The 23rd Congress of the European Hematology Association
STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).
In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.
There was a trend toward improved event-free survival (EFS) with quizartinib as well.
“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.
Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).
The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.
Patients and treatment
QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.
Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).
Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.
Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.
Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.
The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.
In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.
The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.
The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.
In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).
Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.
Results
The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.
The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.
The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.
The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.
The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.
Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.
Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).
Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).
Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.
“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.
He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).