ATLANTA—Treatment with the new tyrosine kinase inhibitor quizartinib produced high response rates not previously seen in a patient population very difficult to treat—those with relapsed/refractory acute myeloid leukemia (AML) after second-line chemotherapy or hematopoietic stem cell transplantation.
As reported here at the American Society of Hematology Annual Meeting, final results of the open-label Phase II trial of oral quizartinib in patients with both FLT3-ITD-positive and -negative AML showed a 46 percent composite complete response rate for patients with FLT3-positive disease, and 32 percent for patients with FLT3-negative disease (Abstract 673).
First author Mark J. Levis, MD, PhD, Associate Professor of Oncology, Pharmacology, and Medicine at Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Medicine, explained that about 25 to 33 percent of patients with AML have a mutation in the FLT3-ITD (internal tandem duplications) enzyme. FLT3 normally occurs in cells within the bone marrow and is associated with cell regeneration. FLT3 mutation is associated with high blast counts, increased relapse rate, more rapid relapse, and reduced overall survival.
He said that he and his co-researchers expect that treatment with quizartinib will increase the number of double-refractory patients who remain in remission long enough to then qualify for stem cell transplant.
“We've been trying to inhibit this enzyme for the last 10 years,” he said, naming the tyrosine kinase inhibitors lestaurtinib and midostaurin as candidate compounds presented at previous ASH Annual Meetings. Those, however, inhibited multiple other kinases and caused serious side effects.
Levis explained that quizartinib (formerly called ACC220 and made by Ambit Biosciences) is the first drug designed as a FLT3 inhibitor. The drug is extremely selective and less protein bound, making it 20 to 50 times more potent in vivo than any other FLT3 inhibitor, he said.
“Importantly, its half life in humans is quite long, 24-plus hours, which is a tremendous advantage in a drug like this. You've got to suppress the target for a prolonged period of time to produce a cytotoxic effect.”
The study had two cohorts:
* Cohort 1 included patients age 60 or over with the FLT3-ITD mutation who had not had a remission with standard chemotherapy, or who had recently relapsed for the first time.
* Cohort 2 included patients over age 18 with the FLT3-ITD mutation who presented with relapsed or refractory AML and had received salvage chemotherapy after not responding to prior treatment, or who had relapsed after a stem cell transplant.
Most patients in this study had the FLT3-ITD mutation, but a small number in each cohort lacked the mutation.
The ASH report was the results for Cohort 2, based on an analysis of 138 patients (100 with the mutation and 38 without) who received continuous treatment with quizartinib at a fixed dose during 28-day cycles (135 mg/day for males, 90 mg/day for females).
After treatment with single-agent quizartinib, the composite complete remission (CRc) rate for patients with disease mutation was 46 percent, with a median duration of 12.1 weeks and median overall survival of 22.9 weeks, Levis reported. (CRc included complete remission [CR], CR with incomplete platelet recovery [CRp], and CR with incomplete hematologic recovery [Cri].)
The CRc rate in patients without the mutation was 32 percent, with a median duration of response of 7.0 weeks and median overall survival of 25.6 weeks.
Among patients in both cohorts who did not respond to their last prior AML therapy, 79 percent of those with the FLT3 mutation and 48 percent of those without the mutation achieved a partial response or better.
Common toxicities (seen in more than 20% of patients) were QT prolongation (26%), nausea (38%), vomiting (26%), anemia (29%), fever (25%), diarrhea (20%), and fatigue (20%). Myelosuppression, possibly related to KIT inhibition, was manageable, Levis said.
Bridged to Stem Cell Transplantation
In both cohorts, 37 percent of patients were successfully bridged to have a potentially curative allogeneic transplant. Patients bridged to hematopoietic stem cell transplant had an median overall survival of 33.3 weeks, vs. 17.7 weeks for those without transplant.
“Our focus for this drug is to clear the leukemia out of the bone marrow to a sufficient degree to allow a bone marrow transplant in these young patients,” he said. “Twelve patients actually had beautiful disease control, for more than five months, and more than a third of patients were taken to a potentially curative transplant with several long-term survivors.”
He noted that a randomized two-dose study (30 vs. 60 mg) is currently accruing patients, and a Phase III study is planned for later this year.
Also Active in Elderly Patients
Also reported at the meeting was a separate presentation with the data from Cohort 1, by Jorge Cortes, MD, Professor of Medicine, Deputy Chair of the Department of Leukemia, and Chief of the CML and AML Section at the University of Texas MD Anderson Cancer Center (Abstract 48). Among the 92 patients with FLT3-positive disease, the CRc rate was 54 percent, and 32 percent among the 41 patients with FLT3-negative disease.
The median CRc duration was 12.7 and 22.1 weeks, respectively; and median overall survival was 25.3 and 19.0 weeks respectively. A total of 10 percent of the older patients bridged to transplant.
ASH 2012 President Armand Keating, Professor of Medicine and Director of the Division of Hematology at the University of Toronto, said the issue with patients with AML and FLP3 mutations is that although they can be put into remission, they typically then relapse very quickly.
“Keeping them in remission long enough until they can undergo transplantation is an enormous advantage,” Keating said in a news briefing before the meeting. “Normally the disease progresses so quickly that the patient doesn't get to transplant.”
Also speaking at the news briefing, ASH 2012 Secretary Charles Abrams, MD, Associate Chief of the Hematology/Oncology Division at the University of Pennsylvania, also emphasized that these are difficult patients to treat: “What is exciting about this new compound is that it apparently can be given alone, and is safe to give to patients who have been resistant to other drugs. This gives hope to people who have had little hope before.”
New Definition of CR?
Mikkael Sekeres, MD, MPH, OT's Clinical Advisory Editor for Hematology/Oncology, noted that the composite complete response rates in this study—44 percent for FLT3+ patients and 34 percent for FLT3- patients—were almost entirely CRs with incomplete hematologic recovery.
“We need to come to some consensus over whether altering the definition of CR is appropriate in AML,” he said in his review in OT of the most important AML and MDS research at the ASH Annual Meeting (2/10/13 issue).
Asked to elaborate on the question of definitions for this article, he said that the composite CR response definition in this study included a variety of responses, ranging from a true complete response—as defined by the International Working Group for AML—to a partial response.
“The validity of these non-CR definitions, with respect to interim markers for clinically, meaningful endpoints, remains to be seen,” said Sekeres, Director of the Leukemia Program and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee at the Cleveland Clinic Taussig Cancer Institute; and Chair of the FDA Oncologic Drugs Advisory Committee.
“This type of response rate may be ‘good enough’ to transition patients to potentially curative therapy—and that will have an impact in a desperate population.” he said.
And increasing the number of patients who go on to receive a hematopoietic stem cell transplant “represents a true shift in goals of care, from palliative to potentially curative.”