Quizartinib Poised to Expand FLT3 Inhibition Options in AML

Jorge E. Cortes, MD

Quizartinib, a novel small molecule FLT3 inhibitor, is moving through the pipeline of new drugs under development for patients with FLT3-mutated acute myeloid leukemia (AML), part of a menu of targeted treatment options that is expanding as investigators learn more about the molecular heterogeneity of the disease.

FLT3 mutations are expressed in approximately 30% of patients with AML, mostly within the internal tandem duplication (ITD), making the alterations among the most common molecular aberrations identified in the malignancy. Quizartinib specifically targets AML with FLT3-ITD mutations, which are associated with early relapse and a poor prognosis.¹

In November 2018, the FDA granted a priority review designation to a new drug application (NDA) for quizartinib for adult patients with relapsed/ refractory FLT3-ITD—positive AML. In April 2019, the FDA added 3 months to the review period for quizartinib to review more data, extending the deadline for a decision on the NDA to August 25, 2019. To date, the FDA has approved 2 drugs that inhibit FLT3 and other kinases in patients with AML: midostaurin (Rydapt) and gilteritinib (Xospata).

The NDA for quizartinib is based on findings from the phase III QuANTUM-R trial (NCT02039726) that demonstrated prolonged overall survival (OS) compared with salvage chemotherapy, according to data presented at the 2018 American Society of Hematology Annual Meeting.²

At a median follow-up of 23.5 months, patients treated with quizartinib had a median OS of 6.2 months (95% CI, 5.3-7.2) compared with 4.7 months (95% CI, 4.0-5.5) for those who received salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).

The study randomized patients 2:1 to receive quizartinib (n = 245) as a monotherapy or physician’s choice of chemotherapy (n = 122). Salvage chemotherapy options were low-dose cytarabine; the combination of mitoxantrone, etoposide, and intermediate-dose cytarabine; and a regimen of fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin.

Figure. Quizartinib in Adult Patients With Relapsed/Refractory AML²

To be eligible for inclusion, patients had to be in first relapse (with duration of remission ≤6 months) or refractory after prior therapy, with or without hematopoietic stem cell transplantation. Participants had to have presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood. The primary endpoint was OS, and the secondary endpoint was event-free survival (Figure).² “The results of the QuANTUM-R trial showed an improvement in survival. The hazard ratio was 0.76, essentially meaning an approximately 24% reduction in the risk of death during the observation period of the study,” said Jorge E. Cortes, MD, in an interview with OncologyLive^®.

“This, of course, came with an improvement in the response rate for patients treated with quizartinib. We looked at the composite complete remission [CRc] and CRc with incomplete hematologic recovery,” added Cortes, the principal investigator on the QuANTUM-R trial and the deputy chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Overall, when we put them together, around 60% of patients responded in some way. This is much better than the chemotherapy arm.”

The CRc rate was 48% in those who received quizartinib compared with 27% in those who were given salvage chemotherapy; the overall response rate, comprised of CRc and partial responses, was 69% with quizartinib versus 30% with chemotherapy.

Further, the median event-free survival rate was 1.4 months (95% CI, 0.0-1.9) with quizartinib versus 0.9 months (95% CI, 0.4-1.3) with chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; P = .1071). The median time to first CRc was comparable in both groups: 4.9 weeks (range, 3.7-19.7) with quizartinib versus 4.0 weeks (range 2.0-14.9) with salvage chemotherapy. However, results showed that patients in the quizartinib arm had a median duration of CRc of 12.1 weeks (95% CI, 10.4-27.1) versus 5.0 weeks (95% CI, 3.3-12.6) for those in the salvage chemotherapy arm.

Treatment was well tolerated, with low incidence of grade 3 (4%) and no grade 4 QT prolongation. Two patients in the quizartinib arm discontinued treatment because of QT prolongation. “The concern about QT prolongation, which had been the main dose-limiting toxicity in the phase I study, is [that it is] at a very low rate and really not associated with serious arrhythmias or any other problems,” said Cortes.

Regarding other safety signals, the most common all-grade treatment-emergent adverse events in the quizartinib arm compared with the chemotherapy cohort, respectively, were sepsis or septic shock (22% vs 27%), peripheral edema (21% vs 23%), and constipation (20% vs 23%). “This was a very well-tolerated, oral, outpatient therapy that beats intensive, aggressive chemotherapy where patients would spend a lot of time in the hospital,” added Cortes.

Investigators are further evaluating the efficacy of quizartinib in the first-line setting in the ongoing QuANTUM-First trial (NCT02668653), randomizing patients with FLT3-mutant AML to the FLT3 inhibitor or placebo.

“In the long term, combination therapy will likely be...quizartinib and other drugs, but initially, it will be as a single agent in the salvage setting after resistance or relapse after initial therapy,” Cortes concluded.

References

1. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.
2. Cortes JE, Khaled SK, Martinelli G. Efficacy and safety of single-agent quizartinib (Q), a potent and selective FLT3 inhibitor (FLT3i), in patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)—mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) enrolled in the global, phase 3, randomized controlled Quantum-R Trial. Presented at: 2018 ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract 563.
3. (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive. clinicaltrials.gov/ct2/show/NCT02039726. Updated February 12, 2019. Accessed April 3, 2019.