The pooled safety population in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14)]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.

The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection (RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1)]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year.

The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino.

Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3).

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in ≥ 2% of patients included pneumonitis (3.2%), and pneumonia (2.8%).

Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine phosphokinase, fatigue, pyrexia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting.

Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia.

Table 5 summarizes the adverse reactions in patients with NSCLC in ARROW.

Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%).

Table 6 summarizes the laboratory abnormalities in ARROW.

Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%).