A Risk-Adapted Study to Assess the Efficacy of Enasidenib and Subsequent Response-Driven Addition of Azacitidine for Newly Diagnosed IDH2-Mutant AML Patients: 3-Year Follow-up

Background: Enasidenib (ENA) is an oral inhibitor of IDH2 currently approved for the treatment of relapsed/refractory (R/R) AML with IDH2 mutations. Recent clinical studies suggest that ENA alone or in combination with azacitidine (AZA) is a safe and effective therapy for newly diagnosed (ND) as well as R/R AML. Here, we report the updated results and extended 3-year follow-up of the Beat AML Master Trial Phase 2/1b sub-study to assess the efficacy of ENA monotherapy (ENAm) and subsequent response-driven addition of AZA in ND IDH2-mutated (IDH2m) AML patients (pts) ≥ 60 years of age. (ClinicalTrials.gov NCT03013998).

Methods: Patients ≥ 60 years of age with AML were screened under the Beat AML Master Trial and assigned to this sub-study if they had R140/R172 mutations in IDH2 and met other eligibility criteria. Patients started on the phase 2 portion of the study received ENAm for up to 5 cycles. Patients who failed to achieve CR/CRi after 5 cycles or with progression/intolerance were eligible to have AZA added to ENA as combination therapy in the phase 1b portion. ENA and AZA were dosed as per FDA prescribing information. The primary endpoint wasof CR/CRi rate for ENAm. Secondary objectives included response of patients to ENA + AZA combination and evaluation of safety and survival of patients on both monotherapy and combination therapy.

Results: At data cut-off (05/08/2022), all 60 patients were evaluable for the primary endpoint. The median age of patients treated on study was 75 years. The majority of patients had unfavorable-risk disease. At the time of data cut-off, the median time on ENAm was 4.8 months. The most common reasons for discontinuation were treatment failure (33%), disease progression (23%), and adverse events (AEs) (10%). Six patients (10%) proceeded to an allogeneic stem cell transplant. The primary objective was met, with 29 patients (48%, adjusted 95% CI 30.3-60.5) achieving CR/CRi. The median overall survival was 17.1 months (median f/u 36.1 mos, 95% CI 11.0-44.2) (Fig. 1). The median duration of response was 11.1 months (95% CI 5.6-41.4) (Table 1). There are no updates to previously reported AEs or ENA-related SAEs. The most common SAEs were differentiation syndrome (20%), tumor lysis syndrome (1.7%) and 1 grade 5 renal failure/death. Most common AEs of any grade are nausea, anemia and low potassium. The 7-day/30-day/60-day deaths observed with ENA remain 2%/5%/10%, respectively, as previously reported.

Phase 1b: Seventeen patients failed to respond to ENAm and began the phase 1b study of ENA +AZA. Median duration of ENA + AZA was 1.7 months. 1 patient (5.9%) remains on treatment. The most common reasons for discontinuation were disease progression (24%), treatment failure (18%), AEs (18%), death and transplant (12% each). Seven patients (41%, 95% CI 18-67) achieved CR/CRi on ENA + AZA. With a median follow up of 41.1 months, the median overall survival from the initiation of ENA + AZA treatment was 12.5 months (95% CI 4.5-not reached (NR)). The median duration of response was 14.6 months (95% CI 0.5-NR). No additional ENA-related SAEs occurred beyond the previously reported differentiation syndrome (2 pts, 12%), nausea (1 pt, 6%), and increased serum bilirubin (1 pt, 6%). Most common AEs of any grade continue to be anemia, vomiting, nausea. As reported previously, only one death occurred at 13 days after starting ENA + AZA.

Conclusions: At three-year follow-up, ENAm continues to be a safe and well-tolerated therapy in ND patients ≥ 60 years old with IDH2m AML both alone and with the risk-adapted addition of AZA. CR/CRi rates are high (48%, adjusted 95% CI 30.3-60.5) and remissions are durable (11.1 months, 95% CI 5.6-41.4). The composite CR (cCR) rate of ENAm appears comparable to the cCR rate achieved with ENA + AZA in AG221-AML-005, a phase 2 study comparing ENA + AZA to AZA alone in ND AML. The rates of response to ENAm are also comparable to other studies evaluating upfront ENAm in ND IDH2m AML. As reported previously, the most common ENA-related SAE is differentiation syndrome, occurring in 20% of patients. No significant additional AEs or ENA-related SAEs occurred with longer follow-up. Finally, addition of AZA in patients who did not achieve CR/CRi with ENAm led to additional responses in a subset of patients (41%). This finding suggests that a risk-adapted approach in which AZA is added later can be a means of mitigating toxicity conferred by AZA.

