Drug Trials Snapshots: VANFLYTA

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the VANFLYTA Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

VANFLYTA (quizartinib)
van flit’ uh
Daiichi Sankyo, Inc.
Original Approval date: July 20, 2023

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

VANFLYTA is a kinase inhibitor (a kinase is a type of protein that regulates the function of cells in your body) that is used in combination with certain chemotherapy medicines and alone as maintenance therapy to treat adults with newly diagnosed acute myeloid leukemia (AML) with a specific mutation called FLT3 internal tandem duplication (FLT3-ITD) mutation. VANFLYTA is not indicated for use alone as maintenance therapy following a stem cell transplantation (bone marrow transplant).

How is this drug used?

VANFLYTA is a tablet. One or two tablets are taken once every day by mouth. VANFLYTA can be taken with or without food.

Who participated in the clinical trials?

The FDA approved VANFLYTA based on evidence from one clinical trial of 539 patients with newly diagnosed AML. The selected patients had to have a certain type of mutation (FLT3-ITD mutation) which was confirmed using a validated assay. The trial was conducted at 193 study sites across 26 countries in North America, Europe, Asia, and other regions.

How were the trials designed?

VANFLYTA was evaluated in a clinical trial of 539 patients with newly diagnosed AML. The selected patients had to have a certain type of mutation (FLT3-ITD mutation) which was confirmed using a validated assay and had to have received no prior treatment for AML. Patients were randomly assigned to receive either VANFLYTA or placebo once a day following a specific dosing plan in combination with chemotherapy during induction and consolidation and then alone during maintenance. Neither the doctor nor the patient knew whether the patient was receiving VANFLYTA or placebo until the trial was over.

The benefit of VANFLYTA was evaluated by measuring how long and how many patients survived. The Sponsor did not know the results until the trial was completed.

How were the trials designed?

The efficacy of VANFLYTA in combination with chemotherapy was evaluated in the QuANTUM-First clinical trial (NCT02668653), a randomized, double-blind, placebo-controlled study of 539 patients with newly diagnosed FLT3-ITD positive AML. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively using an FDA-approved test.

Patients were randomized (1:1) to receive VANFLYTA (N=268) or placebo (N=271) in combination with induction and consolidation therapy and as maintenance monotherapy as shown in Table 1.

Table 1. VANFLYTA Dosage Regimen

VANFLYTA Initiation	Induction1	Consolidation2	Maintenance
	Starting on Day 8 (for 7 + 3 Regimen)3	Starting on Day 6	Starting on Day 1
Dose	35.4 mg once daily by mouth	35.4 mg once daily by mouth	26.5 mg once daily by mouth Days 1 through 14 of first cycle if QTcF is less than or equal to 450 ms. Increase dose to 53 mg once daily on Day 15 of first cycle if QTcF is less than or equal to 450 ms. Maintain the 26.5 mg once daily dose if QTcF greater than 500 ms was observed during induction or consolidation.
Duration (28‑day cycles)	Two weeks in each cycle (Days 8 to 21)3	Two weeks in each cycle (Days 6 to 19)	Once daily with no break between cycles for up to 36 cycles

Source: Adapted from VANFLYTA Prescribing Information
¹ Patients can receive up to 2 cycles of induction.
² Patients can receive up to 4 cycles of consolidation.
³ For 5 + 2 regimen as the second induction cycle, VANFLYTA will be given on Days 6 to 19.
Abbreviations: QTcF, corrected QT interval by Fridericia

Efficacy was established on the basis of overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of 24 months after the randomization of the last patient.

DEMOGRAPHICS SNAPSHOT

Figure 1 summarizes how many male and female patients were enrolled in the clinical trial used to evaluate the efficacy of VANFLYTA.

Figure 1. Baseline Demographics by Sex

Source: Adapted from FDA Review

Figure 2 summarizes the percentage of patients by race enrolled in the clinical trial used to evaluate the efficacy of VANFLYTA.

Figure 2. Baseline Demographics by Race

Source: Adapted from FDA Review

Figure 3 summarizes the percentage of patients by age group enrolled in the clinical trial used to evaluate the efficacy of VANFLYTA.

Figure 3. Baseline Demographics by Age

Source: Adapted from FDA Review

Figure 4 summarizes the percentage of patients by ethnicity enrolled in the clinical trial used to evaluate the efficacy of VANFLYTA.

