Venetoclax (VEN) and azacitidine (AZA) with gilteritinib (GILT) in patients with newly diagnosed (ND) FLT3mut+ Acute Myeloid Leukemia (AML) ineligible for intensive induction chemotherapy (chemo): Interim results from the phase 1/2 VICEROY study
Year: 2025
Type: conference-abstract
Abstract: VEN/AZA is the standard frontline treatment for adults with ND AML (including FLT3mut+ disease) ineligible for intensive induction chemo due to older age or comorbidities. Complete remission (CR; 38.1%) and 12-month overall survival (OS; 54%) rates are poor following VEN/AZA in patients with FLT3mut+ disease. In a single-center study, VEN/AZA/GILT demonstrated a CR rate of 90% and a 12-month OS rate of 83%. However, most patients required dose and treatment duration reductions due to myelosuppression. Optimized VEN/AZA/GILT doses need to be determined, and the clinical efficacy of the triplet in a multicenter setting (including academic and community centers) awaits confirmation. VICEROY (NCT05520567), a multicenter, open-label, randomized, phase 1/2, dose-ranging/expansion study, is evaluating efficacy, safety and optimal dosing of VEN/AZA/GILT in patients with ND FLT3mut+ AML ineligible for intensive induction (≥75 years old or younger with prohibitive comorbidities). Here, we present phase 1 results. In phase 1, patients were randomized 1:1 to VEN 200mg (VEN200) or 400mg (VEN400) once daily (qd), with AZA (75mg/m2 qd from days 1–7) and GILT (80mg qd), all in 28-day cycles. Bone marrow (BM) testing was done on cycle 1 day 14 (C1D14), and patients with <5% blasts in BM or ≥5% blasts and <5% cellularity had VEN and GILT interrupted for the rest of C1. VEN/AZA/GILT exposure duration was further adjusted based on tolerability in subsequent cycles. Granulocyte colony-stimulating factor treatment was recommended for patients in BM remission with an absolute neutrophil count (ANC) ≤500/µL on C1D42 or later. Primary endpoints included dose-limiting toxicities (DLTs; first 28 days of treatment), safety events (grade ≥3 nonhematological adverse events [AEs] triplet-related or leading to treatment discontinuation/death in the first 3 cycles), CR rate, and pharmacokinetics (PK). Secondary endpoints included composite CR (CRc) rate, OS, and measurable residual disease status (MRD; centrally assessed by a FLT3-internal tandem duplication [ITD] next-generation sequencing assay with a lower limit of 10-6). In total, 44 randomized patients received VEN200 (n=20) or VEN400 (n=24). In VEN200 vs VEN400, median age was 73 vs 77 years; 55% vs 54% were male, 65% vs 83% had FLT3-ITD mutations alone, and 35% vs 13% had FLT3-tyrosine kinase domain (TKD) mutations alone, respectively. No DLTs were observed in VEN200, and 2 patients experienced DLTs in VEN400 (1 patient with prolonged grade 4 neutropenia and thrombocytopenia; 1 patient with tumor lysis syndrome). Safety events occurred in 25% of patients in each arm. Most common safety events were febrile neutropenia (15%) in VEN200 and increased aspartate aminotransferase (8%) in VEN400. 1 patient discontinued VEN200 due to a safety event (pericardial effusion). Serious treatment-emergent AE rate was 85% in VEN200 and 79% in VEN400. No patients died in the first 30 days; 1 patient in VEN400 died in the first 60 days. Median (range) number of treatment cycles for the triplet was 4 (1–17) in VEN200 and 4 (1–11) in VEN400. VEN PK showed an increase in exposure with dose. Mean GILT steady-state Ctrough value was 286 ng/mL (n=37), not affected by VEN dose. As of May 30, 2025, median follow-up was 14 months in VEN200 (n=20) and 12 months in VEN400 (n=23). CR rate (95% CI) was 70% (46–88) and 65% (43–84) in VEN200 and VEN400, respectively; CRc rate (95% CI) was 90% (68–99) and 91% (72–99). In C1, median (range) time to hematologic recovery (ANC >1x109/L and platelets >100x109/L) was 38 (31–53) days in VEN200 and 42 (29–63) days in VEN400. 12-month OS rate (95% CI) was 64% (39–81) in VEN200 and 77% (54–90) in VEN400. At their last available visit, a total of 85% (11/13) of patients in VEN200 and 57% (8/14) of patients in VEN400 achieved MRD <10-4, including 6 (VEN200) and 5 patients (VEN400) with no detectable MRD (<10-6). Based on the safety/response profile, VEN400 was the recommended phase 2 dose (RP2D). Phase 1 results indicate that VEN/AZA/GILT shows promising efficacy and a low incidence of DLTs for both VEN doses in patients with ND FLT3mut+ AML ineligible for intensive induction chemo, with a safety profile consistent with VEN/AZA therapy. RP2D for VEN is 400mg qd in 28-day cycles. Dosing holds were closely monitored during C1 after marrow response, and VEN/AZA/GILT duration was reduced on subsequent cycles after remission. The phase 2 portion is ongoing and enrolling patients.
Source: Blood
Authors: Jessica Altman, Alexander Perl, Eunice Wang, Uma Borate, Elie Traer, James Dugan, Margaret Kasner, Richard Larson, Yehuda Deutsch, Aditi Shastri, Maria Baer, Steven Tsai, Deepa Jeyakumar, Hoda Pourhassan, Alireza Eghtedar, Caroline Chen, Alexandra Heinloth, Rishita Nuthethi, Stanley Gill, Jason Hill, Nahla Hasabou, Mark Levis, Naval Daver
Institutions: Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Abramson Cancer Center, University of Pennsylvania, Roswell Park Comprehensive Cancer Center, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Oregon Health & Science University, Novant Health, Thomas Jefferson University, Sidney Kimmel Cancer Center, University of Chicago, Memorial Healthcare System, Albert Einstein College of Medicine, Montefiore Einstein Comprehensive Cancer Center, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of California, Los Angeles, UCLA Jonsson Comprehensive Cancer Center, University of California, Irvine Medical Center, City Of Hope National Medical Center, Colorado Blood Cancer Institute, Astellas Pharma (United States), Johns Hopkins University, The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417004932