Vitrakvi Adverse Reactions

Adverse Reaction Overview: The safety of VITRAKVI was evaluated in 279 patients. Overall, 99% of patients experienced at least one TEAE. The most commonly reported TEAEs (≥ 20%), in order of decreasing frequency, were fatigue, cough, ALT increased, constipation, diarrhea, dizziness, anemia, AST increased, vomiting, nausea, and pyrexia.
The most common serious adverse events (≥ 2%) regardless of attribution included pneumonia, pyrexia, abdominal pain, diarrhea, and dyspnea.
Grade 3 or 4 TEAEs occurred in 53% of patients. Grade 4 events included sepsis, neutrophil count decreased, lymphocyte count decreased, ALT increased, hyponatremia, and hypoglycemia (1% for each). Grade 3 events included anemia (9%), weight increased (4%), hypophosphatemia (3%), fatigue (3%), ALT increased (3%), neutrophil count decreased (6%), dyspnea (3%), lymphocyte count decreased (4%), pneumonia (3%) and hypokalemia (3%).
Dose modification (interruption or reduction) of VITRAKVI dosage due to a TEAE occurred in 41% of patients. The most common TEAEs (≥ 3%) leading to dose modification were ALT increased (5%), AST increased (5%), and neutrophil count decreased (4%). The majority of adverse events leading to dose modification occurred in the first three months of treatment.
Permanent discontinuation of VITRAKVI for treatment emergent adverse events occurred in 9% of patients. The TEAEs that led to discontinuation of VITRAKVI and occurred in more than one patient were dehydration, malignant neoplasm progression, increased ALT, and increased AST.
Clinical Trial Adverse Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety of VITRAKVI was evaluated in 279 patients (overall safety population) who received at least one dose of VITRAKVI in one adult dose-finding trial [Study 1 (LOXO-TRK-14001) (n=75)], one single arm trial [Study 2 (NAVIGATE) (n=116)], and one pediatric trial [Study 3 (SCOUT) (n=88)]. The median time on treatment was 6.8 months (range: 0.03 month to 51.6 months). One hundred fifty (54%) patients were exposed to VITRAKVI for ≥ 6 months and 83 (30%) patients were exposed for ≥ 1 year. The majority of patients had an unresectable or metastatic solid tumour, including metastatic (72%) and locally advanced (18%) disease extent at enrollment.
Overall, patients had a median age of 46 years (range: 0.1 year to 84 years) with 33% of patients being pediatric patients. Forty-eight percent of patients were males and 74% were white.
The majority (86%) of adult patients (18 years and older) received 100 mg VITRAKVI taken twice daily as their starting dose. Three pediatric dose levels were evaluated with 85% of pediatric patients having received a starting dose of 100 mg/m² (with a maximum of 100 mg) taken twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m² twice daily to 120 mg/m² twice daily in pediatric patients. (See Table 8.)

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Additional Information in Selected Adverse Reactions: Neurologic/Psychiatric events: In the overall safety database (n=279), neurologic/psychiatric TEAEs of any grade were reported in 63% of patients. Neurologic/psychiatric adverse events occurring in > 5% of patients included dizziness (26%), headache (15%), mood disorders (14%), cognitive impairment (11%), sleep disorders (10%), gait disturbance (6%), paresthesia (6%), dysgeusia (6%), and peripheral sensory neuropathy (5%). Mood disorders is collectively made up of the adverse events anxiety (5%), depression (4%), agitation (3%), irritability (3%), depressed mood (< 1%), and euphoric mood (< 1%). Cognitive impairment is collectively made up of the adverse events memory impairment (4%), confusional state (3%), disturbance in attention (3%), delirium (2%), cognitive disorder (1%), aphasia (1%), hallucination (2%), mental status change (1%), amnesia (< 1%), and mental impairment (< 1%). Sleep disorders is collectively made up of the adverse events insomnia (7%), somnolence (3%), and sleep disorder (< 1%). Grade 3 and Grade 4 neurologic/psychiatric events were reported in 11% and < 2% of patients, respectively. Events led to dose modification (interruption or reduction) in 30 (11%) patients.
Transaminase Elevations: In the overall safety database (n=279), TEAEs of ALT increased occurred in 28% of patients, and AST increased occurred in 25% of patients. The maximum grade transaminase elevations observed were Grade 4 ALT increased in 2 patients (1%), Grade 4 AST increased in 1 patient (< 1%), Grade 3 ALT increased in 7 (3%) patients and Grade 3 AST increased in 6 (2%) patients. The incidence of transaminase elevations was higher in pediatric compared with adult patients (see Clinical Trial Adverse Reactions (Pediatrics) as follows).
ALT and AST increases leading to study drug interruption or dose modifications occurred in 14 (5%) patients and 13 (5%) patients, respectively. Increased transaminases led to permanent discontinuation of VITRAKVI in 2% of patients.
Clinical Trial Adverse Reactions (Geriatrics): Of 279 patients in the overall safety population who received VITRAKVI, 54 (19%) patients were ≥ 65 years of age and 13 (5%) patients were ≥ 75 years of age. The safety profile in elderly patients (≥ 65 years) was generally consistent with that seen in adult patients < 65 years of age. The TEAEs that were more frequent in patients ≥ 65 years of age included fatigue, anemia, dizziness, fall, gait disturbance, and hyponatremia.
Clinical Trial Adverse Reactions (Pediatrics): Of 279 patients treated with VITRAKVI, 92 (33%) patients were pediatrics, including 33 infants and toddlers aged up to 23 months, 38 children aged 2 to 11 years, and 21 adolescents aged 12 to < 18 years. The safety profile in the pediatric population was generally consistent in the types of reported adverse events to those observed in the adult population. A majority of adverse events were Grade 1 or 2 in severity and were resolved without VITRAKVI dose modification or discontinuation. The TEAEs that were more frequent in pediatric patients compared with adult patients regardless of attribution (≥ 10% difference) included vomiting (42% versus 17% in adults); transaminase elevations (ALT 37% versus 24% and AST 32% versus 22%); neutrophil count decreased (29% versus 5%); diarrhea (34% versus 22%); pyrexia (43% versus 13%); platelet count decreased (13% versus 3%); upper respiratory tract infection (23% versus 8%); leukocyte count decreased (20% versus 7%); nasopharyngitis (16% versus 6%); otitis media (13% versus 1%) and rhinitis (14% versus 1%). Treatment-emergent adverse events reported in the infant and toddler subgroup (n=33) at a higher incidence than in the other pediatric subgroups included vomiting (n=19); cough (n=15); diarrhea (n=19); pyrexia (n=26); ALT increased (n=15); neutrophil count decreased (n=15); and anemia (n=10).
Abnormal Laboratory Findings (Hematologic, Clinical Chemistry and other Quantitative Data): Clinically relevant laboratory abnormalities are shown in Table 9. (See Table 9.)

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