Figure 4. Baseline Demographics by Ethnicity

Source: Adapted from FDA Review

Who participated in the trials?

The demographic characteristics of the efficacy population are summarized in Table 2.

Table 2. Baseline Demographic Characteristics

Demographic Characteristic	VANFLYTA N=268	Placebo N=271	Total N=539
Age, yearsa
Median	56.0	56.0	56.0
Min, max	23, 75	20, 75	20, 75
Age group, years, n (%)
<60	161 (60.1)	162 (59.8)	323 (59.9)
≥60 to <65	37 (13.8)	44 (16.2)	81 (15.0)
≥65	70 (26.1)	65 (24.0)	135 (25.0)
Sex, n (%)
Male	124 (46.3)	121 (44.6)	245 (45.5)
Female	144 (53.7)	150 (55.4)	294 (54.5)
Race, n (%)
Asian	80 (29.9)	78 (28.8)	158 (29.3)
Black or African American	2 (0.7)	5 (1.8)	7 (1.3)
American Indian or Alaska Native	0	1 (0.4)	1 (0.2)
White	159 (59.3)	163 (60.1)	322 (59.7)
Other	27 (10.1)	24 (8.9)	51 (9.5)
Ethnicity, n (%)
Hispanic or Latino	7 (2.6)	15 (5.5)	22 (4.1)
Not Hispanic or Latino	236 (88.1)	234 (86.3)	470 (87.2)
Not reported	25 (9.3)	22 (8.1)	47 (8.7)
Region, n (%)
United States	8 (3.0)	13 (4.8)	21 (3.9)
Canada	8 (3.0)	5 (1.8)	13 (2.4)
Europe	163 (60.8)	163 (60.1)	326 (60.5)
Asia or other regions	89 (33.2)	90 (33.2)	179 (33.2)

Source: Adapted from FDA Review
^a Age in years is calculated using the birth date and informed consent date.

What are the benefits of this drug?

In the clinical trial, patients who received VANFLYTA in combination with chemotherapy lived longer than patients who received chemotherapy alone. The median duration of a complete remission in the 55% of patients that achieved a complete remission was 26.2 months longer when VANFLYTA was added to chemotherapy.

What are the benefits of this drug (results of trials used to assess efficacy)?

In the clinical trial, 539 patients were either given VANFLYTA (N=268) or a sugar pill (placebo; N=271) in combination with induction and consolidation chemotherapy and as maintenance monotherapy. Figure 5 summarizes efficacy results established on the basis of OS, measured from the date of randomization until death by any cause.

Figure 5. Kaplan-Meier Curve for Overall Survival in QuANTUM-First

Source: VANFLYTA Prescribing Information
Abbreviations: CI, confidence interval

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

• Sex: The observed effect of VANFLYTA was similar for females and males.
• Race: The observed effect of VANFLYTA was similar in White and Asian patients. The number of patients of races other than White and Asian was small; therefore, differences in how VANFLYTA worked among other races could not be determined.
• Age: The observed effect of VANFLYTA was similar across all age groups.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 3 summarizes efficacy results based on OS by age, sex, and race. These analyses were exploratory and therefore should be interpreted with caution.

Table 3. Overall Survival by Demographic Subgroup

Subgroup	VANFLYTA N=268 n/N (%)	Placebo N=271 n/N (%)	Hazard Ratioa (95% CI)
Age, years
<60	63/161 (39)	83/162 (51)	0.68 (0.49, 0.95)
≥60 to <65	22/37 (59)	26/44 (59)	0.94 (0.53, 1.66)
≥65	48/70 (69)	49/65 (75)	0.87 (0.58, 1.29)
Sex
Female	63/144 (44)	85/150 (57)	0.69 (0.50, 0.96)
Male	70/124 (56)	73/121 (60)	0.86 (0.62, 1.19)
Race
White	85/159 (53)	103/163 (63)	0.80 (0.60, 1.06)
Black or African American	2/2 (100)	3/5 (60)	Not estimable
Asian	36/80 (45)	39/78 (50)	0.80 (0.51, 1.26)
Other	10/27 (37)	12/24 (50)	0.64 (0.27, 1.47)

Source: Adapted from FDA Review
^a Hazard ratio was obtained from unstratified Cox Proportional Hazard model.
Abbreviations: CI, confidence interval; n, number of events; N, number of subjects

In an exploratory subgroup analysis of the 89/208 (43%) of patients who received maintenance therapy with VANFLYTA or placebo following consolidation chemotherapy, the OS hazard ratio was 0.40 (95% CI: 0.19, 0.84). Of 119/208 (57%) of patients who received maintenance therapy with VANFLYTA or placebo following hematopoietic stem cell transplant, the OS hazard ratio was 1.62 (95% CI: 0.62, 4.22).

