6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Intracranial hemorrhage [see Warnings and Precautions (5.1)]
Cognitive effects [see Warnings and Precautions (5.2)]
Photosensitivity [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to AYVAKIT at 25 mg to 600 mg orally once daily in 995 patients enrolled in one of five clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER, PATHFINDER and PIONEER [see Clinical Studies (14.1, 14.2, 14.3)]. These patients included 601 patients with GIST, 148 patients with AdvSM and 246 patients with ISM. Among the 995 patients receiving AYVAKIT, 54% were exposed for 6 months or longer and 26% were exposed for greater than 1 year.

Gastrointestinal Stromal Tumors

Unresectable or Metastatic GIST

The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR [see Clinical Studies (14.1)]. The trial excluded patients with history of cerebrovascular accident or transient ischemic attacks, known risk of intracranial bleeding, and metastases to the brain. Patients received AYVAKIT 300 mg or 400 mg orally once daily (n = 204). Among patients receiving AYVAKIT, 56% were exposed for 6 months or longer and 44% were exposed for greater than one year.

The median age of patients who received AYVAKIT was 62 years (range: 29 to 90 years), 60% were <65 years, 62% were male, and 69% were White. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7).

Serious adverse reactions occurred in 52% of patients receiving AYVAKIT. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%), and tumor hemorrhage (1%). Fatal adverse reactions occurred in 3.4% of patients. Fatal adverse reactions that occurred in more than one patient were sepsis and tumor hemorrhage (1% each).

Permanent discontinuation due to adverse reactions occurred in 16% of patients who received AYVAKIT. Adverse reactions requiring permanent discontinuation in more than one patient were fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy.

Dosage interruptions due to an adverse reaction occurred in 57% of patients who received AYVAKIT. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain.

Dose reduction due to an adverse reaction occurred in 49% of patients who received AYVAKIT. Median time to dose reduction was 9 weeks. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea, and periorbital edema.

The most common adverse reactions (≥ 20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, increased lacrimation, abdominal pain, constipation, rash, dizziness, and hair color changes. Table 5 summarizes the adverse reactions observed in NAVIGATOR.

Table 5. Adverse Reactions (≥ 10%) in Patients with GIST Receiving AYVAKIT in NAVIGATOR
Adverse Reactions*	AYVAKIT N=204
Adverse Reactions*	All Grades %	Grade ≥ 3 %
* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 † Edema includes face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema. ‡ Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort. § Cognitive impairment includes memory impairment, cognitive disorder, confusional state, disturbance in attention, amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, mental disorder, and retrograde amnesia. ¶ Sleep disorders includes insomnia, somnolence, and sleep disorder. # Taste effects include dysgeusia and ageusia. Þ Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered, nervousness, personality change, and suicidal ideation. ß Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular.
General
Edema†	72	2
Fatigue/asthenia	61	9
Pyrexia	14	0.5
Gastrointestinal
Nausea	64	2.5
Vomiting	38	2
Diarrhea	37	4.9
Abdominal pain‡	31	6
Constipation	23	1.5
Dyspepsia	16	0
Nervous System
Cognitive impairment§	48	4.9
Dizziness	22	0.5
Headache	17	0.5
Sleep disorders¶	16	0
Taste effects#	15	0
Mood disordersÞ	13	1
Metabolism and nutrition
Decreased appetite	38	2.9
Eye
Increased lacrimation	33	0
Skin and subcutaneous tissue
Rashß	23	2.1
Hair color changes	21	0.5
Alopecia	13	0
Respiratory, thoracic and mediastinal
Dyspnea	17	2.5
Pleural effusion	12	2
Investigations
Weight decreased	13	1

Clinically relevant adverse reactions occurring in <10% of patients were:

Vascular: hypertension (8%)

Endocrine: thyroid disorders (hyperthyroid, hypothyroid) (3%)

Skin and subcutaneous: palmar-plantar erythrodysesthesia (1%)

Table 6 summarizes the laboratory abnormalities observed in NAVIGATOR.

