An open-label, randomized phase III study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation-positive acute myeloid leukemia.

Abstract

TPS7067 Background: FLT3 mutations occur in 30% of patients with acute myeloid leukemia (AML), most often as internal tandem duplications (FLT3-ITD) or point mutations at codon D835. FLT3-ITDs are associated with high relapse rates, short remission duration, and poor overall survival (OS); FLT3-D835 can confer resistance to other tyrosine kinase inhibitors (TKIs). Gilteritinib is a highly selective FLT3/AXL TKI with activity against both FLT3-ITD and FLT3-D835 mutations. A recent phase 1/2 study of gilteritinib (20–450 mg/d) in relapsed/refractory (R/R) AML showed favorable tolerability at doses ≤300 mg/d, and consistent, potent FLT3 inhibition at doses ≥80 mg/d. Patients with FLT3 mutation-positive (FLT3mut+) AML receiving doses ≥80 mg/d had an ORR of 52% (CR/CRp/CRi = 41%, PR = 11%) and longer OS than historic experience in R/R AML with combination cytotoxic chemotherapy or other FLT3 TKIs as monotherapy. Given these results, we initiated a phase 3 trial of once-daily (QD) 120 mg gilteritinib. Methods: This randomized, open-label phase 3 study (NCT02421939) will enroll 369 adults with FLT3mut+ AML in first relapse or refractory to front-line therapy. Patients who have not previously received FLT3 inhibitors, except sorafenib and midostaurin, will be randomized 2:1 to either 120 mg gilteritinib QD or the investigator’s pre-randomization specified salvage chemotherapy choice (LoDAC, Aza, MEC, FLAG-IDA), and stratified by prior chemotherapy response and salvage chemotherapy intensity. Gilteritinib or low-intensity chemotherapy cohorts will receive continuous 28-day treatment cycles until a discontinuation event occurs; the high-intensity chemotherapy cohort will receive ≤2 treatment cycles before response measurement. Primary objective is OS; key secondary objectives are event-free survival and CR rate. Other secondary objectives: leukemia-free survival, remission duration, composite CR rate, subsequent transplantation rate, patient-reported fatigue, and safety. A formal interim analysis is planned when ~50% of planned death events have occurred. Study enrollment began on Oct 23, 2015; as of Jan 20, 2017, 167 subjects have been randomized. Clinical trial information: NCT02421939.

New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise

“…Besides, all transretinoic acid (ATRA) for the treatment of retinoic-acid receptor rearranged acute promyelocytic leukemia, midostaurin was the first drug approved in a genetic-specific, non-acute promyelocytic leukemia manner. Recently, additional mutation-specific targeted agents followed midostaurin in the daily clinical use including another FLT3 inhibitor gilteritinib [6], as well as compounds targeting mutant isocitrate dehydrogenase (IDH), enasidenib and ivosidenib [7,8]. In addition to these mutation-specific approvals, two other targeted novel agents have been FDA approved, venetoclax and glasdegib, disrupting anti-apoptotic or cell maintenance pathways without damaging DNA, respectively [9,10,11].…”

The Time Has Come for Targeted Therapies for AML: Lights and Shadows

“…Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, p = 0.0830) [20]. Based on the interim data [21], in November 2018 the FDA approved gilteritinib for the secondary treatment of AML in adults with a FLT3 mutation.…”

Target Therapy in Acute Myeloid Leukemia

“…369 adults with FLT3 mutated AML in first relapse or refractory to front-line therapy were enrolled. The 21% of patients who achieved had a median time to response of 3.6 months [54].…”