Stein:Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Auron Therapeutics: Current equity holder in private company; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Consultancy, Research Funding; Bayer: Research Funding; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy. Cai:Imago Biosciences: Consultancy, Current equity holder in publicly-traded company. Huang:AstraZeneca: Other: Statistical support. Baer:Takeda: Research Funding; Forma: Research Funding; Kura Oncology: Research Funding; AbbVie: Research Funding; Kite, a Gilead Company: Research Funding; Ascentage: Research Funding. Stock:MorphoSys: Honoraria; Kura Oncology: Honoraria; Kite: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Agios: Honoraria; Servier: Honoraria; Pluristem: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Syndax: Consultancy, Honoraria; Newave Pharmaceuticals: Consultancy. Kovacsovics:Abbvie: Research Funding; Caelum: Research Funding; Gilead: Research Funding; Glycomimetics: Research Funding; Janssen: Research Funding; Jazz Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Syndax: Research Funding; Kite: Honoraria. Schiller:Constellation: Research Funding; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; Millennium: Research Funding; Arog: Research Funding; Daiichi-Sankyo: Research Funding; Gamida: Research Funding; Samus: Research Funding; AstraZeneca: Honoraria; FujiFilm: Research Funding; Deltafly: Research Funding; Janssen: Research Funding; Cyclacel: Research Funding; Forma: Research Funding; Deciphera: Research Funding; Sellas: Research Funding; AltruBio: Research Funding; Regimmune: Research Funding; Geron: Research Funding; Glycomimetics: Research Funding; Cellerant: Research Funding; CTI: Research Funding; PreCOG LLC: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Trovagen: Research Funding; Mateon: Research Funding; Stemline: Speakers Bureau; Actuate: Research Funding; Jazz: Consultancy; Cellectis: Research Funding; AVM Biopharma: Research Funding; Medimmune: Research Funding; Agios: Consultancy, Honoraria; Actinium: Research Funding; AbbVie: Research Funding, Speakers Bureau; Ono Pharma: Honoraria; Genentech-Roche: Research Funding; Astellas: Research Funding, Speakers Bureau; Kite, a Gilead Company: Research Funding, Speakers Bureau; Novartis: Honoraria, Other: Speaker fees, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Stemline: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; Johnson & Johnson: Current equity holder in publicly-traded company; Celgene: Consultancy, Research Funding, Speakers Bureau; Onconova: Research Funding; Sangamo: Research Funding; Takeda: Research Funding; Tolero: Research Funding. Olin:Cellectis: Other: NA; Actinium: Consultancy; Astellas: Consultancy; Abbvie: Consultancy. Foran:Novartis, Servier, Pfizer, BMS, Taiho: Other: Formal Advisory Activities; AbbVie, Actinium, Aptose, Astex, H3Biosciences, Kura Oncology, Trillium, Xencor: Research Funding. Litzow:Abbvie: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Syndax: Research Funding; Jazz: Consultancy; Actinium: Research Funding; Pluristem: Research Funding; Biosight: Other: Data Monitoring Board. Lin:AbbVie, Aptevo, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Mateon Therapeutics, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Patel:Agios: Membership on an entity's Board of Directors or advisory committees. Foster:Zentalis Pharmaceuticals: Consultancy; Rafael Pharmaceuticals: Research Funding; Newave Pharmaceuticals: Research Funding; Macrogenics: Research Funding; LOXO Oncology: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum Pharmaceuticals: Research Funding. Boyiadzis:Genentech: Current Employment. Vergilio:Foundation Medicine: Current Employment, Current equity holder in publicly-traded company. Druker:Nemucore Medical Innovations: Other: Scientific Advisory Board ; DNA SEQ: Other: Scientific Advisory Board ; Novartis: Other: Scientific Advisory Board; Clinical Trial Funding , Patents & Royalties: 6958335 (exclusive license), Research Funding; RUNX1 Research Program: Other: Scientific Advisory Board ; Aptose Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Therapy Architects (ALLCRON): Other: Scientific Advisory Board ; Cepheid: Other: Scientific Advisory Board ; Celgene: Other: Scientific Advisory Board ; Aileron Therapeutics: Other: Scientific Advisory Board ; Adela Bio: Other: Scientific Advisory Board ; (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license, one CytoImage, Inc. exclusive license, and one Sun Pharma Advanced Research Company non-exclusive license): Patents & Royalties: Patent 6958335; CytoImage: Patents & Royalties: QD Molecular Assay for Personalized Oncoprotein Detection in Leukemia (exclusive license); Sun Pharma Advanced Research Company: Patents & Royalties: Mutated ABL Kinase Domains (non-exclusive license); Blueprint Medicines: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Enliven Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Iterion Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; GRAIL: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Recludix Pharma: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board ; Amgen: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; CureOne: Membership on an entity's Board of Directors or advisory committees; Beat AML LLS: Other: Joint Steering Committee ; Multicancer Early Detection Consortium: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Other: Founder; Enliven Therapeutics: Other: Sponsored Research Agreement ; Recludix Pharma: Other: Sponsored Research Agreement ; Astra-Zeneca: Other: Clinical Trial Funding, Research Funding; US Patent: Patents & Royalties: 4326534; US Patent: Patents & Royalties: 6958335; US Patent: Patents & Royalties: 7416873; US Patent: Patents & Royalties: 7592142; US Patent: Patents & Royalties: 10473667; US Patent: Patents & Royalties: 10664967; US Patent: Patents & Royalties: 11049247; Merck: Patents & Royalties: Monoclonal antiphosphotyrosine antibody 4G10. Mims:Astellas: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Ryvu: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Other: Data Safety and Monitoring Board; Zentalis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety and Monitoring Board; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Borate:Genentech: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Byrd:Syndax: Consultancy; Newave: Consultancy; Kura: Consultancy; Vincerx: Consultancy, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Pharmacyclics: Research Funding; Zencor: Research Funding; Trillium: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Ohio State University: Patents & Royalties; AbbVie: Consultancy; Janssen: Consultancy. Levine:Imago, Mission Bio, Bakx, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics and Isoplexis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ajax, Abbvie, Constellation, Zenalis, Celgene, Roche, and Prelude: Other: research support; Syndax, Incyte, Janssen, Astellas, Morphosys and Novartis: Consultancy; Qiagen: Other: supervisory board member; Gilead and Novartis: Other: Grant reviews; Astra Zeneca and Kura: Other: honoraria for invited lectures .

enasidenib is an inhibitor of mutant IDH2 for the treatment of relapsed/refractory AML