6 ADVERSE REACTIONS

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

Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions (5.1)]
New Primary Cutaneous Malignancies [see Warnings and Precautions (5.2)]
Hypertension [see Warnings and Precautions (5.3)]
Cardiac Dysfunction [see Warnings and Precautions (5.4)]
Photosensitivity [see Warnings and Precautions (5.6)]

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.

Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to QINLOCK as a single agent in 351 patients with advanced solid tumors enrolled in either an open-label dose finding with cohort expansion trial or INVICTUS. Among the patients who received QINLOCK in these trials, 52% were exposed for 6 months or longer and 21% were exposed for greater than one year.

Gastrointestinal Stromal Tumor

Patients Who Received Prior Treatment with Imatinib, Sunitinib and Regorafenib

The safety of QINLOCK was evaluated in INVICTUS [see Clinical Studies (14)]. Patients received QINLOCK 150 mg taken orally once daily (n=85) or placebo (n=43). Among the patients who received QINLOCK, 46% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.

Serious adverse reactions occurred in 31% of patients who received QINLOCK. Serious adverse reactions that occurred in >2% of patients were abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%).

Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received QINLOCK. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included general physical health deterioration (2.4%), anemia (1.2%), cardiac failure (1.2%), PPES (1.2%), and vomiting (1.2%).

Dosage interruptions due to an adverse reaction occurred in 24% of patients who received QINLOCK. Adverse reactions requiring dosage interruption in >2% of patients included nausea (3.5%), increased blood bilirubin (2.4%), and PPES (2.4%).

Dose reductions due to an adverse reaction occurred in 7% of patients who received QINLOCK. Adverse reactions resulting in a dose reduction in ≥1.2% of patients were abdominal pain, agitation, alopecia, arthritis, dermatosis, gastrointestinal disorder, hyperesthesia, myalgia, PPES, and decreased weight.

The most common adverse reactions (≥20%), were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.

Table 2 summarizes the adverse reactions in INVICTUS.

Table 2: Adverse Reactions (≥10%) in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK in INVICTUS
Adverse Reaction	QINLOCK (N=85)		Placebo (N=43)
Adverse Reaction	Grades 1-4	Grades 3-4	Grades 1-4	Grades 3-4
Skin and subcutaneous tissue
Alopecia	52	0	4.7	0
Palmar-plantar erythrodysesthesia syndrome	21	0	0	0
Dry skin	13	0	7	0
Pruritus	11	0	4.7	0
General
Fatigue	42	3.5	23	2.3
Peripheral edema	17	1.2	7	0
Asthenia	13	1.2	14	4.7
Gastrointestinal
Nausea	39	3.5	12	0
Abdominal pain	36	7	30	4.7
Constipation	34	1.2	19	0
Diarrhea	28	1.2	14	2.3
Vomiting	21	3.5	7	0
Stomatitis	11	0	0	0
Musculoskeletal and connective tissue
Myalgia	32	1.2	12	0
Arthralgia	18	0	4.7	0
Muscle spasms	15	0	4.7	0
Metabolism and nutrition
Decreased appetite	27	1.2	21	2.3
Investigations
Decreased weight	19	0	12	0
Nervous system
Headache	19	0	4.7	0
Vascular
Hypertension	14	7	4.7	0
Respiratory, thoracic and mediastinal
Dyspnea	13	0	0	0

Table 3 summarizes the laboratory abnormalities in INVICTUS.

Table 3: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK with a Difference Between Arms of >5% Compared to Placebo in INVICTUS
CPK=creatine phosphokinase; INR=international normalized ratio; AST=aspartate aminotransferase; ALT=alanine aminotransferase
a. The denominator used to calculate the rate varied from 82 to 83 for QINLOCK and 34 to 40 for placebo based on the number of patients with a baseline value and at least one post-treatment value.
b. Only includes Grade 3 laboratory abnormalities.
Laboratory Abnormality	QINLOCKa (N=85)		Placeboa (N=43)
Laboratory Abnormality	Grades 1-4	Grades 3-4b	Grades 1-4	Grades 3-4
Hematology
Increased activated partial thromboplastin time	35	0	9	0
Increased INR	21	3.8	15	0
Decreased neutrophil count	10	0	2.5	0
Chemistry
Increased lipase	32	7	13	8
Decreased phosphate	26	4.9	2.5	0
Increased triglycerides	26	2.4	23	0
Decreased calcium	23	0	8	0
Increased blood bilirubin	22	0	5	2.5
Increased CPK	21	1.2	10	0
Decreased sodium	17	2.4	10	2.5
Increased creatinine	16	0	18	0
Increased serum amylase	13	1.2	5	0
Increased ALT	12	1.2	5	0

Other Adverse Reactions

Clinically relevant adverse reactions that occurred in <10% of QINLOCK-treated patients in INVICTUS included peripheral sensory neuropathy, dermatitis acneiform, and rash.

Clinically relevant adverse reactions that occurred in <10% of patients in the pooled safety population included cardiac ischemic events (including acute coronary syndrome and fatal cardiac arrest or myocardial infarction). Photosensitivity occurred in 0.6% [see Warnings and Precautions (5.6)].