FDA News

FDA advisory committee does not support quizartinib for leukemia subtype

An FDA panel today did not support approval of quizartinib for the treatment of adults with FLT3-internal tandem duplication positive relapsed or refractory acute myeloid leukemia.

The Oncologic Drug Advisory Committee (ODAC), in a 3-8 vote, concluded that study results failed to show the benefits of quizartinib (Daiichi Sankyo) — an investigational FLT3 inhibitor —outweigh the risks for this population. The panel specifically expressed concern over the modest survival results, lack of robust data, the high proportion of randomized but untreated patients, and the risk for QT prolongation with the treatment.

In the randomized Study AC220-007, or QUANTUM-R, researchers randomly assigned 367 adults with relapsed or refractory acute myeloid leukemia positive for FLT3-internal tandem duplication (ITD), as detected by an FDA-approved test, to treatment with quizartinib (n = 245) or standard-of-care chemotherapy (n = 122). Researchers stratified randomization by the type of preselected chemotherapy (intensive cytotoxic vs low-dose cytarabine) and response to prior therapy.

OS served as the study’s primary endpoint.

According to an FDA analysis, median OS was 26.9 weeks (95% CI, 23.1-31) in the quizartinib group and 20.4 weeks (95% CI, 17-25.2) in the chemotherapy group, representing a statistically significant, albeit small, difference in favor of quizartinib (HR = 0.77; 95% CI, 0.59-0.99).

Median EFS was 6 weeks with quizartinib and 3.7 weeks with chemotherapy, which did not represent a significant difference (HR = 0.9; 95% CI, 0.71-1.16).

The first issue ODAC discussed were these survival data.

Despite being a positive study, “the significance was marginal, the OS results were not robust, the OS treatment effect appeared to be driven by the stratum of patients preselected for low-intensity chemotherapy, and the OS treatment effect may have been confounded by imbalances in poststudy therapy, including allogeneic hematopoietic stem cell transplantation,” the FDA wrote in briefing document provided before the meeting.

The panel also expressed concern over the high dropout rate in the trial.

In the intent-to-treat population, four patients (2%) assigned quizartinib were not treated, and one patient (0.4%) was censored for the OS endpoint prior to week 8. Twenty-eight patients (23%) assigned to the standard-of-care group were not treated, and nine patients (7%) were censored for the OS endpoint prior to week 8.

The panel also discussed safety of quizartinib. The most common adverse events during cycle one of quizartinib were nausea, anemia, QT prolongation, thrombocytopenia, pyrexia, hypokalemia, febrile neutropenia, vomiting, fatigue, diarrhea, neutropenia, decreased white blood cell count, decreased platelet count, decreased neutrophil count, headache and decreased appetite.

Twenty-seven percent of patients experienced at least one event of QT prolongation. Researchers observed a substantially higher risk for cardiac events with quizartinib compared with intensive chemotherapy or low-dose cytarabine.

Across the quizartinib clinical development program, the estimated risk for on-treatment deaths due to cardiac events was 1% to 2%.

The ODAC panel noted potential gender differences, with an indication that women may be at higher risk for cardiac events and less likely to benefit from treatment.

Because quizartinib causes delayed cardiac repolarization by inhibition of slowly activating delayed rectifier potassium channels, FDA proposed strategies to reduce the risk for serious cardiac events, such as a contraindication for use with drugs that prolong QT via the rapidly activating delayed rectifier potassium channels, and using beta-blockers to prevent arrythmias. However, the ODAC panel expressed concern about universally recommending beta-blockers for these patients.

Although many clinicians on the panel expressed desire for quizartinib to be another treatment option for their patients — especially as a bridge to transplant — they mostly agreed that more data are needed to answer these questions regarding efficacy and data robustness.

Although FDA is not obligated to follow the advice of ODAC, it often does so.