Table 6. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with GIST Receiving AYVAKIT in NAVIGATOR
Laboratory Abnormality	AYVAKIT* N=204
Laboratory Abnormality	All Grades (%)	Grade ≥ 3 (%)
* The denominator used to calculate the rate varied from 154 to 201 based on the number of patients with a baseline value and at least one post-treatment value.
Hematology
Decreased hemoglobin	81	28
Decreased leukocytes	62	5
Decreased neutrophils	43	6
Decreased platelets	27	0.5
Increased INR	24	0.6
Increased activated partial thromboplastin time	13	0
Chemistry
Increased bilirubin	69	9
Increased aspartate aminotransferase	51	1.5
Decreased phosphate	49	13
Decreases potassium	34	6
Decreased albumin	31	2
Decreased magnesium	29	1
Increased creatinine	29	0
Decreased sodium	28	7
Increased alanine aminotransferase	19	0.5
Increased alkaline phosphatase	14	1

Advanced Systemic Mastocytosis

The safety of AYVAKIT in patients with AdvSM was evaluated in EXPLORER and PATHFINDER [see Clinical Studies (14.2)]. Patients received a starting dose of AYVAKIT ranging from 30 mg to 400 mg orally once daily (n = 131), including 80 patients who received the recommended starting dose of 200 mg once daily. Among patients receiving AYVAKIT, 70% were treated for 6 months or longer and 37% were exposed for greater than one year.

The median age of patients who received AYVAKIT was 68 years (range: 31 to 88 years), 38% were <65 years, 57% were male, and 88% were White.

Serious adverse reactions occurred in 34% of patients receiving the recommended starting dose of 200 mg once daily and in 50% of patients receiving AYVAKIT at all doses. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (5%), subdural hematoma (4%), pleural effusion, ascites and pneumonia (3% each), acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each). Fatal adverse reactions occurred in 2.5% of patients receiving the recommended starting dose of 200 mg once daily and in 5.3% of patients receiving AYVAKIT at all doses. No specific adverse reaction leading to death was reported in more than one patient.

Permanent discontinuation due to adverse reactions occurred in 10% of patients receiving the recommended starting dose of 200 mg once daily and in 15% of patients who received AYVAKIT at all doses. Of patients receiving 200 mg once daily, subdural hematoma was the only adverse reaction requiring permanent discontinuation in more than one patient.

Dosage interruptions due to an adverse reaction occurred in 60% of patients receiving the recommended starting dose of 200 mg once daily and in 67% of patients who received AYVAKIT at all doses. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, neutrophil count decreased, platelet count decreased, anemia, white blood cell decreased, cognitive disorder, blood alkaline phosphatase increased, and edema peripheral.

Dose reduction due to an adverse reaction occurred in 68% of patients receiving the recommended starting dose of 200 mg once daily and 70% of patients who received AYVAKIT at all doses. Median time to dose reduction was 1.7 months. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, edema peripheral, neutrophil count decreased, platelet count decreased, periorbital edema, cognitive disorder, anemia, fatigue, arthralgia, blood alkaline phosphatase increased, and white blood cell count decreased.

The most common adverse reactions (≥ 20%) at all doses were edema, diarrhea, nausea, and fatigue/asthenia. Table 7 summarizes the adverse reactions observed in EXPLORER and PATHFINDER.

Table 7. Adverse Reactions (≥ 10%) in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER
Adverse Reactions*	AYVAKIT (200 mg once daily) N=80
Adverse Reactions*	All Grades %	Grade ≥ 3 %
* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 † Edema includes face swelling, eyelid edema, orbital edema, periorbital edema, face edema, peripheral edema, edema, generalized edema, and peripheral swelling. ‡ Abdominal pain includes abdominal pain, upper abdominal pain, and abdominal discomfort. § Cognitive effects include memory impairment, cognitive disorder, confusional state, delirium, and disorientation. ¶ Taste effects include dysgeusia.
General
Edema†	79	5
Fatigue/asthenia	23	4
Gastrointestinal
Diarrhea	28	1
Nausea	24	1
Vomiting	18	3
Abdominal pain‡	14	1
Constipation	11	0
Nervous system
Headache	15	0
Cognitive effects§	14	1
Taste effects¶	13	0
Dizziness	13	0
Musculoskeletal and connective tissue
Arthralgia	10	1
Respiratory, thoracic and mediastinal
Epistaxis	11	0

Clinically relevant adverse reactions occurring in <10% of patients were:

Cardiac: cardiac failure (2.5%), and cardiac failure congestive (1.3%)

Gastrointestinal: ascites (5%), gastrointestinal hemorrhage (1.3%), and large intestine perforation (1.3%)

Hepatobiliary: cholelithiasis (1.3%)

Infections and infestations: upper respiratory tract infection (6%), urinary tract infection (6%), and herpes zoster (2.5%)

