FDA Issues Complete Response Letter for Quizartinib in AML

The FDA has issued a complete response letter to Daiichi Sankyo informing the company that its new drug application would not be approved for quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD–positive acute myeloid leukemia.

Antoine Yver, MD

Antoine Yver, MD

Antoine Yver, MD

The FDA has issued a complete response letter to Daiichi Sankyo informing the company that its new drug application (NDA) would not be approved for quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive acute myeloid leukemia (AML).

The final decision follows a May 2019 recommendation from the FDA’s Oncologic Drugs Advisory Committee (ODAC). The panel voted 8 to 3 that the available data did not definitively demonstrate that the benefit of quizartinib outweighed the potential risks.

"Daiichi Sankyo is evaluating the complete response letter and will determine next steps in the [United States]" Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development, Daiichi Sankyo, said in a press release.

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).1 At a median follow-up of 23.5 months, the median overall survival (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).

Prior to the ODAC meeting, the FDA conducted its own efficacy analysis, and determined the median OS was 26.9 weeks (95% CI, 23.1-31) with quizartinib compared with 20.4 weeks (95% CI, 17-25.2) with chemotherapy (HR, 0.77; 95% CI, 0.59-0.99; P = .019).2

Although this analysis confirmed a benefit with quizartinib, the FDA explained in its ODAC briefing document that it found issues in its review raising concerns over the “credibility” and “generalizability” of the trial data.

These issues included, “imbalances in the rates of patients who were early-censored for OS (prior to week 8 after randomization) and in the number of patients randomized but not treated; inconsistent OS treatment effect by strata based on intensive versus low-intensity chemotherapy; confounding of the assessment of OS by the follow-on therapies which patients received after discontinuation from study treatment; and lack of treatment effect in additional efficacy endpoints.”

“I voted no based on the data available. The efficacy results that we were shown are a modest 6 weeks. And if I felt confident in those data, that would have been enough for me in the setting of AML, but a lot of the questions that were raised with respect to bias, confounding, and I do think the issue of equipoise is a real one in the setting of this particular study—it raises questions about whether or not that survival benefit is real,” said Heidi D. Klepin, MD, associate professor of Internal Medicine, Section of Hematology and Oncology, Wake Forest University Health Sciences.

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.

The data submitted with the NDA showed that the median event-free survival (EFS) 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).

The internal FDA analysis also did not demonstrate a significant EFS benefit with quizartinib versus chemotherapy. The median EFS was 6.0 weeks (95% CI, 0.1-8.3) versus 3.7 weeks (95% CI, 0.4-6.0), respectively (HR, 0.9; 95% CI, 0.71-1.16; P = .114).

The NDA data showed that 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 FDA’s internal safety analysis of the QuANTUM-R study was mostly consistent with the safety findings included in the NDA, which listed the most common (≥10%) treatment-emergent adverse events in cycle 1 for quizartinib as nausea, anemia, electrocardiogram QT prolonged, thrombocytopenia, pyrexia, hypokalemia, febrile neutropenia, vomiting, fatigue, diarrhea, neutropenia, white blood cell count decreased, platelet count decreased, neutrophil count decreased, headache, and decreased appetite.

The NDA also listed AEs of special interest, including infection (77%), hemorrhage (49%), hepatic disorders (32%), QT prolongation (31%), cardiac arrhythmias (12%), and cardiac failure (2%).

In its ODAC briefing document, the FDA focused on cardiac toxicity as a key concern with quizartinib, noting the risk of cardiac AEs was substantially higher with quizartinib versus chemotherapy. Additional safety issues identified in the FDA safety analysis included potentially fatal differentiation syndrome, acute febrile neutrophilic dermatosis, and prolonged cytopenias.

Despite this setback in the United States, quizartinib (Vanflyta) was approved in Japan earlier this month for the treatment of adult patients with relapsed/refractory FTL3-ITD—positive acute myeloid leukemia (AML), as detected by an assay approved by Japan’s Ministry of Health, Labor and Welfare. Japanese regulatory authorities reviewed the same QuANTUM-R data as the FDA when making their approval decision.


  1. Cortes JE, Khaled SK, Martinelli, G, et al. 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.
  2. FDA Briefing Document Oncologic Drugs Advisory Committee (ODAC) Meeting May 14, 2019 NDA 212166 Quizartinib Applicant: Daiichi-Sankyo, Inc. Accessed May 14, 2019.
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