For patients diagnosed with RET fusion-positive, metastatic non-small cell lung cancer (NSCLC), understanding treatment options is crucial.
Part of the decision-making process may include considerations from the National Comprehensive Cancer Network (NCCN), which provides expert-developed guidelines that doctors use to determine the best course of action for treatment.
For first-line treatment, the NCCN guidelines strongly recommend targeted therapies aimed at the RET fusion, which is the genetic change driving a patient’s cancer growth.
These medications, such as Retevmo (selpercatinib) and Gavreto (pralsetinib), are taken orally and have shown significant promise in shrinking tumors and improving patient outcomes compared to traditional chemotherapy among patients with metastatic RET fusion-positive NSCLC.
Gavreto in the First Line
Gavreto is recommended as a category 2A preferred first-line treatment for metastatic RET fusion-positive NSCLC in the NCCN guidelines. This recommendation is based on evidence supporting its use in patients with a RET fusion-positive mutation.
Glossary:
Complete response: disappearance of all cancer signs after treatment.
Interstitial lung disease: a group of lung disorders causing scarring and difficulty breathing.
Pneumonitis: Inflammation of lung tissue, causing symptoms like cough, shortness of breath and chest pain.
Hepatotoxicity: Liver damage from chemicals or drugs, leading to abnormal liver function and potential failure.
AST (Aspartate aminotransferase): an enzyme in the liver and other tissues, elevated levels suggest liver damage.
ALT (Alanine aminotransferase): a liver enzyme, elevated levels indicate liver damage.
Tumor lysis syndrome (TLS): rapid tumor cell destruction, causing kidney failure and other complications.
The Food and Drug Administration (FDA) approval of Gavreto was based on results from the phase 1/2 ARROW study, which demonstrated a 57% overall response rate in patients with RET fusion-positive NSCLC, regardless of prior therapy or central nervous system involvement. Among 87 patients previously treated with platinum-based chemotherapy, 5.7% had a complete response, and 70% of 27 patients who were treatment-naive responded, with 11% achieving a complete response.
Side Effects and Dosing
Gavreto may cause severe, life-threatening interstitial lung disease or pneumonitis, with 12% of patients experiencing pneumonitis, including 3.3% with grade 3 (severe) to 4 (life-threatening) reactions and 0.2% with fatal cases. According to the agent’s manufacturer, Rigel Pharmaceuticals, patients should be monitored for pulmonary symptoms, and Gavreto should be withheld for investigation if symptoms worsen.
Hypertension occurred in 35% of patients, with 18% experiencing grade 3 hypertension. Dose interruptions and reductions due to hypertension occurred in 8% and 4.8% of patients, respectively. Hepatotoxicity occurred in 1.5% of patients, with increased aspartate aminotransferase (AST) in 49% and alanine aminotransferase (ALT) in 37%. Grade 3 to 4 AST was observed in 7%, and grade 3 to 4 ALT in 4.8% of patients.
Hemorrhagic events, including fatal cases, were observed in 4.1% of patients, with one fatal case. Tumor lysis syndrome (TLS) was reported in patients with medullary thyroid carcinoma. Common adverse reactions (25% or more) included musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. Grade 3 to 4 laboratory abnormalities (2% or more) included decreased lymphocytes, neutrophils, hemoglobin and phosphate, along with increased AST, ALT, alkaline phosphatase and bilirubin.
The recommended starting dose of Gavreto is 400 milligrams (mg) once daily. Treatment should continue until disease progression or unacceptable toxicity occurs. If a dose is missed, patients can take it on the same day, resuming their regular schedule the next day. If vomiting occurs, patients should not take an additional dose but continue with the next scheduled dose. Treatment should continue until disease progression or unacceptable toxicity occurs, with patients selected for Gavreto based on the presence of a RET gene fusion.
Gavreto and RET Fusion NSCLC
Gavreto works by selectively inhibiting the RET fusion protein, which drives tumor growth in RET fusion-positive NSCLC.
RET fusion-positive NSCLC is characterized by a fusion in the RET gene, present in 1% to 2% of NSCLC cases, according to Rigel Pharmaceuticals. The mutation leads to abnormal cell signaling, contributing to tumor growth. It is most commonly seen in patients with adenocarcinoma histology. Prior to Gavreto’s approval, treatment options for these patients were limited.
Testing for RET fusion is necessary before initiating treatment with Gavreto.
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