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

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.