Is there any data comparing quizartinib versus midostaurin?

Comment by InpharmD Researcher

There is an overall lack of data comparing survival rates and safety between midostaurin and quizartinib in AML. A 2023 study comparing midostaurin and quizartinib in FLT3-ITD AML found that midostaurin demonstrated favorable results, with a 2-year OS of 68% and an 83.4% complete response rate, suggesting its effectiveness and indicating superior efficacy based on quizartinib’s phase 3 trial. Notably, the OS in midostaurin’s phase 3 trial (RATIFY) was 72.4 months, while the OS in quizartinib’s phase 3 trial (QuANTUM-First) was 32 months. Current NCCN guidelines recommend both drugs but don’t favor one over the other. Both drugs carry cytopenia and nausea risks, while quizartinib additionally has QTc prolongation risk. Comprehensive comparative studies are needed to fully assess their survival and safety differences.

Background

A 2023 study (Table 1), presented as a poster abstract, analyzed the safety and effectiveness of midostaurin in FLT3-ITD acute myeloid leukemia (AML) in a real-world setting and compared the findings with previously reported phase 3 trials on quizartinib. A total of 175 patients, of whom 93 were female, were included in this study. The OS for the entire population had not reached a median value, and at 24 months, the OS was 68%. Among these patients, 133 had FLT-3ITD mutated AML. Notably, 40 patients were 60 years or older. Eighty patients had an Eastern Cooperative Oncology Group score of less than 2, and 74 patients had a high allelic ratio (AR) of 0.5 or greater. Based on European LeukemiaNet (ELN) 2017 criteria, 30 patients had a low AR (0.5) along with mutated NPM1, while 58 patients had a low AR without NPM1 or a high AR with NPM1. Additionally, 23 patients had a high AR without NPM1. The total number of midostaurin cycles administered was 393, with a median of 2 cycles. QT prolongation occurred in 11 patients (8.3%), but there were no deaths related to midostaurin. [1]

In terms of effectiveness, 111 patients (83.4%) achieved complete remission (CR) after either induction 1 or 2, and among them, 55 patients (49.5%) underwent consolidation with allogeneic stem cell transplant. With a median follow-up period of 13.5 months, the median OS had not been reached, and the 2-year OS rate was 65%. The study showed that a high AR (≥0.5) was associated with significant differences in OS (p = 0.04). The ELN 2017 classification demonstrated variations in the low-risk group, but no significant differences were observed between the intermediate and high-risk groups. ECOG scores below 2 and ages below 60 exhibited a trend but did not result in a significant difference in OS. The findings suggest that midostaurin plus intensive chemotherapy as first-line in FLT-3-ITD AML patients is highly effective with a CR of 83.4% and a 2-year OS of 65%. These results appear to surpass what was reported in the quizartinib phase 3 trial. Comparative studies are essential to validate these findings. These findings were presented in a poster abstract; thus the obtained results may not be comprehensive. [1]

According to National Comprehensive Cancer Network (NCCN) guidelines, midostaurin is recommended in combination with standard 7+3 therapy for patients with AML with FLT3-ITD or TKD mutation (category 1), while quizartinib is recommended only for FLT3-ITD mutation in combination with standard 7+3 therapy (category 1). In patients with FLT3-ITD disease, in which either quizartinib or midostaurin could be utilized, guidelines do not indicate a preference for one regimen over another based on survival or safety benefit. [2]

A 2022 review discusses the use of FLT3 targeting agents as a treatment option for AML. At the time of publication, quizartinib was still under investigation in the United States, but was already approved for use in Japan. Unfortunately, there is a lack of direct clinical data comparing midostaurin and quizartinib. In a summary of notable toxicities between FLT3 agents, both midostaurin and quizartinib are noted to possess risk of severe cytopenia and nausea. Quizartinib has additional risk for QTc prolongation. The RATIFY trial provided primary support for the use of midostaurin, while the QuANTUM-R trial served as the primary supporting trial for quizartinib. Within RATIFY, the median OS for midostaurin was 72.4 months compared to 25.6 months in the placebo group. The Japanese-based QuANTUM-R trial reported an OS of 6.2 months for quizartinib versus 4.7 months with standard of care. However, the patients in the QuANTUM-R trial had worse prognosis and received quizartinib as part of salvage chemotherapy. Therefore, comparing the results of the two studies is not feasible. In both studies, treatment was considered well tolerated with grade 3 events associated with midostaurin consisting of higher anemia and rash while grade 3 events for quizartinib included febrile neutropenia, sepsis, QT prolongation, and nausea. In general, prospective post-marketing reports of FLT3 inhibitors are lacking, and the safety profile depends on whether the agent is combined with chemotherapy. [3], [4], [5], [6]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is quizartinib better than midostaurin?