Vascular: flushing (3.8%), hypertension (3.8%), hypotension (3.8%), and hot flush (2.5%)

Nervous: insomnia (6%)

Musculoskeletal and connective tissue: pain in extremity (6%)

Respiratory, thoracic and mediastinal: dyspnea (9%), and cough (2.5%)

Skin and subcutaneous tissue: rash1 (8%), alopecia (9%), pruritus (8%), and hair color changes (6%)

Metabolism and nutrition: decreased appetite (8%)

Eye: lacrimation increased (9%)

Laboratory abnormality: decreased phosphate (9%)

Rash includes rash and rash maculo-papular

Table 8 summarizes the laboratory abnormalities observed in EXPLORER and PATHFINDER.

Table 8. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER
Laboratory Abnormality	AYVAKIT (200 mg once daily) N=80
Laboratory Abnormality	All Grades (%)	Grade ≥ 3 (%)
Hematology
Decreased platelets	64	21
Decreased hemoglobin	55	23
Decreased neutrophils	54	25
Decreased lymphocytes	34	11
Increased activated partial thromboplastin time	14	1
Increased lymphocytes	10	0
Chemistry
Decreased calcium	50	3
Increased bilirubin	41	3
Increased aspartate aminotransferase	38	1
Decreased potassium	26	4
Increased alkaline phosphatase	24	5
Increased creatinine	20	0
Increased alanine aminotransferase	18	1
Decreased sodium	18	1
Decreased albumin	15	1
Decreased magnesium	14	1
Increased potassium	11	0

1: Grouped terms

Other Clinically Relevant Adverse Reactions in <10% of patients

In the pooled GIST and AdvSM safety populations, photosensitivity occurred in 2.5% of patients [see Warnings and Precautions (5.3)].

Indolent Systemic Mastocytosis

The safety of AYVAKIT in patients with ISM was evaluated in PIONEER [see Clinical Studies (14.3)]. Patients received AYVAKIT 25 mg orally once daily with best supportive care (n = 141) or placebo once daily with best supportive care (n = 71).

Serious adverse reactions occurred in 1 patient (0.7%) who received AYVAKIT due to pelvic hematoma.

Permanent discontinuation of AYVAKIT due to an adverse reaction occurred in 1 patient (0.7%) due to dyspnea and dizziness.

Dosage interruptions of AYVAKIT due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dosage interruption included dizziness, blood alkaline phosphatase increased, dyspnea, face edema, pelvic hematoma, liver transaminase increased and respiratory tract infection (1 patient each).

Table 9 summarizes the frequency of adverse reactions in the PIONEER study. The most common adverse reactions (≥ 10%) in the AYVAKIT group were eye edema, dizziness, peripheral edema and flushing. Of all adverse reactions, 55% were Grade 1, 38% were Grade 2 and 7% were Grade 3. Among patients with edema adverse reactions, 95% were Grade 1 and 5% were Grade 2. Among patients with hemorrhage adverse reactions, 86% were Grade 1 and 14% were Grade 2.

Table 9. Adverse Reactions Occurring in AYVAKIT-Treated Patients with Indolent Systemic Mastocytosis During PIONEER Trial
Adverse Reactions*,†	AYVAKIT (25 mg once daily) + BSC N=141 %	Placebo + BSC N=71 %
Abbreviations: BSC=best supportive care
* Adverse reactions that occurred in ≥5% of AYVAKIT-treated patients and ≥2% more than placebo-treated patients. † Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 ‡ Eye edema includes periorbital edema, eye edema, swelling of eyelid, orbital edema, eye swelling, eyelid edema and eyelid ptosis. § Term includes several similar terms. ¶ Respiratory tract infection includes pneumonia, upper respiratory tract infection, bronchitis and respiratory tract infection. # Hematoma includes contusion, hematoma and pelvic hematoma. Þ Hemorrhage includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, retinal hemorrhage.
Eye edema‡	13	7
Dizziness§	13	10
Peripheral edema§	12	6
Flushing§	11	4
Respiratory tract infection¶	8	1
Face edema	7	1
Rash§	6	4
Liver transaminase increased§	6	3
Insomnia	6	3
Hematoma#	6	1
Blood alkaline phosphatase increased	6	1
HemorrhageÞ	5	3

Clinically relevant adverse reactions occurring in <5% of patients were:

Skin and subcutaneous tissue: photosensitivity (2.8%)