Gavreto Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in Precautions section (see Precautions): Interstitial Lung Disease/Pneumonitis; Hypertension; Hepatotoxicity; Hemorrhagic Events; Tumor Lysis Syndrome; Risk of Impaired Wound Healing.
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.
The pooled safety population in the Precautions section reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 438 patients with RET-altered solid tumors, including with RET fusion-positive NSCLC (n = 220), and RET-altered thyroid cancer (n=138), in ARROW [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Among 438 patients who received GAVRETO, 47% were exposed for 6 months or longer and 23% were exposed for greater than one year.
The most common adverse reactions (≥ 25%) were constipation, hypertension, fatigue, musculoskeletal pain and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium (corrected), decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased platelets, and increased alkaline phosphatase.
RET Fusion-Positive Non-Small Cell Lung Cancer: The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 220 patients with metastatic rearranged during transfection (RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Among the 220 patients who received GAVRETO, 42% were exposed for 6 months or longer and 19% were exposed for greater than one year.
The median age was 60 years (range: 26 to 87 years); 52% were female, 50% were White, 41% were Asian, and 4% were Hispanic/Latino.
Serious adverse reactions occurred in 45% of patients who received GAVRETO. The most frequent serious adverse reaction (in ≥ 2% of patients) was pneumonia, pneumonitis, sepsis, urinary tract infection, and pyrexia. Fatal adverse reactions occurred in 5% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n = 3) and sepsis (n = 2).
Permanent discontinuation due to an adverse reaction occurred in 15% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in > 1 patient included pneumonitis (1.8%), pneumonia (1.8%), and sepsis (1%).
Dosage interruptions due to an adverse reaction occurred in 60% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included neutropenia, pneumonitis, anemia, hypertension, pneumonia, pyrexia, increased aspartate aminotransferase (AST), increased blood creatine phosphokinase, fatigue, leukopenia, thrombocytopenia, vomiting, increased alanine aminotransferase (ALT), sepsis, and dyspnea.
Dose reductions due to adverse reactions occurred in 36% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included neutropenia, anemia, pneumonitis, neutrophil count decreased, fatigue, hypertension, pneumonia, and leukopenia.
Table 6 summarizes the adverse reactions in RET Fusion-Positive NSCLC Patients in ARROW. (See Table 6.)

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Table 7 summarizes the laboratory abnormalities in ARROW. (See Table 7.)

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Clinically relevant laboratory abnormalities < 20% of patients who received GAVRETO included increased phosphate (10%).