FLT3 INHIBITOR FOR AML

Targeted therapy with a single agent has improved survival in comparison with standard-of-care chemotherapy in a subgroup of patients with acute myeloid leukemia (AML).

The drug, quizartinib (under development by Daiichi Sankyo), is a highly potent and selective fms-like tyrosine kinase 3 (FLT3) inhibitor that has shown survival benefit in patients with relapsed/refractory (R/R) AML in whom there was FLT3-internal tandem duplication (FLT3-ITD).

FLT3-ITD mutations are present in about 30% of AML patients. Typically, for patients with the mutation, response to salvage therapy is lower and overall survival is shorter. There are currently no approved targeted therapies for the mutation, underscoring the need for an effective therapy.

"This is the first study to show that a single-agent targeted therapy in general, and an FLT3 in particular, has produced a survival benefit compared to standard chemotherapy," first author Jorge E. Cortes, MD, deputy chair and professor of medicine in the Department of Leukemia at the MD Anderson Cancer Center, in Houston, Texas, told Medscape Medical News.

"More impressively, this is in a setting of refractory and/or relapsed patients," he said.

The late-breaking findings from the phase 3 QuANTUM-R trial were presented here at the European Hematology Association (EHA) 2018 Congress.

In the multicenter trial, 367 patients with an FLT3-ITD allelic burden of at least 3% were randomly assigned in a 2:1 ratio to receive treatment either with once-daily single-agent oral quizartinib (n = 245; 60 mg, with a 30-mg lead-in of 15 days) or standard salvage chemotherapy (n = 122).

The chemotherapy used was selected on the basis of investigators' choice from among the following: either low-dose cytarabine (n = 29); or mitoxantrone, etoposide, and intermediate-dose cytarabine (n = 40); or fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin (n = 53).

The study achieved its primary endpoint, with a median overall survival of 6.2 months with quizartinib compared to 4.7 months for salvage chemotherapy (hazard ratio, 0.76; 95% confidence interval, 0.58 - 0.98; P = .0177).

"At a median follow-up of almost 24 months, there is a 24% lower probability of dying among patients receiving quizartinib," Cortes said.

"At 1 year, 27% of patients treated with quizartinib are alive, compared to 20% treated with standard chemotherapy," he said.

For patients in the quizartinib arm, the median drug exposure was four cycles (range, 1 - 43 cycles) for a median of 97 days. For patients in the salvage chemotherapy arm, the median was one cycle.

The median age was 55 years for patients in the quizartinib arm (range, 19 to 81 years) and 57.5 years (range, 18 to 78) for patients in the salvage chemotherapy arm. For more than a third of patients in both groups, the FLT3-ITD allelic ratio was greater than 50%.

Disease was refractory among 80 patients (32.7%) in the quizartinib group and 41 patients (33.6%) in the salvage chemotherapy group. For patients in the quizartinib group, 165 (67.3%) experienced relapse after a first complete remission of less than 6 months; for patients in the salvage chemotherapy group, 81 (66.4%) experienced such relapse.

In the quizartinib group, 25% of patients underwent prior allogeneic hematopoietic stem cell transplant (HSCT) during the study; in the salvage therapy group, 23% underwent HSCT. Those who responded to therapy were allowed to receive HSCT, and those in the quizartinib arm could again receive the drug after HSCT.

Exploratory endpoints of the data demonstrated a composite complete remission rate of 48% in quizartinib-treated patients vs 26% with salvage chemotherapy. Incomplete hematologic recovery occurred in 40% of quizartinib patients, compared to 26% of patients who received salvage therapy.

A partial response occurred in 21% of quizartinib patients vs 3% in the control arm, for an overall response rate of 69% with quizartinib vs 30% with salvage chemotherapy.

The median duration of remission achieved in the quizartinib group was 12 weeks, compared to 5 weeks in the salvage chemotherapy arm. Of patients in the quizartinib arm, 32% went on to receive HSCT following quizartinib therapy; only 12% went on to receive HSCT after salvage therapy.

In an intent-to-treat analysis, a secondary endpoint was event-free survival. For patients who received quizartinib, median event-free survival was 6 weeks, compared to 3.7 weeks for the patients who received salvage chemotherapy.

There were no significant differences between the two groups in treatment-emergent adverse events. Hematologic toxicities (ie, thrombocytopenia, anemia, neutropenia, febrile neutropenia, and leukopenia) were similar between the two arms.

Rates of QT prolongation, which was a limiting toxicity in a phase 1 study, were higher in the quizartinib arm (27% vs 2%); however, Cortes noted that only 4% of cases in the quizartinib arm were of grade 3 or 4.

"Even through QT prolongation was more common in the quizartnib arm, it was of little consequence to patients," Cortes said.

The new findings, combined with data from previous studies, support the safety and efficacy of quizartinib in R/R AML with FLT3 mutation, Cortes said.

"The results remain consistent and show a very high rate of composite complete remission of nearly 50% across a variety of studies and with an overall response rate of about 70% across these studies, with a high number of patients going to transplant," he said.

"The safety of the drug has remained constant among the 1600 patients that have been treated with quizartinib in a variety of studies, with the frequency of grade 3 QTcF [corrected QT interval by Fredericia] prolongation being very low," he said.

Cortes noted that ongoing studies with quizartinib are investigating quizartinib in combination with chemotherapy compared to chemotherapy alone in the frontline setting, as well as quizartinib in combination with milademetan (DS-3032), an investigational drug.

"Milademetan is an MDM2 inhibitor, and there is preclinical work that suggests synergy between the two agents," he said. "This is the basis for a study that is being initiated, initially phase 1.... We feel excited and very hopeful about this combination."