The complete remission (CR) rate in the VANFLYTA arm was 55% (95% CI: 48.7, 60.9) with a median duration of CR of 38.6 months (95% CI: 21.9, NE), and the CR rate in the placebo arm was 55% (95% CI: 49.2, 61.4) with a median duration of CR of 12.4 months (95% CI: 8.8, 22.7).

What are the possible side effects?

VANFYTA may cause serious side effects including changes in the electrical activity of the heart called QT prolongation, irregular heart rhythm called torsade de pointes, and cause the heart to stop beating (cardiac arrest), which is life-threatening and can lead to death.

VANFLYTA may cause harm to an unborn baby (embryo-fetal toxicity).

The most common side effects of VANFLYTA are low white blood cell counts with or without fever, reduced levels of electrolytes (potassium, magnesium or calcium) in blood, increased levels of liver or muscles enzymes, diarrhea, ulcers or redness inside the mouth (mucositis), nausea, abdominal pain, sepsis (serious infection throughout the body and organs), headache, vomiting, and upper respiratory tract infection.

What are the possible side effects (results of trials used to assess safety)?

Table 4 and Table 5 summarize adverse reactions and laboratory abnormalities in the clinical trial.

Table 4. Adverse Reactions (≥10%) in Patients With Newly Diagnosed FLT3-ITD Positive AML Who Received VANFLYTA (With a Difference Between Arms of ≥2% Compared to Placebo) in the Clinical Trial

Body System     Adverse Reaction	VANFLYTA N=265		Placebo N=268
	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Blood and lymphatic system disorders
Febrile neutropenia1	44	43	42	41
Neutropenia2	29	26	14	12
Thrombocytopenia2	18	13	13	12
Anemia2	11	6	7	5
Gastrointestinal disorders
Diarrheaa	42	8	39	8
Mucositisb	38	5	33	4.1
Nausea	34		31	1.9
Abdominal pain2	30	2.3	22	1.1
Vomiting	25	0	20	1.5
Dyspepsia	11	0.4	9	0.7
Infections and infestations
Sepsisc,1	30	19	26	20
Upper respiratory tract infection2	21	2.6	12	3
Fungal infectiond,1	16	6	10	3
Herpesvirus infectione	14	2.6	8	1.9
Nervous system disorders
Headache2	28	0		0.7
Hepatobiliary disorders
Hypertransaminasemiaf	19	7	14	6
Metabolism and nutrition disorders
Decreased appetite	17	4.9	13	1.9
Respiratory, thoracic and mediastinal disorders
Epistaxis	15	1.1	11	0.4
Psychiatric disorders
Insomnia	14	0	11	0
Investigations
Electrocardiogram QT prolonged2	14	3	4.1	1.1
Eye disorders
Eye irritationg	11	0	7	0

Source: VANFLYTA Prescribing Information
¹ Including fatalities.
² Includes other related terms.
^a Diarrhea includes colitis, diarrhea, enteritis, enterocolitis, gastroenteritis, and neutropenic colitis.
^b Mucositis includes anal inflammation, anal ulcer, anorectal discomfort, aphthous ulcer, laryngeal inflammation, laryngeal pain, mucosal inflammation, edema mucosal, esophageal pain, esophageal ulcer, esophagitis, oral blood blister, oral disorder, oral mucosa erosion, oral mucosal blistering, oral mucosal erythema, oral pain, oropharyngeal pain, pharyngeal inflammation, proctalgia, proctitis, stomatitis, tongue ulceration, and vaginal ulceration.
^c Sepsis includes acinetobacter infection, bacteremia, bacterial sepsis, corynebacterium bacteremia, device related bacteremia, device related sepsis, enterobacter sepsis, enterococcal bacteremia, enterococcal sepsis, escherichia bacteremia, escherichia sepsis, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, pseudomonal bacteremia, pulmonary sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal infection, staphylococcal sepsis, stenotrophomonas sepsis, streptococcal sepsis, and streptococcal bacteremia.
^d Fungal infection includes aspergillosis oral, aspergillus infection, bronchopulmonary aspergillosis, candida infection, candida sepsis, fungal infection, fungal sepsis, fungal skin infection, fusarium infection, gastrointestinal candidiasis, hepatic infection fungal, hepatosplenic candidiasis, lower respiratory tract infection fungal, mucormycosis, oral candidiasis, oral fungal infection, oropharyngeal candidiasis, systemic candida, systemic mycosis, tinea cruris, and vulvovaginal candidiasis.
^e Herpesvirus infection includes disseminated varicella zoster virus infection, genital herpes, herpes simplex, herpesvirus infection, herpes zoster, oral herpes, and varicella zoster virus infection.
^f Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatic enzymes increased, and hypertransaminasemia.
^g Eye irritation includes dry eye, eye inflammation, eye irritation, eye pain, eye pruritus, foreign body sensation in eyes, keratitis, and ulcerative keratitis.

