ane (25 mg/day)
b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.
Laboratory parameter AFINITOR (10 mg/day)
+ exemestanea
N=482 Placebo
+ exemestanea
N=238
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
% % % % % %
Hematologyb
Hemoglobin decreased 68 6 0.6 40 0.8 0.4
WBC decreased 58 1 0 28 5 0.8
Platelets decreased 54 3 0.2 5 0 0.4
Lymphocytes decreased 54 11 0.6 37 5 0.8
Neutrophils decreased 31 2 0 11 0.8 0.8
Clinical chemistry
Glucose increased 69 9 0.4 44 0.8 0.4
Cholesterol increased 70 0.6 0.2 38 0.8 0.8
Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4
Alanine transaminase (ALT) increased 51 4 0.2 29 5 0
Triglycerides increased 50 0.8 0 26 0 0
Albumin decreased 33 0.8 0 16 0.8 0
Potassium decreased 29 4 0.2 7 1 0
Creatinine increased 24 2 0.2 13 0 0
6.2 Clinical Study Experience in Advanced Pancreatic Neuroendocrine Tumors
In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression.
The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on AFINITOR and one patient on placebo. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. There was one death due to pulmonary embolism on the placebo arm. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm.
Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 1 |
