Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation

Abstract

673 FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that is active against both ITD mutant and wild type FLT3, and has shown promising activity in a Phase 1 study of patients (pts) with AML. This Phase 2 study was conducted to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD positive (+) and FLT3-ITD negative (−) pts with a total of 333 pts included in two cohorts. Cohort 2 included pts aged ≥ 18 yrs with AML relapsed or refractory to 2nd-line, salvage chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT). A total of 137 pts were included in this cohort and constitute the basis for this analysis. Data through 31 January 2012 from 137 pts in this cohort were analyzed. These pts included 99 (72%) who were FLT3-ITD(+) and 38 (28%) who were FLT3-ITD(-). A total of 50% of the 99 FLT3-ITD(+) pts and 61% of the 38 FLT3-ITD(-) pts were male. The FLT3-ITD(+) pts had a median age of 50 yrs (range 19 to 77 yrs), and the FLT3-ITD(-) pts had a median age of 55 yrs (range 30 to 73 yrs). Pts received quizartinib at a starting dose of 90 mg/day (females) or 135 mg/day (males), and were treated continuously during 28-day cycles. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). For FLT3-ITD(+) pts the CRc rate was 44% (4% CR, 0 CRp, and 40% CRi), with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. Of those refractory to their last AML therapy, 47% achieved a CRc with quizartinib. For FLT3-ITD(-) pts the CRc rate was 34% (3% CR, 3% CRp, and 29% CRi), with a median duration of response of 5.0 weeks and median overall survival of 25.6 weeks. Of those refractory to their last AML therapy, 31% achieved a CRc with quizartinib. Efficacy Results in AML Pts Relapsed/Refractory to 2nd-line Therapy or HSCT FLT3-ITD(+) N = 99 FLT3-ITD(−) N = 38 Cumulative CRc, n (%) 44 (44) 13 (34) CRc + PR, n (%) 67 (68) 18 (47) Prior nonresponders achieving CRc to quizartinib, n (%) 27/57 (47) 9/29 (31) Subjects discontinuing quizartinib because of HSCT, n (%) 34 (34) 13 (34) Median CRc duration, weeks 11.3 5.0 Median overall survival, weeks 23.1 25.6 CRc = composite complete remission; HSCT = hematopoietic stem cell transplantation; NR = not reached; PR = partial remission. The most common (≥20%) treatment-related adverse events (AEs) were nausea (38%), anemia (29%), QT interval prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). The most common (≥10%) Grade 3 or 4 treatment-related AEs were anemia (26%), febrile neutropenia (25%), thrombocytopenia (15%), neutropenia (12%), and QT interval prolongation (10%). An AE of QT interval prolongation occurred in 36/137 pts (26%) and was Grade 3 in 13 pts (10%). No Grade 4 QT interval prolongation occurred. A total of 14 pts (10%) experienced a treatment-related AE resulting in discontinuation of quizartinib. The final data from this Phase 2 study confirm the high degree of activity of quizartinib monotherapy in FLT3-ITD(+) and FLT3-ITD(-) AML pts relapsed/refractory to 2nd-line treatment or HSCT. These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in FLT3-ITD(+) relapsed/refractory AML. Of clinical significance in this heavily pretreated population, approximately 1/3 of pts were successfully bridged to potentially curative HSCT, and many pts who were refractory to prior therapy responded to quizartinib. Safety findings were manageable, and were primarily myelosuppression and QT prolongation that was mitigated with dose modifications. Further Phase 1 and 2 studies with lower doses of quizartinib as monotherapy and in combination with other agents in FLT3-ITD(+) and FLT3-ITD(-) AML are being planned/ongoing. Disclosures: Levis: Ambit Biosciences: Consultancy. Perl:Ambit Biosciences: Consultancy. Dombret:Celgene: Consultancy. Döhner:Celgene, Amgen, Lilly, Genzyme: Consultancy. Steffen:Novartis: Travel/accommodations/meeting expenses Other. Rousselot:Ambit Biosciences: Consultancy. Martinelli:BMS, Novartis; Pfizer, Roche: Consultancy. Estey:Ambit Biosciences: Consultancy. Burnett:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Leo:Ambit Biosciences: Employment. Cortes:Novartis: Consultancy.

Treatment of relapsed/refractory acute myeloid leukaemia in adults

“…A phase 2 study of 34 relapsed/refractory FLT3-mutated patients (median age 61 years) used crenolanib and achieved an ORR of 47% (CRi 12%), with a median event-free survival (EFS) of 8 weeks (Randhawa et al, 2014). Quizartinib (AC220) monotherapy in 90 relapsed/refractory FLT3-ITD patients resulted in an ORR of 74% (CR/ CRi 53%) (Levis et al, 2012). A recently completed, but not reported, randomized study is seeking the optimal dose of quizartinib in FLT3-mutated relapsed/refractory patients (NCT01565668).…”

The role of FLT3 inhibitors in the treatment of FLT3‐mutated acute myeloid leukemia

“…57,58 The second group consisted of younger patients (n=137), and once again demonstrated an impressive CRc rate of 44% among FLT3/ITD participants, with more than a third of patients successfully proceeding to HSCT after clinical response. 59 Quizartinib has also been studied in combination with conventional chemotherapy for newly diagnosed AML, and data from a British study reported a CR rate of 79% among 42 evaluable patients. 60 There are now multiple ongoing trials of quizartinib as monotherapy and in combination with conventional regimens.…”

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance‐conferring FLT3/tyrosine kinase domain/F691 mutation

“…26,27 Over the last decade, multiple inhibitors of FLT3-activating mutations have emerged and have been studied in clinical trials with varying degrees of selectivity for the FLT3 target. [4][5][6]8 Midostaurin, a less specific FLT3 inhibitor, was recently shown to improve survival when it was combined with conventional chemotherapy for newly diagnosed FLT3-mutant patients, and it is now approved for use in this setting. 8 Potent and selective FLT3 inhibitors such as quizartinib, crenolanib, and gilteritinib all lead to impressive responses as monotherapy in patients with FLT3 mutations.…”

“…In the last few years, a variety of targeted therapies for AML, including agents inhibiting FMS-like tyrosine kinase 3 (FLT3) [4][5][6][7][8] and isocitrate dehydrogenase enzymes, 9,10 have emerged with remarkable therapeutic promise. FLT3-activating mutations, consisting of internal tandem duplication (ITD) and tyrosine kinase domain (TKD) variants, affect approximately a third of AML patients and are traditionally associated with proliferative disease, frequent relapses, and poor outcomes.…”