Table 5. Select Laboratory Abnormalities (≥10%) That Worsened From Baseline in Patients With Newly Diagnosed FLT3-ITD Positive AML (With a Difference Between Arms of ≥2% Compared to Placebo) in the Clinical Trial

Laboratory Abnormality	VANFLYTA1 N=265		Placebo1 N=268
	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Lymphocytes decreased	60	57	55	51
Potassium decreased	59	22	56	18
Albumin decreased	53	1.6	45	4.3
Phosphorus decreased	52	22	48	19
Alkaline phosphatase increased	51	1.6	47	1.9
Magnesium decreased	44	2	42	1.1
Calcium decreased	33	2.4	27	1.6
Creatine phosphokinase increased	26	2.5	7	0.5
Potassium increased	15	1.2	11	0.8
Magnesium increased	14	2.8	9	1.2
Sodium increased	13	0	10	0.4

Source: VANFLYTA Prescribing Information
¹ The denominator used to calculate the rate varied from 199 to 260 in VANFLYTA and from 187 to 267 in PLACEBO based on the number of patients with a baseline value and at least one post-treatment value.

Were there any differences in side effects of the clinical trials among sex, race, and age?

• Sex: The occurrence of side effects was similar in males and females.
• Race: The occurrence of side effects was similar in White and Asian patients. The number of patients of races other than White and Asian was small; therefore, differences in the occurrence of side effects among Black or African American patients or patients of other races could not be determined.
• Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Table 6, Table 7, and Table 8 summarize adverse events during the clinical trial by sex, race, and age subgroups.

These analyses were exploratory and therefore should be interpreted with caution.

Table 6. Subgroup Analysis of Adverse Events by Sex (Safety Analysis Set)

Adverse Event	Female N=141 n (%)	Male N=124 n (%)
Any grade event	140 (99.3)	124 (100)
Grade ≥3 event	132 (93.6)	112 (90.3)
Any SAE	83 (58.9)	60 (48.4)
Grade ≥3 SAE	79 (56.0)	55 (44.4)

Source: Adapted from FDA Review
Abbreviations: SAE, serious adverse event

Table 7. Subgroup Analysis of Adverse Events by Race (Safety Analysis Set)

Adverse Event	White N=157 n (%)	Asian N=79 n (%)	Othera N=27 n (%)
Any grade event	157 (100)	78 (98.7)	27 (100)
Grade ≥3 event	145 (92.4)	73 (92.4)	25 (92.6)
Any SAE	89 (56.7)	39 (49.4)	14 (51.9)
Grade ≥3 SAE	86 (54.8)	34 (43.0)	13 (48.1)

Source: Adapted from FDA Review
^a Excluding Black or African American. Two patients out of a total of 7 patients enrolled received VANFLYTA and were Black or African American. Therefore, differences in safety in this subgroup compared to other races could not be assessed. Abbreviations: SAE, serious adverse event

Table 8. Subgroup Analysis of Adverse Events by Age (Safety Analysis Set)

Adverse Event	<60 Years N=159 n (%)	≥60 to <65 Years N=37 n (%)	≥65 Years N=69 n (%)
Any grade event	159 (100)	37 (100)	68 (98.6)
Grade ≥3 event	145 (91.2)	35 (94.6)	64 (92.8)
Any SAE	84 (52.8)	19 (51.4)	40 (58.0)
Grade ≥3 SAE	78 (49.1)	18 (48.6)	38 (55.1)

Source: Adapted from FDA Review
Abbreviations: SAE, serious adverse event

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

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