Antileukemic Activity and Tolerability of ASP2215 80mg and Greater in FLT3 Mutation-Positive Subjects with Relapsed or Refractory Acute Myeloid Leukemia: Results from a Phase 1/2, Open-Label, Dose-Escalation/Dose-Response Study

Introduction: ASP2215 is a highly selective inhibitor of AXL and FMS-like tyrosine kinase-3 (FLT3) receptors. ASP2215 is active against both FLT3 internal tandem duplication [ITD] and D835 mutations. Prior analyses of an open-label, dose-escalation/dose-expansion study in subjects with relapsed or refractory acute myeloid leukemia (R/R AML) show ASP2215 was well tolerated from 20–300 mg and associated with antileukemic activity in FLT3 mutation-positive (FLT3+) patients at ≥80 mg with minimal activity observed in wild-type FLT3 subjects. Here we describe the tolerability and potent activity of ASP2215 in a large cohort of FLT3+ patients. 

Methods: Patients (≥18 years) with R/R AML were assigned to treatment in dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. Although FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 FLT3+ subjects; 120 mg and 200 mg dose levels were further expanded with ≥40 FLT3+ subjects. Tolerability was assessed by adverse event (AE) monitoring. Response assessment was based on modified Cheson criteria and duration of response and overall survival were calculated using Kaplan–Meier estimates.  

Results: As of June 19, 2015, 215 patients with a median age of 61 yr (range: 21–90) had received ≥1 dose of ASP2215 (safety population). Across the safety population, 65% of subjects received ≥2 prior lines of AML therapy, 29% had a hematopoietic stem cell transplant prior to ASP2215 treatment, and 23% had prior tyrosine kinase inhibitor (TKI) treatment. Approximately 73% of patients were FLT3+, of which 137 had FLT3-ITD mutation, 7 were FLT3-D835+, and 9 had both FLT3-ITD and D835. Treatment-related AEs  of all Grades, reported in ≥10% of the safety population were diarrhea (16%), fatigue (13%), and increased AST (11%); <2% of subjects reported a Grade ≥3 QTc prolongation. Activity was assessed in the 133 FLT3+ patients treated with ASP2215 ≥80 mg. Overall response rate (ORR; composite complete [CRc] plus partial remission [PR]) for all FLT3+ subjects was 55% (Table). Median overall survival for FLT3+ patients receiving ASP2215 ≥80 mg was ~29 weeks (95% CI: 22–32) and was similar for patients who achieved CRc or PR (Figure). Treatment with ≥80 mg ASP2215 was associated with an ORR of 60% in FLT3-ITD subjects; ORR for the other FLT3 populations was 29% (Table). No difference was observed in median ORR of ASP2215 (≥80 mg) in TKI-naïve patients (55%) and patients with prior TKI treatment (55%).

Conclusions: ASP2215, a novel AXL/FLT3 TKI, was well tolerated in subjects with R/R AML and demonstrated a strong antileukemic activity in FLT3+ subjects. Importantly, the ASP2215 response rate in these FLT3+ patients was independent of prior TKI treatment. Even in this heavily pretreated population, the survival of R/R FLT3+ AML patients who received ≥80 mg ASP2215 was longer than prior reports of cytotoxic chemotherapy or other FLT3 inhibitors.

Table. ASP2215 Response Assessment

	80 mg	120 mg	200 mg	300 mg	450 mg	Total
All FLT3+ Subjects
Population, n	12	52	57	10	2	133
CRc, n (%)	5 (42)	25 (48)	28 (49)	3 (30)	0	61 (46)
PR, n (%)	3 (25)	3 (6)	3 (5)	3 (30)	0	12 (9)
ORR, n (%)	8 (67)	28 (54)	31 (54)	6 (60)	0	73 (55)
Subjects with FLT3-ITD Only
Population, n	10	46	50	8	0	114
CRc, n (%)	4 (40)	23 (50)	26 (52)	3 (38)	0	56 (49)
PR, n (%)	3 (30)	3 (7)	3 (6)	3 (38)	0	12 (11)
ORR, n (%)	7 (70)	26 (57)	29 (58)	6 (75)	0	68 (60)
Subjects with FLT3-D835 and Subjects with FLT3-ITD and FLT3-D835
Population, n	2	5	5	1	1	14
CRc, n (%)	1 (50)	1 (20)	2 (40)	0	0	4 (29)
PR, n (%)	0	0	0	0	0	0
ORR, n (%)	1 (50)	1 (20)	2 (40)	0	0	4 (29)
CRc, composite complete remission (complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery); ORR, overall response rate; PR, partial response.

 

Figure: Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects 

NR, no response.  Subjects with non-evaluable data (N=8) were not included in this curve.