A Phase 1b Study of IDH Inhibition with Enasidenib and MEK Inhibition with Cobimetinib in Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring IDH2 and RAS Signaling Gene Mutations

Background:

For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with IDH2 and RAS-pathway mutations involving NRAS, KRAS, PTPN11, and CBL genes, low responses and poor survival remain unmet clinical needs. Although enasidenib, a potent inhibitor of IDH2, is approved in R/R IDH2-mutant AML, patients with co-occurring RAS-pathway mutations exhibit primary resistance.[1,2] , Additionally, new RAS mutations confer acquired resistance to IDH inhibitors.[3] Preclinical studies suggest that RAS and IDH2 mutations cooperate to promote leukemogenesis.[4] In IDH2-mutant AML, aberrant production of the oncometabolite 2-hydroxyglutarate (2HG) suppresses the TET2 demethylase leading to a hypermethylation phenotype. Inhibition of TET2 induces epigenetic silencing of key RAS negative regulators (Sprouty family of proteins).[4] Enasidenib promotes demethylation to restore expression of RAS negative regulators. Meanwhile, MEK inhibitors were shown to suppress RAS-signaling. Co-targeting of IDH2 and MEK in mice with IDH2 /NRAS-dependent AML resulted in greater improvement in splenomegaly and cytopenia than either drug alone. Thus, we designed a phase 1 study to evaluate combined targeting of IDH2 and MEK in patients with R/R AML.

Study Design and Methods:

This is an open-label, multi-center, phase 1b study evaluating the safety of the combination of MEK inhibitor cobimetinib and IDH2 inhibitor enasidenib in patients with R/R AML and RAS-pathway mutations. The study will consist of 1) a dose escalation cohort to determine the maximum tolerated dose and the recommended phase 2 dose (RP2D) and 2) a dose expansion cohort to better characterize safety of the combination as well as preliminary efficacy, both in patients with R/R AML. Key eligibility criteria include R/R AML or newly diagnosed AML not eligible for chemotherapy; presence of co-occurring IDH2 and either NRAS, KRAS, PTPN11, NF1, or CBL mutations. The study will evaluate two dose levels of cobimetinib 40mg (DL1) or 60mg (DL2) daily on days 1-21 of a 28 day cycle and the FDA approved dose of enasidenib 100mg daily. The study primary endpoint is safety. Dose-limiting toxicities will be defined during the first cycle of therapy (28 days) as ≥ grade 3 toxicities according to the NCI CTCAE version 5.0. Dose escalation will occur according to a 3+3 design. Secondary endpoints will include overall response (CR, CRi, MLFS, and PR) by ELN 2022 response criteria, median to first response, response duration, median and 1-year OS and EFS, pharmacokinetics, and pharmacodynamics (phospho-ERK by CYTOF). Correlative objectives include determining the expression of RAS negative regulators by RNA sequencing and epigenetic regulation of RAS regulators by bisulfite sequencing and H3K4me3 and H3K27Ac ChIP-Seq. The study will accrue at the City of Hope National Medical Center and Memorial Sloan Kettering Cancer Center. This trial is registered on clinicaltrials.gov: NCT04243785

1. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017 Aug 10;130(6):732-741.

2. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731.

3. Wang F, Morita K, DiNardo CD, et al. Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nature Communications. 2021 2021/05/10;12(1):2607.

4. Kunimoto H, Meydan C, Nazir A, et al. Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity. Cancer cell. 2018 Jan 8;33(1):44-59.e8.

Ball:Oncovalent: Membership on an entity's Board of Directors or advisory committees. Stein:Auron Therapeutics: Current equity holder in private company; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Bayer: Research Funding; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy. Levine:Astra Zeneca and Kura: Other: honoraria for invited lectures ; Syndax, Incyte, Janssen, Astellas, Morphosys and Novartis: Consultancy; Ajax, Abbvie, Constellation, Zenalis, Celgene, Roche, and Prelude: Other: research support; 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; Qiagen: Other: supervisory board member; Gilead and Novartis: Other: Grant reviews. Stein:Amgen: Honoraria. Marcucci:Lynx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Speaker and advisory scientific board meetings. Danilov:Beigene: Consultancy; Takeda Oncology: Research Funding; Abbvie: Consultancy, Research Funding; Bristol-Meyers-Squibb: Consultancy, Research Funding; Bayer Oncology: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy; Nurix: Consultancy, Research Funding; Cyclacel: Research Funding; MEI: Consultancy, Research Funding; Morphosys: Consultancy; Genentech: Consultancy; Incyte: Consultancy; GSK: Consultancy.