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159 Final Results of the Phase Ib/II Study Evaluating Enasidenib in Combination with Venetoclax in Patients with IDH2-Mutated Relapsed/Refractory Myeloid Malignancies

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Novel Uses of Approved Therapeutic Agents
Hematology Disease Topics & Pathways:
Research, adult, Acute Myeloid Malignancies, AML, MDS, clinical trials, Combination therapy, Clinical Research, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies, Study Population, Human
Saturday, December 9, 2023: 2:30 PM

Guillaume Richard-Carpentier, MD, FRCPC1, Gopila Gupta1*, Charina Cameron, BSc, RN1*, Severine Cathelin, PhD1*, Aniket Bankar, MD, MBBS, MSc, DM1, Marta Beata Davidson, MD, PhD1, Vikas Gupta, MD1, Dawn C. Maze, MD, FRCPC, MSc1, Mark D. Minden1*, Tracy Murphy, MD, FRCP, FRCPath1*, Aaron D. Schimmer, MD1, Andre C. Schuh, MD, FRCPC2, Hassan Sibai, MD1, Karen Yee, MD, FRCPC1*, Courtney D. DiNardo, MD, MSc3, Joseph Brandwein, MD4, Caroline Jane McNamara, MBBS5* and Steven M. Chan, MD, PhD6

1Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
2Department of Medical Oncology and Hematology, University Health Network- University of toronto, Toronto, ON, Canada
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4University of Alberta Hospital, Edmonton, AB, Canada
5Haematology and Bone Marrow Transplant, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
6Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

BACKGROUND: The isocitrate dehydrogenase 2 (IDH2) gene is mutated in ∼10-15% cases of acute myeloid leukemia (AML) and ∼5% cases of myelodysplastic syndromes (MDS). Enasidenib (ENA) is an oral selective IDH2 inhibitor used for treatment of IDH2­-mutated (mIDH2) relapsed/refractory (R/R) AML. Preclinical studies showed that mIDH2 AML cells are particularly sensitive to BCL2 inhibition with venetoclax (VEN) and combination of ENA and VEN is more effective than single agents in patient-derived xenograft models of mIDH2 AML. Based on this rationale, we conducted a phase Ib/II trial evaluating the safety and efficacy of ENA plus VEN in patients (pts) with mIDH2 R/R AML or MDS (NCT04092179).

METHODS: This single-arm phase Ib/II trial was conducted at the Princess Margaret Cancer Centre and the University of Alberta Hospital in Canada. Pts ≥ 18 years with mIDH2 R/R AML or MDS, adequate organ function and ECOG performance status ≤ 2 were eligible. Participants were not eligible if they had prior exposure to IDH2 or BCL2 inhibitors. Pts were treated continuously by 28-day cycles of VEN 400 mg daily starting with a 3-day ramp-up on cycle 1 day 1 and with ENA 100 mg daily starting on cycle 1 day 15. The primary endpoints were safety, tolerability and recommended phase 2 dose (RP2D) for the phase Ib part and overall response rate (ORR) for the phase II part. ORR included complete remission (CR), CR with partial hematological recovery (CRh), CR with incomplete hematological recovery (CRi), morphologic leukemia-free state (MLFS) and partial remission (PR) as defined by the European Leukemia Network (ELN). Duration of response (DOR), overall survival (OS), pharmacokinetic (PK) analysis for VEN and bone marrow (BM) IDH2­ variant allele frequency (VAF) by droplet digital PCR (ddPCR) were also evaluated.

RESULTS: From November 2020 to July 2022, 27 pts were enrolled: 12 in the phase Ib and 15 in the phase II. Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The data cutoff date was June 30, 2023. The median age was 70 years (range, 23 – 84) (Table 1). Patients had a median of 1 prior line of treatment (range, 1-2) including 5 (19%) who had previously undergone allogeneic stem cell transplant (HSCT). Fifteen (56%) and 12 (44%) pts had R140Q and R172K/W IDH2 mutation (mut), respectively. The median BM IDH2 VAF at baseline was 23.4 (range 2.3 – 49.9).

