FDA Extends Review Period for Quizartinib in AML

The FDA has added 3 months to the review period for a new drug application (NDA) for quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive acute myeloid leukemia (AML), allowing the agency to review additional data provided by Daiichi Sankyo, the manufacturer of the FLT3 inhibitor.

The NDA was filed based on findings from the phase III QuANTUM-R study, in which 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).

"We look forward to continued dialogue with the FDA throughout the review process of quizartinib," Arnaud Lesegretain, vice president, Oncology Research and Development and head, AML Franchise, Daiichi Sankyo, said in a press release. "We remain confident in the data supporting our NDA submission and are committed to bringing quizartinib forward as a potential treatment for relapsed or refractory FLT3-ITD AML, a particularly aggressive and difficult-to-treat subtype of AML, where patients need additional targeted treatment options."

The OS benefit with quizartinib in QuANTUM-R 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.

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).

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.

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 in the trial. Grade 3 QT prolongation was uncommon and there were no grade 4 cases. 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.

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The FDA initially granted a priority review designation to the NDA in November 2018, with an action date set for May 25, 2019. Under the new timeframe, the FDA is now scheduled to make a final decision on the NDA by August 25, 2019.