Benefits From a Single Agent

Approached for comments about the new study, Kimmo Porrka, MD, PhD, agreed that the study is important in that it shows benefits of a single agent in targeting FLT3. However, combination therapies may still be preferred in some settings.

"To me, the most important finding in the study was that targeted, single-agent therapy is equally effective as, and even slightly better than, conventional chemotherapy," said Porrka, who is professor of clinical hematology at the University of Helsinki and head of the Department of Hematology at the Helsinki University Hospital Comprehensive Cancer Center, in FinlandDisease was refractory among 80 patients (32.7%) in the quizartinib group and 41 patients (33.6%) in the salvage chemotherapy group. For patients in the quizartinib group, 165 (67.3%) experienced relapse after a first complete remission of less than 6 months; for patients in the salvage chemotherapy group, 81 (66.4%) experienced such relapse.

In the quizartinib group, 25% of patients underwent prior allogeneic hematopoietic stem cell transplant (HSCT) during the study; in the salvage therapy group, 23% underwent HSCT. Those who responded to therapy were allowed to receive HSCT, and those in the quizartinib arm could again receive the drug after HSCT.

Exploratory endpoints of the data demonstrated a composite complete remission rate of 48% in quizartinib-treated patients vs 26% with salvage chemotherapy. Incomplete hematologic recovery occurred in 40% of quizartinib patients, compared to 26% of patients who received salvage therapy.

A partial response occurred in 21% of quizartinib patients vs 3% in the control arm, for an overall response rate of 69% with quizartinib vs 30% with salvage chemotherapy.

The median duration of remission achieved in the quizartinib group was 12 weeks, compared to 5 weeks in the salvage chemotherapy arm. Of patients in the quizartinib arm, 32% went on to receive HSCT following quizartinib therapy; only 12% went on to receive HSCT after salvage therapy.

In an intent-to-treat analysis, a secondary endpoint was event-free survival. For patients who received quizartinib, median event-free survival was 6 weeks, compared to 3.7 weeks for the patients who received salvage chemotherapy.

There were no significant differences between the two groups in treatment-emergent adverse events. Hematologic toxicities (ie, thrombocytopenia, anemia, neutropenia, febrile neutropenia, and leukopenia) were similar between the two arms.

Rates of QT prolongation, which was a limiting toxicity in a phase 1 study, were higher in the quizartinib arm (27% vs 2%); however, Cortes noted that only 4% of cases in the quizartinib arm were of grade 3 or 4.

"Even through QT prolongation was more common in the quizartnib arm, it was of little consequence to patients," Cortes said.

The new findings, combined with data from previous studies, support the safety and efficacy of quizartinib in R/R AML with FLT3 mutation, Cortes said.

"The results remain consistent and show a very high rate of composite complete remission of nearly 50% across a variety of studies and with an overall response rate of about 70% across these studies, with a high number of patients going to transplant," he said.

"The safety of the drug has remained constant among the 1600 patients that have been treated with quizartinib in a variety of studies, with the frequency of grade 3 QTcF [corrected QT interval by Fredericia] prolongation being very low," he said.

Cortes noted that ongoing studies with quizartinib are investigating quizartinib in combination with chemotherapy compared to chemotherapy alone in the frontline setting, as well as quizartinib in combination with milademetan (DS-3032), an investigational drug.

"Milademetan is an MDM2 inhibitor, and there is preclinical work that suggests synergy between the two agents," he said. "This is the basis for a study that is being initiated, initially phase 1.... We feel excited and very hopeful about this combination."

Benefits From a Single Agent

Approached for comments about the new study, Kimmo Porrka, MD, PhD, agreed that the study is important in that it shows benefits of a single agent in targeting FLT3. However, combination therapies may still be preferred in some settings.

"To me, the most important finding in the study was that targeted, single-agent therapy is equally effective as, and even slightly better than, conventional chemotherapy," said Porrka, who is professor of clinical hematology at the University of Helsinki and head of the Department of Hematology at the Helsinki University Hospital Comprehensive Cancer Center, in Finland.

"It also verifies FLT3-ITD as a clinically useful target of therapy," he said, adding that "there are varied opinions on this.

"However, in clinical practice, I would assume that many doctors may opt for combination therapy, especially with hypomethylating agents or low-dose cytosine arabinoside, and for younger patients, even with high-dose chemotherapy," he said.

In addition, although as many as 35% to 40% of AML patients can currently be treated with a targeted therapy, such as FLT3 or IDH1/2 inhibitors, more work is necessary to help target the remaining 60% or more patients, Porkka said.

"Genomics-based stratification will in time come for all AML patients, but that will take 5 to 15 years," Porrka said." In the meantime, functional assays may turn out to be very valuable.

"For some of the new very promising AML drugs, such as BCL2 inhibitors, there are no reliable genomic predictors thus far, but ex vivo drug testing can most likely identify responders quickly," he said.

"Finding synergistic, or, more importantly, not antagonistic combination regimens will take time and many trials," Porrka said.

An overriding caveat in the discussion is cost, which, when combined with immunotherapy and allogeneic HSCT, can exceed $1 million per year per patient, Porrka noted.

"Thus, open discussion of these issues with pharma, regulators, and caregivers is mandatory for enabling precision medicine to become a reality," he said.

The study was funded by Daiichi Sankyo. Dr Cortes has consulting and/or advisory relationships with Astellas Pharma, Daiichi Sankyo, Novartis, and Pfizer. Dr Porrka has disclosed no relevant financial relationships.

European Hematology Association (EHA) 2018 Congress. Abstract LB2600, presented June 16, 2018.

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