%) pts, with grade 3 events in 19 (12%) pts and grade 4 events in 4 (3%); the most common (>1%) grade 3/4 events were increases in laboratory liver function parameters. Hepatic AEs were manageable with dose modifications and concomitant medications as indicated.

Conclusions Olutasidenib induced durable remissions with a well-characterized and manageable side-effect profile. Transfusion independence was achieved across all response groups. The observed activity is clinically meaningful and represents a therapeutic advance in the treatment of this molecularly defined, poor-prognosis patient population with R/R AML, including those with prior venetoclax failure. Investigation of olutasidenib as monotherapy and in combination with azacytidine is ongoing in other mIDH1 hematologic malignancies.

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Cortes:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sun Pharma: Consultancy, Research Funding; Biopath Holdings: Consultancy, Current equity holder in private company; Abbvie: Consultancy, Research Funding; Forma Therapuetic: Consultancy; Gilead: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Kartos: Research Funding. Fenaux:BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Yee:Geron: Research Funding; Forma Therapeutics: Research Funding; Astex: Research Funding; Abbvie: Honoraria; Takeda: Consultancy; Astellas: Consultancy; GlaxoSmithKline: Consultancy; F. Hoffmann La Roche: Consultancy, Research Funding; Bristol-Myers Squibb/Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy; TaiHo: Consultancy; Gilead: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Treadwell: Research Funding; Shattuck Labs: Consultancy. Recher:Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie, Janssen, Jazz Pharmaceuticals, Novartis, BMS-Celgene, Otsuka, Astellas, Daiichi-Sankyo, Macrogenics, Roche, Takeda, Servier, Pfizer: Other: Advisory role; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, Novartis, BMS-Celgene, Jazz Pharmaceuticals, Agios, MaatPharma, Astellas, Roche, Iqvia, Daiichi-Sankyo: Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wei:Janssen: Honoraria, Research Funding; Gilead: Honoraria; Shoreline: Honoraria; Agios: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Pfizer: Honoraria; Roche: Honoraria; Macrogenics: Honoraria; BeiGene: Consultancy; Astellas: Honoraria, Speakers Bureau; Astex: Research Funding; Syndax: Research Funding; Servier: Consultancy, Honoraria, Other: Travel, Accommodations, and Expenses, Patents & Royalties: Filing Date: 21/07/2017. Combination of a BCL-2 inhibitor and a MCL-1 inhibitor, uses and pharmaceutical compositions thereof. A. Wei, D. Moujalled, G. Pomilio, A.L. Maragno, O. Geneste, A. Claperon, H. Maacke, E. Halilovic, D. Porter, E. Morris, Y. Wang, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, and Expenses, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau. Montesinos:BEIGENE: Consultancy; JAZZPHARMA: Consultancy, Research Funding, Speakers Bureau; ASTELLAS: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Research Funding, Speakers Bureau; INCYTE: Consultancy; KURA ONCOLOGY: Consultancy; PFIZER: Consultancy, Research Funding, Speakers Bureau; ABBVIE: Consultancy, Research Funding, Speakers Bureau; RYVU: Consultancy; TAKEDA: Consultancy, Research Funding; OTSUKA: Consultancy; GILEAD: Consultancy, Speakers Bureau; MENARINI/STEMLINE: Consultancy, Research Funding; NERVIANO: Consultancy. Taussig:Abbvie: Other: Funding to attend ASH annual meeting & exposition. Pigneux:abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Other: travel; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizzer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Curti:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Grove:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: chairperson at local Abbvie Education Event for which my institution received hororaria., Speakers Bureau; Australian advisory boards as below: Consultancy. Jonas:AbbVie: Consultancy, Other: Travel Reimbursement, Research Funding; Pfizer: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: protocol steering committee , Research Funding; Gilead: Consultancy, Other: data monitoring committee , Research Funding; 47: Research Funding; BMS: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Accelerated Medical Diagnostics: Research Funding; Amgen: Research Funding; AROG: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Roche: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; LP Therapeutics: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding. Polyanskaya:Forma Therapeutics Inc.: Current Employment. Sweeney:Forma Therapeutics Inc.: Current Employment. Brevard:Forma Therapeutics Inc.: Current Employment. Barrett:Forma Therapeutics Inc.: Current Employment. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Bayer: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Forma Therapuetics: Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau.

Author notes

*

Asterisk with author names denotes non-ASH members.

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2022
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