In April, Daiichi Sankyo announced FDA extended the PDUFA action date to Aug. 25 to review additional data on quizartinib, which is being evaluated under priority review. – by Alexandra Todak

 

 

An FDA panel today did not support approval of quizartinib for the treatment of adults with FLT3-internal tandem duplication positive relapsed or refractory acute myeloid leukemia.

The Oncologic Drug Advisory Committee (ODAC), in a 3-8 vote, concluded that study results failed to show the benefits of quizartinib (Daiichi Sankyo) — an investigational FLT3 inhibitor —outweigh the risks for this population. The panel specifically expressed concern over the modest survival results, lack of robust data, the high proportion of randomized but untreated patients, and the risk for QT prolongation with the treatment.

In the randomized Study AC220-007, or QUANTUM-R, researchers randomly assigned 367 adults with relapsed or refractory acute myeloid leukemia positive for FLT3-internal tandem duplication (ITD), as detected by an FDA-approved test, to treatment with quizartinib (n = 245) or standard-of-care chemotherapy (n = 122). Researchers stratified randomization by the type of preselected chemotherapy (intensive cytotoxic vs low-dose cytarabine) and response to prior therapy.

OS served as the study’s primary endpoint.

According to an FDA analysis, median OS was 26.9 weeks (95% CI, 23.1-31) in the quizartinib group and 20.4 weeks (95% CI, 17-25.2) in the chemotherapy group, representing a statistically significant, albeit small, difference in favor of quizartinib (HR = 0.77; 95% CI, 0.59-0.99).

Median EFS was 6 weeks with quizartinib and 3.7 weeks with chemotherapy, which did not represent a significant difference (HR = 0.9; 95% CI, 0.71-1.16).

The first issue ODAC discussed were these survival data.

Despite being a positive study, “the significance was marginal, the OS results were not robust, the OS treatment effect appeared to be driven by the stratum of patients preselected for low-intensity chemotherapy, and the OS treatment effect may have been confounded by imbalances in poststudy therapy, including allogeneic hematopoietic stem cell transplantation,” the FDA wrote in briefing document provided before the meeting.

The panel also expressed concern over the high dropout rate in the trial.

In the intent-to-treat population, four patients (2%) assigned quizartinib were not treated, and one patient (0.4%) was censored for the OS endpoint prior to week 8. Twenty-eight patients (23%) assigned to the standard-of-care group were not treated, and nine patients (7%) were censored for the OS endpoint prior to week 8.

The panel also discussed safety of quizartinib. The most common adverse events during cycle one of quizartinib were nausea, anemia, QT prolongation, thrombocytopenia, pyrexia, hypokalemia, febrile neutropenia, vomiting, fatigue, diarrhea, neutropenia, decreased white blood cell count, decreased platelet count, decreased neutrophil count, headache and decreased appetite.

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Twenty-seven percent of patients experienced at least one event of QT prolongation. Researchers observed a substantially higher risk for cardiac events with quizartinib compared with intensive chemotherapy or low-dose cytarabine.

Across the quizartinib clinical development program, the estimated risk for on-treatment deaths due to cardiac events was 1% to 2%.

The ODAC panel noted potential gender differences, with an indication that women may be at higher risk for cardiac events and less likely to benefit from treatment.

Because quizartinib causes delayed cardiac repolarization by inhibition of slowly activating delayed rectifier potassium channels, FDA proposed strategies to reduce the risk for serious cardiac events, such as a contraindication for use with drugs that prolong QT via the rapidly activating delayed rectifier potassium channels, and using beta-blockers to prevent arrythmias. However, the ODAC panel expressed concern about universally recommending beta-blockers for these patients.

Although many clinicians on the panel expressed desire for quizartinib to be another treatment option for their patients — especially as a bridge to transplant — they mostly agreed that more data are needed to answer these questions regarding efficacy and data robustness.

Although FDA is not obligated to follow the advice of ODAC, it often does so.

In April, Daiichi Sankyo announced FDA extended the PDUFA action date to Aug. 25 to review additional data on quizartinib, which is being evaluated under priority review. – by Alexandra Todak