CHMP recommended the rejection of a marketing application for quizartinib’s use in the treatment of relapsed or refractory acute myeloid leukaemia (AML) patients with a specific mutation in the FLT3 gene.
The negative opinion from the CHMP was based on the results of the QuANTUM-R trial Phase 3 trial (NCT02039726), which showed the therapy led to moderate improvement in median survival among enrolled patients with AML.
“While we are disappointed by this opinion, we will evaluate feedback received from the CHMP in order to determine next steps for quizartinib for the treatment of patients with relapsed/refractory FLT3-ITD AML in Europe,” Antoine Yver, MD, MSc, Daiichi Sankyo’s executive vice president and global head, oncology research and development, said in a press release.
FLT3 is a protein that helps regulate the survival and proliferation of blood stem cells. This protein normally gets activated when it interacts with another protein. However, some mutations in the FLT3 gene create a protein that is constantly active, encouraging the growth of abnormal leukemia cells.
Quizartinib was designed as a treatment for the most common FLT3 mutation — the internal tandem duplication (FLT3-ITD) of the protein — which affects one in four AML patients. This mutation is associated with a poor prognosis, including higher relapse rates and increased risk of death after relapse.
QuANTUM-R was an open-label study that compared quizartinib with standard-of-care chemotherapy in AML patients with FLT3-ITD mutations who had failed first-line therapy, with or without a stem cell transplant consolidation.
The trial’s main goal was to determine if quizartinib increased overall survival compared with chemotherapy. Secondary measures included the time after treatment that patients remained without failing treatment, relapsing after a complete response, or dying.
The results showed that quizartinib significantly extended overall survival to 6.2 months, from 4.7 months with chemotherapy. This 24% reduction in the risk of death meant that after one year of treatment, 27% of patients on quizartinib were still alive, compared with 20% of those on chemo.
While the improvement was moderate, “the results are a substantial step forward in the treatment of acute myeloid leukaemia, since they represent the first published (with the exception of meeting abstracts) randomised evidence that tyrosine kinase inhibition by a single agent can be more efficacious than standard chemotherapy,” the researchers said in an editorial comment accompanying the study.
The researchers also noted that the higher response rates were likely due to more patients on quizartinib achieving a response to treatment, which allowed them to receive a stem cell transplant. Nevertheless, only 32% of patients on quizartinib and 11% of those on chemotherapy underwent a transplant.
Likely based on these findings, the CHMP concluded that “the study had important limitations which meant that the effectiveness of [quizartinib] could not be sufficiently demonstrated.”
“Therefore, the Agency’s opinion was that the benefits of [quizartinib] did not outweigh its risks,” the EMA said.
Daiichi Sankyo is now conducting another Phase 3 trial, called QuANTUM-First (NCT02668653). This study will evaluate quizartinib versus a placebo, given along with standard induction and consolidation chemotherapy, followed by a continuation therapy, to patients with newly diagnosed FLT3-ITD AML.
“Despite this setback, we continue to believe in the potential benefit of quizartinib for patients with FLT3-ITD AML and we look forward to the results of the global, pivotal phase 3 QuANTUM-First study evaluating quizartinib in combination with chemotherapy for patients with newly-diagnosed FLT3-ITD AML,” Yver said.
“We remain committed to bringing quizartinib forward as a potential treatment option for this aggressive and difficult-to-treat subtype of AML in the U.S., Europe and other parts of the world,” said Yver.
Additional studies include a Phase 1 clinical trial (NCT03552029) assessing quizartinib in combination with milademetan. That trial is ongoing at nine clinical sites in the U.S., and is recruiting 156 participants with FLT3-ITD AML who are relapsed or refractory, or newly diagnosed and unfit for intensive chemotherapy.
Quizartinib was recently approved in Japan under the brand name Vanflyta for the treatment of relapsed or refractory FLT3-ITD AML.