Iadademstat Combination with Azacitidine Is a Safe and Effective Treatment in First Line Acute Myeloid Leukemia. Final Results of the Alice Trial

Background: Acute myeloid leukemia (AML) is a heterogenous disease with a broad spectrum of cytogenetic and molecular aberrations. Emerging targeted therapies have improved overall survival (OS) for some specific subgroups. Outcomes, however, remain poor, particularly for patients (pts) with high-risk characteristics and not eligible for intensive treatments. Combinations with hypomethylating agents are the standard of care (SoC) for unfit patients. Azacitidine (aza) plus venetoclax has shown an OS of 14.7 months (mo) and a complete remission or complete remission with incomplete hematological recovery (CR/CRi) rate of 66% (VIALE-A trial). The presence of mutations in TP53 or FLT3-ITD predicts resistance to this combination. Overall, 50% of AML pts relapse after first line treatments, generally attributed to the persistence of leukemic stem cells (LSC) and/or their clonal evolution, emphasizing the need to develop new strategies targeting LSC, to improve outcomes.

One such investigational strategy is iadademstat (iada), an oral, potent and selective inhibitor of the Lysine-Specific Demethylase 1 (LSD1/KDMA1) enzyme. This enzyme works as a master regulator of transcription by a double mechanism of action: 1) removing methyl groups from histone 3 lysines (epigenetic eraser); and 2) disrupting multiprotein transcriptional complexes on genes governing cell differentiation and stemness. In myeloid cells, LSD1 provides a scaffold for assembly of the GFI1/CoREST transcriptional repressor complex, which regulates hematopoietic differentiation. Iada-induced gene expression shifts from a proliferation to differentiation signature has been preclinically characterized in AML cells (Maes, et al., Cancer Cell 2018) and in the clinic in a Ph1 study in Relapsed/Refractory AML (Salamero, et al., JCO 2020). To date, iada has been administered to more than 100 oncology pts in Ph1 and Ph2 trials, showing manageable toxicity and encouraging preliminary activity.

Herein, we present the results of the Phase 2 ALICE study (EudraCT 2018-000482-36) testing the combination of iada plus aza for the frontline treatment of unfit AML patients, with a median follow-up of 6.9 mo (range 0.7-41.9) (cut-off June 30, 2022). The final data (cut-off September 30, 2022) will be presented at the ASH meeting.

Methods: Unfit adult patients with AML per WHO 2017 classification who had not received previous treatment were enrolled. Two cohort doses of iada at 60 or 90μg/m²/d (PO, 5d ON, 2d OFF weekly) were explored in combination with aza (75mg/m² SC for 7d, either d1-5, 8-9, or d1-7 every cycle) in a 28d cycle.

Primary endpoints are safety, tolerability, and establishment of the recommended phase 2 dose (RP2D); secondary endpoints include remission rates, time to response (TTR), duration of responses (DoR) and OS. Additional assessments include measurable residual disease (MRD), PK/PD determinations and molecular correlations with response.

Results: Baseline characteristics for 34 per protocol pts out of 36 accrued are shown in Table 1. Safety and efficacy results are detailed in Table 2. Main safety events remain consistent with previous updates, with the most frequently reported adverse reactions (AR) being platelet reduction in 53% of pts (58% of pts entered the study with grade ≥3 thrombocytopenia). Only 2 drug-related SAEs have occurred to date.

Of 27 pts evaluable for efficacy, 81% responded (64% of those with CR/CRi). Responses were rapid (91% by end of C2). 71% of CR/CRi pts became transfusion independent and 82% of CR/CRi pts evaluable for MRD were negative by flow cytometry. Mean/median DoR (CR/CRi) are 9.3 mo (SE: 1.0 mo) / NE (95% CI 10.1mo, NE). Mean/median OS are 8.2 mo (SE: 0.80 mo)/9.3 mo (95% CI 11.0 mo, NE). Median OS for pts achieving CR/CRi is ~14.3 mo. Based on PK/PD, safety and efficacy, iada at 90 μg/m2/d is the RP2D for the combination.

Response assessment per specific mutations shows that 3 out of 3 (3/3) with FLT3 mutations, 7/7 with RAS pathway mutations, and 6/8 pts with TP53 mutations responded. Gene expression and cell differentiation analyses are ongoing and correlations with clinical responses will be presented.

Conclusion: The combination of iada with aza produces robust, rapid and durable responses in previously untreated unfit AML patients, including those with high-risk features, with a manageable toxicity profile. Further research with iada in combination with SoC treatments for AML is warranted.

Salamero:Abbie, BMS, Novartis: Consultancy, Honoraria. Somervaille:Oryzon Genomics: Consultancy; Imago Biosciences: Research Funding; Bristol Myers Squibb: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; CellCentric Ltd: Research Funding. Molero:Oryzon Genomics: Consultancy. Perez-Simon:ALEXION: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; JAZZ: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; ABBVIE: Research Funding; PFIZER: Research Funding. Arnan:MNS, JAZZ, Novartis, Abbvie: Consultancy, Speakers Bureau. Arevalo:Oryzon Genomics: Current Employment. Gutierrez:Oryzon Genomics: Current Employment. Buesa:Viracta Therapeutics: Current equity holder in publicly-traded company; Oryzon Genomics SA: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Mendelion, Palo Biopharma: Current equity holder in private company. Faller:Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company; Phoenicia Biosciences: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracta: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Briacell: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Cytea: Consultancy, Current equity holder in private company; Takeda pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Faller Williams LLC: Current equity holder in private company, Patents & Royalties; Molecular Partners: Consultancy; Wuxi Inc: Consultancy. Bosch:Celgene/BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Karyospharm: Honoraria; Takeda: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Montesinos:Astellas: Consultancy, Speakers Bureau; Kura Oncology: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Menarini/Stemline: Consultancy, Research Funding; Incyte: Consultancy; Otsuka: Consultancy; Ryvu: Consultancy; Nerviano: Consultancy; Beigene: Consultancy.