Level of evidence

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Please see Tables 1-3 for your response.

MIDOSTAURIN PLUS 7 + 3 OR QUIZARTINIB PLUS 7 + 3 IN FLT3-ITD MUTATED AML
Design	Patient population	Intervention	Results	Author’s conclusion
Multi-center, cohort study Objective: to analyze the safety and effectiveness of midostaurin in FLT3-ITD AML in a “real-world” setting and to compare with previously reported phase 3 trials RATIFY and QuANTUM	N= 175 (93 female) Inclusion: age > 18 years, FLT3-mutated AML diagnosis according to WHO criteria, and start of treatment with midostaurin in combination with IC 133 patients with FLT-3ITD mutated AML 40 patients aged 60 or older 80 patients with ECOG score < 2 74 patients with high AR of 0.5 or greater 30 patients had low AR (0.5) with mutated NPM1 58 patients had low AR without NPM1 or high AR with NPM1 23 patients had high AR without NPM1	Midostaurin plus 7 + 3 was compared to the findings of previously reported phase 3 trials on quizartinib Total midostaurin cycles: 393, median: 2 cycles	Effectiveness: 111 patients (83.4%) achieved CR after induction 1 or 2 55 of them (49.5%) underwent consolidation with allogeneic stem cell transplant Median follow-up: 13.5 months; median OS not reached; 2-year OS rate: 65% High AR (≥ 0.5) associated with significant differences in OS (p= 0.04) ELN 2017 classification variations in low-risk group; no significant differences in intermediate and high-risk groups ECOG scores < 2 and ages < 60 showed a trend but not a significant difference in OS	Midostaurin plus IC as first line in FLT3-ITD AML patients is highly effective.
Abbreviations: AML= acute myeloid leukemia; AR= allelic ratio; CR= complete remission; ECOG= Eastern Cooperative Oncology Group; ELS= European LeukemiaNet; IC= intensive chemotherapy; NPM1= nucleophosmin 1 gene; OS= overall survival

References:

Tormo M, Diaz-Beya M, Beneit P, et al. P531: MIDOSTAURIN PLUS 7 + 3 OR QUIZARTINIB PLUS 7 + 3 IN FLT3-ITD MUTATED AML. Hemasphere. 2023;7(Suppl ):e4025574. Published 2023 Aug 8. doi:10.1097/01.HS9.0000969032.40255.74

