Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib: 2023 Update
Himachandana Atluri, Jillian Mullin, Koichi Takahashi, Sanam Loghavi, Abhishek Maiti, Koji Sasaki, Naval Daver, Yesid Alvarado Valero, Naveen Pemmaraju, Gautam Borthakur, Danielle Hammond, Kelly S. Chien, Alessandra Ferrajoli, Nicholas J. Short, Hussein A. Abbas, Elias Jabbour, Michael Andreeff, Farhad Ravandi, Rebecca S. Tidwell, Xuemei Wang, Marina Konopleva, Guillermo Garcia‐Manero, Hagop M. Kantarjian, Courtney D. DiNardo
Abstract
Background Isocitrate Dehydrogenase (IDH) 1 or 2 mutations occur in ~20% of acute myeloid leukemia (AML). Both venetoclax (VEN)-based and targeted IDH-inhibitor (IDHi) therapies are effective treatment options for IDH mutated AML in combination with hypomethylating agents (HMA). ASTX727 is an oral, fixed dose (35 mg/100 mg) combination of decitabine and cedazuridine with bioequivalency to IV decitabine. Herein we report interim results including completion of the Phase 1b portion of the first all-oral triplet regimen of ASTX727 (day 1-5) + VEN (day 1-14) in combination with a targeted mutant IDH1i ivosidenib (IVO) or IDH2i enasidenib (ENA), for IDH mutated AML. Methods Eligible patients (pts) were > 18 years old with newly diagnosed (ND) AML not eligible for intensive chemotherapy, or relapsed/refractory (R/R) IDH1 or IDH2 mutated AML. Prior VEN, HMA, and/or IDHi use was not exclusionary in the R/R cohort. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with IVO (Arm A) or ENA (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2]. Results A total of 51 pts (1b: 26 pts, 2: 25 pts) have been enrolled. The phase 1b portion is completed and the RP2D is established at VEN 600mg in combination with IVO (due to the CYP3A4 inducing effects of ivosidenib requiring a higher dose of VEN to maintain therapeutic concentrations), and VEN 400mg in combination with ENA. There are currently 50 evaluable pts (Arm A: 20, Arm B: 30); median follow up is 11.0 months (mos) for ND pts and 14.6 mos for R/R pts. Median age at enrollment was 72 years (41 - 86). 48% (n=24) pts had ND-AML (A: 10, B: 14) and 52% (n = 26) with R/R AML (A: 10, B: 16). ELN 2022 classification was intermediate or adverse in 87% of ND-AML and 92% of the R/R AML cohorts. Median variant allele frequency in ND pts was 22% (7-38, IDH1) and 36% (4-49, IDH2) and was 29% (8-45, IDH1) and 37% (2-48, IDH2) in the R/R arms. Patients with R/R-AML received a median of 2 lines of prior therapy, including 20 pts having received prior VEN and 7 receiving prior IDH-inhibitor. The composite remission rate (CRc), defined as CR + CRh + CRi, was 96% (n=23) in ND-AML and 46% (n=12) with R/R disease (Table 1). Of pts who received prior VEN, 30% (n=6) achieved a CRc (3 CR, 2 CRi, 1CRh) and in those with prior IDHi exposure, 71% (n=5) achieved a CRc (4 CR, 1 CRh)(Table 2). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved as best response in 91% of the responding ND pts (35% IDH1 and 56% IDH2) and 67% (42% IDH1 and 25% IDH2) of R/R pts. Duration of response (DOR) was not reached (NR) for ND pts and 16.1 mos in R/R pts. Event free survival (EFS) was NR and 5.9 mos (2.76 - NA), respectively. Overall survival (OS) was NR for ND and 10.4 mos (4.7 - NA) for R/R AML. The most common non-hematologic grade 3/4 AEs included indirect hyperbilirubinemia (n=3, 6%) all in enasidenib-treated pts, and two pts (4%) had grade 3 mucositis, one which was attributed to prior cytoreductive therapy. AEs of special interest regardless of grade included differentiation syndrome in 10% (n=5, A:3; B:2), all successfully managed with corticosteroids and diuresis. 4% (n=2) had TLS which was medically managed, one pt required CRRT briefly with full recovery of renal function. 19 pts remain on study, 8 transitioned to SCT in response, and 5 pts (4 ND, 1 R/R) withdrew from the study, including 4 in CRc response, after 2 (n=2), 5 (n=1) and 8 (n=1) cycles of protocol therapy. Conclusions Triplet therapy with ASTX727 + VEN + IDH1/2 inhibition appears safe and preliminarily effective for IDH mutated AML, with high rates of MRD-negative CRc particularly in ND pts and in R/R pts not having received prior VEN or IDHi. AEs were anticipated and tolerable. Enrollment is ongoing.