Flotetuzumab As Salvage Therapy for Primary Induction Failure and Early Relapse Acute Myeloid Leukemia

Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 <6 months). While these primary induction failure (PIF) and early relapse (ER) pts are treated collectively with late relapse (LR) pts (CR1 >6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response¹. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts.

Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 < 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up ('priming') lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death.

Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR, <5% bone marrow blast) was 42.1% (16/38; 7 CR, 4 CRh, 4 CRi, and 1 MLFS), with 68.8% (11/16) subsequently undergoing stem cell transplant. PIF pts showed a CRR of 45.8% (11/24; 5 CR, 3 CRh, and 3 CRi); CRR for ER pts was 35.7% (5/14; 2 CR, 1 CRh, 1CRi and 1 MLFS). Median time to first response was 1 cycle (range: 1-3 cycles). Sixty-nine percent (11/16) of responders normalized PB counts while on FLZ. Transfusion independence was achieved in 35.7% (10/28) of pts for whom data were available. Preliminary, median duration of response (mDOR) was 3.1 months (range 0.4-30.0 months) with many pts (29%, 11/38) still ongoing. With a median follow up time of 10.8 months, median overall survival (mOS) was 4.5 months (95% confidence interval [CI]: 2.9, 8.8). In pts that responded (CRR) the mOS was 7.7 months (95% confidence interval [CI]: 2.9, NA). Overall 6 and 12-month survival rates are 41 % (22.1%, 59.0%) and 24 % (6.1%, 42.5%), respectively.

Conclusion: FLZ demonstrated encouraging activity in pts with PIF/ER AML, a population with poor prognosis and high unmet medical need, with 42.1% achieving CRR and over half of those receiving a stem cell transplant. Treatment is tolerable with a minimum 8 day inpatient treatment. The study is currently enrolling patients [NCT02152956]

¹ Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Trans Med 2020.

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