On Tuesday, the FDA’s Oncologic Drug Advisory Committee (ODAC) voted 8 to 3 against approving Daiichi Sankyo’s acute myeloid leukemia (AML) investigational treatment quizartinib in its advisory committee meeting.
At the meeting, the committee challenged the credibility of the data regarding quizartinib for the treatment of adults with AML in the relapsed/refractory setting, according to an ODAC briefing document.
Daiichi Sankyo submitted the New Drug Application (NDA) based on the phase 3 QuANTUM-R study, an open-label trial that evaluated quizartinib monotherapy versus salvage chemotherapy in patients with AML who are FLT3-ITD positive. In the trial, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle of salvage chemotherapy.
Compared with chemotherapy, quizartinib reduced the risk of death by 24%, according to the findings. 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
Through its own analysis, the FDA raised concerns about the credibility of the trial data and uncertainty regarding the generalizability of the results.
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 that patients received after discontinuation from study treatment.
Lack of treatment effect in additional efficacy endpoints.
The FDA’s internal safety analysis of the trial data was mostly consistent with the safety findings included in the NDA. The most common treatment-emergent adverse events (AEs) for quizartinib were 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.
Cardiac toxicity was also cited as a key concern with quiziartinib. The FDA noted the risk of cardiac AEs was substantially higher with quizartinib compared with chemotherapy. In the quizartinib clinical development program, the risk of on-treatment deaths due to cardiac events was estimated as 1% to 2%, despite instructions in the protocol regarding patient management to reduce risks, according to the ODAC.
Moreover, the ODAC stated that “it is not clear to the FDA that the risks of treatment with quizartinib are outweighed by the potential benefits.”
“While we are disappointed by the outcome of today’s ODAC vote, we will work closely with the FDA as it completes the review of our submission,” Antoine Yver, MD, MSc, executive vice president and global head of oncology research and development at Daiichi Sankyo, said in a statement. “Patients with relapsed/refractory FLT3-ITD AML are facing a very aggressive disease with poor prognosis, and we continue to believe that quizartinib could offer an important additional treatment option that specifically targets FLT3-ITD, a driver mutation in AML.”
Although the committee voted against approval, the FDA is not bound by these recommendations. The agency is now expected to make a decision by August 25, 2019, according to Daiichi Sankyo.
Oncologic Drugs Advisory Committee. FDA Briefing Document: Oncologic Drugs Advisory Committee Meeting. FDA.gov. https://www.fda.gov/media/124896/download
. Accessed May 14, 2019.
Daiichi Sankyo Announces Outcome of FDA Oncologic [news release]. Daiichi Sankyo. https://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/007017.html
. Accessed May 15, 2019.