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial
Design	Randomized, double-blind, placebo-controlled, phase 3 trial N= 539
Objective	To compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed acute myeloid leukemia (AML) aged 18–75 years
Study Groups	Quizartinib (n= 268) Placebo (n= 271)
Inclusion Criteria	Patients aged 18–75 years with newly diagnosed AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm with an FLT3-ITD mutation; able to receive standard induction chemotherapy; ECOG status 0-2; received standard 3+7 induction chemotherapy; creatinine clearance (CrCl) >50 mL/min
Exclusion Criteria	Patients diagnosed with acute promyelocytic leukemia, BCR-ABL1-positive leukemia, or AML secondary to prior chemotherapy or radiotherapy; prior treatment for AML; uncontrolled or significant cardiovascular disease
Methods	Patients initially received a standard 7 + 3 induction chemotherapy regimen consisting of cytarabine (either 100 mg/m² or 200 mg/m² per day, based on local standards) for 7 days and an anthracycline (either daunorubicin at 60 mg/m² or idarubicin at 12 mg/m²) on days 1 to 3. On day 7, patients were randomly assigned to receive either quizartinib or a placebo ;quizartinib (40 mg) or placebo was taken orally once daily for 14 days starting from day 8. Between days 21 to 28, a bone marrow aspirate was taken for assessment, and if necessary, this could be repeated up to day 56 for an accurate response evaluation. Patients showing persistent leukemia could undergo a second induction cycle. Patients achieving complete remission could move on to consolidation treatment, which involved high-dose cytarabine plus either quizartinib or placebo, followed potentially by allogeneic hematopoietic cell transplantation (allo-HCT) or further high-dose cytarabine plus quizartinib or placebo then allo-HCT. During consolidation, high-dose cytarabine was administered intravenously every 12 hours on days 1, 3, and 5 for a total of six doses. The quizartinib or placebo was then given orally once per day for 14 days from day 6 to 19. Dosages were adjusted for patients on strong CYP3A4 inhibitors. After induction and consolidation therapies, patients proceeded to continuation therapy with quizartinib or placebo for up to 36 28-day cycles (3 years). The quizartinib dose could be adjusted based on QT interval considerations and concomitant use of strong CYP3A4 inhibitors.
Duration	Treatment: up to 3 years Median follow-up: 39.2 months
Outcome Measures	Primary: overall survival Secondary: event-free survival, rates of complete remission, relapse-free survival
Baseline Characteristics		Quizartinib (n= 268)	Placebo (n= 271)
	Median age, years (range) ≥60 years	56 (23-75) 40%	56 (20-75) 40%
	Female	54%	55%
	Race White Asian	59% 30%	60% 29%
	De novo AML Secondary AML	91% 9%	94% 6%
	Mutated NPM1 Mutated CEBPA	53% 23%	52% 24%
	While blood cells <40x10⁹/L at diagnosis	50%	51%
Results	Endpoint	Quizartinib (n= 268)	Placebo (n= 271)	p-value
	Overall survival, months (95% CI)	31.9 (21.0 to NE)	15.1 (3.2 to 26.2)	0.032
	Relapse-free survival, months (95% CI) Relapse Death	39.3 (22.6 to NE) 30% 14%	13.6 (9.7 to 23.7) 42% 17%	Significant*
	Complete remission With incomplete neutrophil or platelet recovery	54.9% 16.8%	55.4% 9.6%	NS
	In patients with complete remission during induction, relapse-free survival was significantly longer with quizartinib than placebo (hazard ratio, 0.61; 95% CI, 0.44 to 0.85).
	CI= confidence interval; NE= not estimable; NS= not significant
Adverse Events	Similar proportions of patients in both groups experienced at least one adverse event (100% in quizartinib and 99% in placebo groups) and one grade 3 or higher adverse event (92% in quizartinib and 90% in placebo groups).
	Common Adverse Events: febrile neutropenia (44% vs 42%); fever (42% vs 41%); hypokalemia (35% vs 36%); increased ALT (16% vs 10%); pneumonia (15% vs 15%)
	Serious Adverse Events: febrile neutropenia (11% vs 8%); pneumonia (6% vs 6%); septic shock (4% vs 3%)
Study Author Conclusions	The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18–75 years with FLT3-ITD-positive newly diagnosed AML.
InpharmD Researcher Critique	While the study shows a significant improvement in overall survival with quizartinib, some secondary outcomes were not as clear-cut. The study had limitations including the choice of placebo as a comparator given that midostaurin, another FLT3 inhibitor, became a standard care during the trial period.

References:

Erba HP, Montesinos P, Kim HJ, et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2023 Oct 14;402(10410):1328. doi: 10.1016/S0140-6736(23)02235-3]. Lancet. 2023;401(10388):1571-1583. doi:10.1016/S0140-6736(23)00464-6

