6.1Clinical Trial 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. Data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 176 patients, including 70 (40%) patients exposed for greater than 6 months and 35 (20%) patients exposed for greater than 1 year.
VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 70)], one pediatric dose-finding trial [SCOUT (n = 43)], and one single arm trial [NAVIGATE (n = 63)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 176 patients, the median age was 51 years (range: 28 days to 82 years); 25% were 18 years or younger; 52% were male; and 72% were White, 11% were Hispanic/Latino, 8% were Black, and 3% were Asian.
The most common tumors in order of decreasing frequency were soft tissue sarcoma (16%), salivary gland (11%), lung (10%), thyroid (9%), colon (8%), infantile fibrosarcoma (8%), primary central nervous system (CNS) (7%), or melanoma (5%). NTRK gene fusions were present in 60% of VITRAKVI-treated patients. Most adults (80%) received VITRAKVI 100 mg orally twice daily and 68% of pediatrics (18 years or younger) received VITRAKVI 100 mg/m 2 twice daily up to a maximum dose of 100 mg twice daily.
The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m 2 twice daily to 120 mg/m 2 twice daily in pediatrics [see Pediatric Use ( 8.4 )] . The most common adverse reactions (≥ 20%) in order of decreasing frequency were fatigue, nausea, dizziness, vomiting, anemia, increased AST, cough, increased ALT, constipation, and diarrhea. The most common serious adverse reactions (≥ 2%) were pyrexia, diarrhea, sepsis, abdominal pain, dehydration, cellulitis, and vomiting.
Grade 3 or 4 adverse reactions occurred in 51% of patients; adverse reactions leading to dose interruption or reduction occurred in 37% of patients and 13% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1-2% each) that resulted in discontinuation of VITRAKVI were brain edema, intestinal perforation, pericardial effusion, pleural effusion, small intestinal obstruction, dehydration, fatigue, increased ALT, increased AST, enterocutaneous fistula, increased amylase, increased lipase, muscular weakness, abdominal pain, asthenia, decreased appetite, dyspnea, hyponatremia, jaundice, syncope, vomiting, acute myeloid leukemia, and nausea.
The most common adverse reactions (≥ 3%) resulting in dose modification (interruption or reduction) were increased ALT (6%), increased AST (6%), and dizziness (3%). Most (82%) adverse reactions leading to dose modification occurred during the first three months of exposure. Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 5% of patients are summarized in Table 2 and Table 3 , respectively.
Table 2 Adverse Reactions Occurring in ≥ 10% of Patients Treated with VITRAKVI Adverse Reaction VITRAKVI N = 176 All Grades National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. (%) Grade 3-4 One Grade 4 adverse reaction of pyrexia. (%) General Fatigue 37 3 Pyrexia 18 1 Edema peripheral 15 0 Gastrointestinal Nausea 29 1 Vomiting 26 1 Constipation 23 1 Diarrhea 22 2 Abdominal pain 13 2 Nervous System Dizziness 28 1 Headache 14 0 Respiratory, Thoracic and Mediastinal Cough 26 0 Dyspnea 18 2 Nasal congestion 10 0 Investigations Increased weight 15 4 Musculoskeletal and Connective Tissue Arthralgia 14 1 Myalgia 14 1 Muscular weakness 13 0 Back pain 12 1 Pain in extremity 12 1 Metabolism and Nutrition Decreased appetite 13 2 Vascular Hypertension 11 2 Injury, Poisoning and Procedural Complications Fall 10 1 Table 3 Laboratory Abnormalities Occurring in ≥ 5% Patients Treated with VITRAKVI Laboratory Abnormality VITRAKVI Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available which ranged from 170 to 174 patients.
All Grades NCI-CTCAE v 4.03. (%) Grade 3-4 (%) Chemistry Increased ALT 45 3 Increased AST 45 3 Hypoalbuminemia 35 2 Increased alkaline phosphatase 30 3 Hematology Anemia 42 10 Neutropenia 23 7
