dm+d

Unassigned

New Medicines

Vanflyta Newly diagnosed FLT3-ITD-positive acute myeloid leukaemia (AML)

Information

Vanflyta
New molecular entity
Daiichi Sankyo
Daiichi Sankyo

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Yes

Category

Fms-like tyrosine (FLT) kinase 3 inhibitor
FLT3 kinase is mutated in approx one-third of AML pts; these pts are less responsive to traditional therapies
Newly diagnosed FLT3-ITD-positive acute myeloid leukaemia (AML)
Oral

Further information

Yes

Evidence based evaluations

Vanflyta Relapsed or refractory FLT3-ITD-positive acute myeloid leukaemia (AML)

Information

Vanflyta
New molecular entity
Daiichi Sankyo
Daiichi Sankyo

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Yes
Yes
Oct 21No longer listed in company pipeline for relapsed/refractory AML (although is for first-line); presume company proceeding only with flings for first-line use [25].
Jan 21Vanflyta has been available in Japan since Oct 19. Quizartinib is still listed in DS pipeline for relapsed/refractory AML in US/EU/Asia, and also for first-line treatment of AML in Japan/US/EU/Asia. Presume DS is awaiting completion of QuANTUM-R study and hopes to re-file in the US and EU [24].
Oct 19Not recommended for EU approval by CHMP - the committee considered that although the results from the main study indicated a marginal improvement in overall survival for patients given quizartinib, the study had important limitations which meant that the drug´s effectiveness could not be sufficiently demonstrated. CHMP therefore considered the the benefits did not outweigh the risks [22].
Jun 19US FDA panel declines to approve quizartinib for treatment of relapsed/refractory AML [21].
May 19Oncology Drugs Advisory Committee at FDA has voted against approval of quizartinib for the treatment of relapsed/refractory AML. The benefits (efficacy) of the medicine do not outweigh the risks (safety). The FDA fianl decision will follow, but it is expected that they will take the advice of the Advisory Committee [18,19].
May 19The FDA has questioned the reliability of the PIII AC220-007 study results. These were outlined in a briefing document to support independent experts on a panel to assess quizartinib in an upcoming advisory committee meeting. Its concerns were around an imbalance in early censoring and pts randomised but not treated between the arms, the inconsistency of results across stratification subgroups and effects of subsequent therapies on the primary endpoint which, they reported may impact the interpretation of the study results to a degree that renders them unreliable. The FDA also highlighted the divergent performance of pts who received low and high-intensity chemotherapy and differences between the use of post-study therapies as factors that may have affected results. There are also concerns about the risks posed by quizartinib as it has been shown to prolonged the QT interval and was linked to a higher rate of associated adverse events [16,17].
Apr 19US FDA have extended the review period for the NDA of quizartinib to Aug 2019 to allow time to review additional data submitted by the company in association with an FDA request [15].
Nov 18Is also pre-registration in US [14].
Nov 18EMA grants accelerated assessment of quizartinib for treatment of relapsed/refractory FLT3-ITD AML [13].
Aug 18Granted breakthrough therapy designation in US [12].
Oct 17Target financial year for launch in EU & US is 2018 [10].
Jul 15Approval/launch planned for 2018 [9].
Mar 15Both the US FDA and European Commission have granted orphan drug designation to quizartinib for treatment of AML [8].
Jan 15PII in EU and US [7].

Category

Fms-like tyrosine (FLT) kinase 3 inhibitor
FLT3 kinase is mutated in approx one-third of AML pts; these pts are less responsive to traditional therapies
Relapsed or refractory FLT3-ITD-positive acute myeloid leukaemia (AML)
Oral

Further information

Yes

Trial or other data

Feb 20PIII QuANTUM-R trial is ongoing and due to complete in Dec 20. It completed recruitment in Sep 17 and finished collecting primary outcome data in Feb 18. Results were first posted to the US trial registry in Jan 20 [23].
Jun 19PIII QuANTUM-R RCT (NCT02039726; n=367) found a superior overall survival for quizartinib than chemotherapy (6.2 vs 4.7 months, HR for death = 0.76, 95% CI 0.58 to 0.98). Sepsis or septic shock was the most common adverse effect (19% for both quizartinib and chemotherapy) [20].
Jun 18Initial results from PIII QUANTUM-R study (n=367) announced at conference; study found OS of 27% at 52 weeks for quizartinib vs 20% for standard chemotherapies [11].
Jan 17NCT02039726 Estimated Primary Completion Date:February 2018
Apr 14Company announce that the PIII study QUANTUM-R (NCT02039726) has started. Patients will be dosed continually until disease progression or intolerable toxicity. Patients who proceed to HSCT after quizartinib treatment will be able to reinitiate treatment following the transplant. An interim analysis will be conducted and will include an adaptive design component that will allow the Data Safety Monitoring Board (DSMB) to increase the number of patients, if warranted. Enrollment is expected to be completed in the second half of 2015, assuming there is no increase in the number of patients following the interim analysis [6]
Jan 14NCT02039726 is a PIII open-label randomized study of quizartinib (AC220) monotherapy vs salvage chemotherapy in 326 subjects with Feline McDonough Sarcoma (FMS)-like Tyrosine Kinase 3-Internal Tandem Duplication (FLT3-ITD) positive AML refractory to or relapsed after first-line treatment with or without haematopoietic stem cell transplantation (HSCT) consolidation. The primary outcome is overall survival. The study starts Mar 14 and is due to complete Feb 16 [5].
Mar 13Astellas has dropped all rights for quizartinib (AC220) and will no longer be taking the drug into PIII studies later in 2013. Rights have reverted back to Ambit BioSciences [4].
Dec 12More data from PII study above – Cohort 1 included pts aged ≥ 60 yrs with AML relapsed in <1 yr or refractory to 1st-line chemotherapy (n=134). For FLT3-ITD +ve pts, the Composite complete remission (CRc) rate was 54% with median duration of response of 12.7 weeks and median overall survival of 25.3 weeks. Of those refractory to their last AML therapy, 39% achieved CRc. For FLT3-ITD –ve pts, CRc rate was 32%, median duration of response 22.1 weeks and median overall survival 19 wks. Of those refractory to last AML treatment, 44% achieved CRc. [3]
Dec 12Results from PII study conducted to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD positive and FLT3-ITD negative pts, n=333 in two cohorts. Cohort 2 = pts aged ≥ 18 yrs with AML relapsed or refractory to 2nd line, salvage chemotherapy or relapsed after hematopoietic stem cell transplantation (n=137). Composite complete remission (CRc) rate was 44% with median duration of 11.3 weeks and median overall survival of 23.1 weeks. Of those refractory to their last AML therapy, 47% achieved a CRc with quizartinib. For FLT3-ITD –ve patients, the CRc rate was 34% with median duration of response of 5 weeks and median overall survival of 25.6 weeks. [2]
Feb 10Recruitment to a PII trial (NCT00989261) with AC 220 (200mg) monotherapy in pts with AML and FLT3-ITD activating mutations is underway in the US & EU. This single-arm trial will recruit approximately 180 pts from the US, Canada, and the EU. The ACE study will potentially support a regulatory filing in the US. Estimated study completion date is Feb 2011 (1).

Evidence based evaluations