The most common (≥ 20%) grade 3-5 treatment emergent adverse events (TEAEs), regardless of attribution, were febrile neutropenia (41%), lung infection (22%) and thrombocytopenia (26%). Nausea, vomiting and diarrhea occurred each in 41% of pts, but were primarily grade 1-2 (only 1 pt with grade 3 diarrhea). Hyperbilirubinemia of any grade occurred in 48% pts, including grade 3 in 15%. No case of IDH inhibitor associated differentiation syndrome (IDH-DS) occurred in this study. Grade 3 leukocytosis without IDH-DS occurred in 2 (8%) pts. No patient discontinued ENA because of an adverse event and no treatment-related death was reported. The PK profile of VEN was not altered by ENA, and the RP2D was VEN 400 mg daily plus ENA 100 mg daily.

Among 23 pts with R/R AML evaluable for response, the ORR was 70% (16/23), including 57% (13/23) CR (Figure 1). In pts with R172 mut, the ORR and CR rates were 83% (10/12) and 67% (8/12), respectively, versus 55% (6/11) and 45% (5/11) in pts with R140 mut. mIDH2 VAF at baseline was similar between responders and non-responders. On follow-up BM samples, there was an association between response and decrease in mIDH2 VAF. Clearance of mIDH2 was observed in 47% (7/15) of analyzed responders. The median time to initial response was 1 month (range, 0.9 – 5.7), and the median time to best response was 2.8 months (range, 0.9 – 12.5). The median DOR was 16.6 months (95% CI 5.0 – NR) and pts received a median of 7 cycles of treatment (range, 1 – 32).

With a median follow-up of 17.1 months (range, 0.9 – 31.4), 10 (38%) pts were alive, including 9 (35%) in ongoing remission. The median OS was 9.4 months (95% CI, 8.2 – NR) and the 2-year OS rate was 42% (95% CI, 27 – 66). Four pts proceeded to HSCT after achieving remission, of whom 2/4 (50%) are alive in remission on last follow-up.

CONCLUSIONS: The combination of ENA and VEN is safe and well tolerated in pts with R/R mIDH2 myeloid malignancies. The ENA-VEN combination compares favorably to ENA single-agent in this patient population. Further studies of targeted combination therapies using IDH2 and BCL2 inhibitors are warranted.

Disclosures: Richard-Carpentier: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta: Novartis, BMS Celgene, Sierra Oncology, AbbVie, Constellation Biopharma, Pfizer, GSK Pharma, CTI Biopharma: Consultancy; BMS, Celgene, Roche, Abb Vie, Pfizer, Sierra Oncology, CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis, BMS Celgene, GSK: Honoraria; Novartis, BMS Celgene, SMP Oncology, AbbVie, Constellation Biopharma, Pfizer, GSK Pharma, CTI Biopharma: Consultancy; GSK: Other: Travel to EHA 2023 for invited talk at GSK sponsored MPN education session ; BMS Celgene, Roche, AbbVie, Pfizer, Sierra Oncology, CTI Biopharma, GSK: Other: Participation on a Data Safety Monitoring Board or Advisory Board. Schimmer: Medical and Scientific Advisory Board of the Leukemia and Lymphoma Society of Canada: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Medivir AB: Research Funding; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Otsuka Pharmaceuticals: Consultancy, Honoraria; UHN: Patents & Royalties: the use of DNT cells to treat AML; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding. Schuh: Abbvie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Glycomimetics: Research Funding; Kite/Gilead: Research Funding; Pfizer: Consultancy, Honoraria; Servier: Honoraria, Research Funding; Teva: Consultancy, Honoraria. DiNardo: AbbVie/Genentech: Honoraria; Astellas: Honoraria; BMS: Honoraria; Fogham: Honoraria; Notable Labs: Honoraria; ImmuniOnc: Honoraria; Servier: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Schrödinger: Consultancy. Brandwein: Jazz: Honoraria; Paladin: Honoraria; BMS/Celgene: Honoraria; Taiho: Honoraria; Pfizer: Honoraria; Avir: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; Amgen: Honoraria. Chan: AbbVie: Research Funding; Servier: Research Funding; BMS: Research Funding; Agios: Research Funding.

OffLabel Disclosure: Venetoclax is not approved for the treatment of patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes. Enasidenib is not approved for treatment of patients with relapsed or refractory myelodysplastic syndromes.

*signifies non-member of ASH