Quizartinib Update Presented as FDA Weighs AML Approval

Jorge E. Cortes, MD

The overall survival (OS) benefit with quizartinib in patients with relapsed/refractory FLT3-ITD-mutated acute myeloid leukemia (AML) was observed across patient subgroups and reproduced consistently across sensitivity analyses, according to an update of the pivotal phase III QuANTUM-R study presented at the 2018 ASH Annual Meeting.

Previously reported data from the trial showed that the FLT3 inhibitor quizartinib reduced the risk of death by 24% compared with salvage chemotherapy in patients with FLT3-ITD—positive relapsed/refractory AML after first-line treatment with or without hematopoietic stem cell transplantation (HSCT).

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

This OS benefit was upheld across 3 prespecified sensitivity analyses. In the first, which censored for the effect of transplant, the median OS with quizartinib versus salvage chemotherapy was 5.7 versus 4.6 months (HR, 0.79; 95% CI, 0.59-1.05; P = 0.519). An analysis censoring for the use of other FLT3 inhibitors showed a median OS of 6.6 versus 5.0 months, respectively (HR, 0.74; 95% CI, 0.55-0.99; P = .0203).

The third sensitivity analysis examined the per-protocol set (patients who were randomized and treated without significant protocol deviations). For this assessment, the median OS was 6.2 months with quizartinib versus 4.6 months with salvage chemotherapy (HR, 0.75; 95% CI, 0.57-1.00; P = .0246).

The OS benefit was also demonstrated across several patient subgroups. Among patients with prior allogeneic HSCT, the median OS was 5.3 months with quizartinib versus 4.0 months with salvage chemotherapy. The medians were 6.9 versus 5.2 months in those without prior allogeneic HSCT. The OS benefit was also shown across subgroups defined by AML risk scores, including intermediate (6.2 vs 4.6 months) and unfavorable (9.4 vs 5.8 months).

In subgroups defined by response to prior therapy, the median OS was 6.5 vs 4.7 months in patients who relapsed, with no HSCT; 7.9 vs 5.4 months in refractory patients; and 5.1 versus 4.0 months in patients who relapsed, post HSCT.

The benefit with quizartinib versus salvage chemotherapy was also observed across subgroups defined by varying allelic ratio, age, sex, and AML history.

"The results seen across these sensitivity and subgroup analyses further demonstrate the consistency and robustness of the treatment effect seen in the QuANTUM-R study with quizartinib," said Jorge E. Cortes, MD, Deputy Chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.

"Additionally, these new analyses further support the value of targeting the FLT3-ITD driver mutation with a highly selective and potent FLT3 inhibitor such as quizartinib to help reduce leukemic burden and potentially allow patients to live longer as compared to salvage chemotherapy," added Cortes.

Based on the QuANTUM-R study, the FDA granted a priority review designation to a new drug application for quizartinib in November 2018 for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive AML. Under the Prescription Drug User Fee Act, the FDA action date for a decision on the application is May 25, 2019.

Patients on QuANTUM-R were randomized in a 2:1 ratio to once-daily quizartinib at 60 mg, with a 30-mg lead-in (n = 245) or to receive investigators’ choice of salvage chemotherapy that was selected prior to randomization. Chemotherapy choices included low-dose cytarabine (n = 29); the combination of mitoxantrone, etoposide, and cytarabine, (MEC; n = 40); or the combination of fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA; n = 53).

Also among patients receiving quizartinib, the FLT3-ITD variant allele frequency ranges included <3% (1%); ≥3% to ≤25% (27%); >25% to ≤50% (35%), and >50% (37%). Cytogenetic risk status included favorable (5%), intermediate (78%), unfavorable (9%), and unknown (8%).

The overall response rate was 69% with quizartinib versus 30% with salvage chemotherapy. The composite complete remission (CRc) rate was 48% versus 27% and the partial response rate was 21% versus 3%, respectively. The median duration of CRc was 12.1 weeks versus 5.0 weeks, respectively.

The median event-free survival was 1.4 months (95% CI, 0.0-1.9) with quizartinib versus 0.9 months (95% CI, 0.4-1.3) with salvage chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; 1-sided, stratified log-rank P = .1071).

“Single-agent quizartinib was well tolerated,” said Cortes, adding, “grade 3 QT prolongation was uncommon, and no grade 4 [cases] were observed.”

The most common grade ≥3 hematologic adverse events (AEs) in the quizartinib arm included thrombocytopenia (35% vs 34% in the salvage chemotherapy arm), anemia (30% vs 29%, respectively), neutropenia (32% vs 25%), febrile neutropenia (31% vs 21%), and leukopenia (17% vs 16%).

The most common grade ≥3 nonhematologic AEs in the quizartinib arm were nausea (3% vs 1% in the salvage chemotherapy arm), fatigue (8% vs 1%, respectively), pyrexia (3% vs 4%), musculoskeletal pain (4% in each arm), vomiting (3% vs 1%), hypokalemia (12% vs 9%), and diarrhea (2% vs 3%).

Quizartinib is also being explored in the phase III QuANTUM-First study (NCT02668653), which is examining the FLT3 inhibitor in patients with newly-diagnosed FLT3-ITD—positive AML.

Jorge E. Cortes, MD1, Samer K. Khaled, MD2, Giovanni Martinelli, MD. 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: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 563.

<<< 2018 ASH Annual Meeting

Baseline patient characteristics were well balanced across the treatment arms. The median patient age in the quizartinib arm was 55 years (range, 19-81) and 89% had and ECOG performance status of 0-1. Thirty-three percent of patients were refractory to prior therapy, 23% had relapsed after remission with HSCT, and 45% had relapsed after remission without HSCT.