Paper Details

ABSTRACT

Background: VEN+AZA is the standard frontline treatment for adults with ND AML ineligible for intensive induction chemotherapy, but patients (pts) with FLT3^mut+ AML have relatively poor outcomes. VICEROY (NCT05520567) is a multicenter, open-label, phase 1/2, dose-randomized/expansion study evaluating efficacy, safety and optimal dosing of VEN 200mg (VEN200) or VEN 400mg (VEN400)+AZA+GILT in pts with ND FLT3^mut+ AML ineligible for intensive induction (≥75 years old, or younger with comorbidities that preclude intensive chemotherapy). In phase 1, VEN+AZA+GILT showed robust responses and favorable survival outcomes, with a low incidence of dose-limiting toxicities and a safety profile consistent with AZA+VEN. VEN400 was selected as the optimized dose based on phase 1 results. Here, we report phase 2 results which include pts who received the optimized dose in phase 1 and newly enrolled patients in phase 2.

Methods: Pts received VEN400 once daily (qd; from days 1–28), with AZA (75mg/m² qd from days 1–7) and GILT (80mg qd from days 1–28), in up to 28 dosing days per cycle. Bone marrow (BM) testing was performed on cycle 1 day 14 to determine VEN and GILT duration. VEN and GILT were interrupted after day 14 in patients who achieved BM remission (<5% blasts) and/or a hypocellular BM (<5% cellularity). VEN+AZA+GILT exposure duration was further adjusted based on count recovery in subsequent cycles. Efficacy and safety analysis sets included all pts who received ≥1 dose of study treatment. Primary phase 2 endpoint was complete remission (CR) rate per FDA criteria. Hematology values within 14 days from BM sampling could be used to determine the response. CR rate was also calculated per ELN2017 criteria (determined using hematology values from BM sampling date until start of subsequent cycle). Secondary endpoints included composite CR (CRc) rate, duration of response, OS, hematopoietic stem cell transplantation (HSCT) rate, measurable residual disease status (MRD; centrally assessed by a FLT3-internal tandem duplication [ITD] next-generation sequencing [NGS] assay with a lower limit of 5 x 10^-5 and a lower limit of blank of 1 x 10^-6), and safety.

Results: In total, 54 pts received VEN400 across phases 1 (n=24) and 2 (n=30). Median (range) age was 74.0 (59.0–88.0) years, 55.6% (30/54) were male, 87.0% (47/54) had FLT3-ITD, and 13.0% (7/54) had FLT3-tyrosine kinase domain mutations alone. Median (range) number of cycles for VEN, AZA, and GILT was 3 (1–21) cycles each. Median (range) duration of cycles 1, 2 and 3 were 45 (34–134), 49 (28–129), and 42 (28–112) days, respectively.

As of May 29, 2026, median follow-up was 15.2 (range: 9.4–21.7) months. CR rate per FDA criteria was 51.9% (28/54; 95% CI: 40.3–68.9), and the median duration was not estimable (NE; 95% CI: 8.4–NE). CRc rate was 75.9% (41/54; 95% CI: 66.9–90.2) with a median duration of 20.4 (95% CI: 8.4–NE) months. CR and CRc rates per ELN2017 criteria were 64.8% (35/54; 95% CI: 55.1–80.9) and 81.5% (44/54; 95% CI: 73.7–94.3), respectively. Median OS was 26.4 (95% CI: 17.0–NE) months and estimated OS rates at 12, 18 and 24 months were 71.1% (95% CI: 55.6–82.0), 66.9% (95% CI: 49.9–79.2), and 61.3% (95% CI: 42.1–75.8), respectively. For phase 2 pts, 18- and 24-month OS rates were NE.

HSCT rate was 31.5% (17/54; 95% CI: 19.5–45.6) and median time to HSCT was 5.5 (range: 2.8–8.7) months. Among pts with CRc with evaluable MRD data, 54.3% (19/35) achieved FLT3 NGS MRD <10^-5 at any post-baseline visit, including 18/35 pts (51.4%) with undetectable MRD (<10^-6).

Grade ≥3 TEAEs occurred in 94.4% (51/54) of pts; the most frequent grade ≥3 TEAE was decreased neutrophil count (26/54; 48.1%). The most common non-hematologic grade ≥3 TEAEs were hypertension (7/54; 13.0%) and pneumonia (6/54; 11.1%). 30-day and 60-day mortality rates were 3.7% (2/54) and 7.4% (4/54), respectively.

Conclusions: VEN+AZA+GILT demonstrated robust response rates and impressive OS to date in pts with FTL3^mut+ AML ineligible for intensive induction chemotherapy in this multicenter phase 2 study. Results were consistent with those previously reported in a single-center study and phase 1 cohort. With optimized dosing (including dosing duration adjustments), the safety profile of VEN+AZA+GILT, including myelosuppression, was manageable. Extended follow-up is ongoing to evaluate CR duration and OS.