Single-agent therapy with quizartinib slightly but significantly prolonged survival – compared with salvage chemotherapy – for patients with relapsed/refractory acute myeloid leukemia (AML) bearing the FLT3-ITD mutation, results of the phase 3 randomized QuANTUM-R trial showed.
Median overall survival (OS), the trial’s primary endpoint, was 6.2 months for 245 patients randomized to quizartinib, compared with 4.7 months for 122 patients assigned to salvage chemotherapy, a difference that translated into a hazard ratio (HR) for death of 0.76 (P = .0177), reported, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This study is the first study that demonstrates in a randomized fashion an overall survival benefit in the salvage setting for patients with FLT-3 mutated refractory or relapsed AML,” he said at the annual meeting of the American Society of Hematology. “I will also add that these results you saw here are very consistent with all the trials previously with quizartinib with more than 1,000 patients treated.”
Quizartinib, a tyrosine kinase inhibitor (TKI), has previously been shown to be associated with higher response rates among patients with AML bearing the FLT3-ITD mutation than in patients with AML without the deleterious mutation.
Investigators in theenrolled 367 adults with FTL3-ITD mutated AML that was refractory to the most recent line of therapy or had relapsed within 6 months of first remission, with or without hematopoietic stem cell transplant (HSCT).
The patients had all received at least one cycle of standard-dose induction therapy containing an anthracycline or mitoxantrone, and had a 3% or greater FLT3-ITD allelic ratio in their AML cells.
The patients were randomly assigned on a 2:1 basis to receive either quizartinib or salvage chemotherapy. Quizartinib was dosed 30 mg per day for 15 days, which could be titrated upward to 60 mg daily if the corrected QT interval by Fredericia (QTcF) was 450 ms or less on day 16.
Chemotherapy was the investigator’s choice of one of three specified regimens: either low-dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA). Up to two cycles of MEC or FLAG-IDA were permitted; quizartinib and LoDAC were given until lack of benefit, unacceptable toxicity, or until the patient went on to HSCT.
The analysis was by intention-to-treat. In the quizartinib arm, 241 of the 245 randomized patients (98.4%) received treatment. In the chemotherapy arm, 94 of 122 randomized patients (77%) received chemotherapy. Of this group, 22 received LoDAC, 25 received MEC, and 47 received FLAG-IDA.
The median treatment duration was 97 days in the quizartinib arm versus 28 days (one cycle) in the chemotherapy arm.
The 1-year overall survival rate was 27% for patients assigned to quizartinib, compared with 20% for patients assigned to chemotherapy.
An analysis of OS by subgroup indicated a trend or significant benefit for quizartinib in all categories, including age over or under 65 years, sex, low or high-intensity chemotherapy, response to prior therapy, FLT3 variant allele frequency, prior allogenic HSCT, and AML risk score.
For the secondary endpoint of event-free survival in the ITT population, there was no significant difference between the study arms. In a per-protocol analysis, however, median event-free survival was better with quizartinib, at 1.4 months versus 0.0 months (P = .006).
In all, 32% of patients assigned to quizartinib went on to HSCT, compared with 12% of patients randomized to chemotherapy.
Rates of treatment-emergent adverse events (TEAEs) were similar between the study arms, despite higher total drug exposure in patients randomized to quizartinib. The most frequent grade 3 or greater TEAEs in each arm were infections and cytopenia-related events.
Two patients discontinued quizartinib due to QTcF prolongation. Grade 3 QTcF (greater than 500 ms) occurred in 3% of patients treated with quizartinib, but no grade 4 cases were seen.
The adverse event profile for patients who resumed quizartinib following HSCT was similar to that of patients who received the drug pretransplant.
The combination of standard chemotherapy, with or without quizartinib, is currently being explored in the phase 3, Dr. Cortes said.
Daiichi Sankyo sponsored the trial. Dr. Cortes reported financial relationships with Daiichi Sankyo, Pfizer, Arog, Astellas Pharma, and Novartis.
SOURCE: Cortes JE et al. ASH 2018, Abstract 563.