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation
Design	Randomized, double-blind, multicenter, placebo-controlled, phase 3 trial N= 717
Objective	To determine the effect of the addition of midostaurin to standard chemotherapy in patients with acute myeloid leukemia (AML) and an FLT3 mutation
Study Groups	Midostaurin (n= 360) Placebo (n= 357)
Inclusion Criteria	Patients aged 18-59 years with newly diagnosed AML and FLT3 mutations, had not previously received antineoplastic therapy except for limited urgent treatment for the current disease
Exclusion Criteria	Patients with acute promyelocytic leukemia, therapy-related AML, bilirubin level ≥2.5 times the upper limit of normal, other major coexisting illnesses
Methods	Patients were randomly assigned to receive standard induction chemotherapy with daunorubicin and cytarabine, followed by consolidation chemotherapy with high-dose cytarabine. They then received either midostaurin or placebo in a double-blind fashion during induction, consolidation, and maintenance phases. Randomization was stratified according to FLT3 mutation subtype Patients received daunorubicin (60 mg/m²/day via rapid IV injection on days 1-3) and cytarabine (200 mg/m²/day via continuous IV infusion on days 1-7). Participants were randomized to receive either midostaurin 50 mg BID or placebo starting on day 8 through day 21. Treatment with midostaurin or placebo was not given if the patient had a corrected QT interval over 500 ms or showed a grade 3 or 4 non-hematologic toxic effect. A bone marrow examination was scheduled for day 21 to check for residual leukemia. If significant leukemia remained, the same induction therapy, including midostaurin or placebo, was repeated. Patients achieving complete remission underwent four 28-day cycles of consolidation therapy with high-dose cytarabine (3000 mg/m², given over 3 hours every 12 hours on days 1, 3, and 5). Midostaurin or placebo continued on days 8-21 of each cycle, at the same dose as before. Those remaining in remission after consolidation therapy entered a maintenance phase, receiving midostaurin or placebo (50 mg orally twice daily) for twelve 28-day cycles. Complete Remission was defined as less than 5% marrow blasts, an absolute neutrophil count over 1000/µL, a platelet count over 100,000/µL, no blasts in peripheral blood, and these conditions had to be met by day 60. Stem cell transplantation was allowed but not required by the study protocol and was left to the investigator's discretion.
Duration	Median follow-up: 59 months
Outcome Measures	Primary: overall survival Secondary: complete remission, time to complete remission, and rate of severe adverse events
Baseline Characteristics		Midostaurin (n= 360)	Placebo (n= 357)	p-value
	Median age, years (range)	47.1 (19-59.8)	48.6 (18-60.9)	0.22
	Female	51.7%	59.4%	0.04
	White	89.1%	88.9%	0.74
	FLT3 mutation subtype TKD ITD with low allelic ratio ITD with high allelic ratio	22.5% 47.5% 30%	22.7% 47.6% 29.7%	1.00
	White cell count/mL (range)	35.6 (0.6-421.8)	33.0 (0.8-329.8)	0.72
	Absolute neutrophil count/mL (range)	2.2 (0-55.9)	2.3 (0.-55.9)	0.65
Results	Endpoint	Midostaurin (n= 360)	Placebo (n= 357)	p-value
	Overall survival, months (90% CI) 4-year survival	74.7 (31.5 to NE) 51.4%	25.6 (18.6 to 42.9) 44.3%	0.009
	Event-free survival, months (95% CI)	8.2 (5.4 to 10.7)	3.0 (1.9 to 5.9)	0.002
	Complete remission Median days to complete remission (range)	59% 35 (20-60)	54% 35 (20-60)	0.15
	Subgroup analyses of each mutation type were not significant for overall survival; however, they numerically favored the midostaurin group.
	CI= confidence interval; NE= not estimable; NS= not significant
Adverse Events	The rates of severe adverse events were generally similar between the groups. Notable differences included higher rates of grade 3-5 anemia (93% vs. 88%, p= 0.03) and rash (14% vs. 8%, p= 0.008) in the midostaurin group, and higher rates of nausea in the placebo group (10% vs. 6%, p= 0.05).
Adverse Events	Common Adverse Events: thrombocytopenia (97% vs 97%), neutropenia (95% vs 96%), anemia (93% vs 88%; p= 0.03), febrile neutropenia (82% vs 82%), infection (52% vs 50%), rash/desquamation (14% vs 8%; p= 0.008)
Study Author Conclusions	The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation.
InpharmD Researcher Critique	This large multinational trial showed a clear survival benefit with midostaurin, supporting its addition to standard chemotherapy for AML with FLT3 mutations. However, the imbalance in the sex distribution and the high rate of transplantation potentially complicates the interpretation of the survival benefit. Further research may be needed to isolate the independent effects of midostaurin maintenance therapy and to explore its efficacy in other AML subgroups.

References:

Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359