Can entrectinib (Intestinal Alkaloid Protein Kinase inhibitor) cause pulmonary toxicity?

From the Guidelines

Entrectinib can cause lung toxicity, although the incidence is relatively low, and patients should be monitored for pulmonary symptoms. Entrectinib is a multi-targeted, pan-TRK, ROS1, and ALK inhibitor used to treat certain types of cancers with NTRK gene fusions or ROS1-positive non-small cell lung cancer 1. Lung toxicity, specifically interstitial lung disease (ILD) or pneumonitis, has been reported as a potential adverse effect of entrectinib therapy. Symptoms may include shortness of breath, cough, fever, or worsening respiratory symptoms. The incidence of lung toxicity with entrectinib is not explicitly stated in the provided evidence, but it is known that tyrosine kinase inhibitors, such as entrectinib, can cause pneumonitis, with incidence rates varying among different agents 1. For example, the incidence of pneumonitis with ALK inhibitors, a class of drugs that includes entrectinib, has been reported to be around 2.14% for all grades and 1.33% for high-grade pneumonitis 1. Patients taking entrectinib should be monitored for pulmonary symptoms, and if lung toxicity is suspected, the medication may need to be temporarily interrupted, dose-reduced, or permanently discontinued depending on the severity. The mechanism behind this toxicity likely involves the drug's effects on cellular signaling pathways that can trigger inflammatory responses in lung tissue. Patients with pre-existing lung disease or those who have received prior radiation therapy to the chest may be at higher risk for developing this complication.

Some key points to consider when monitoring patients for lung toxicity include:

• Symptoms: shortness of breath, cough, fever, or worsening respiratory symptoms
• Incidence: relatively low, but can be serious or life-threatening in some cases
• Risk factors: pre-existing lung disease, prior radiation therapy to the chest
• Management: temporary interruption, dose reduction, or permanent discontinuation of entrectinib depending on the severity of lung toxicity.

From the FDA Drug Label

Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2. 3%), respiratory failure (2%), and pyrexia (2%). Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2. 5%). Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumor lysis syndrome (0. 3%). The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders. Clinically relevant adverse reactions occurring in ≤ 10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3).

Entrectinib can cause lung toxicity, as evidenced by the following adverse reactions:

• Pneumonia (3.9% serious, 0.6% fatal)
• Dyspnea (3.7% serious, 0.6% fatal, 30% overall)
• Pleural effusion (3.4% serious, 8% overall)
• Lung infection (5% Grade 3 or 4)
• Pulmonary embolism (2.3% serious, 3.9% overall)
• Respiratory failure (2% serious)
• Hypoxia (3.4% Grade 3 or 4.2% overall) 2 2

From the Research

Entrectinib and Lung Toxicity

• There is no direct evidence in the provided studies that specifically addresses entrectinib causing lung toxicity.
• However, the studies do discuss the efficacy and safety of entrectinib in patients with non-small cell lung cancer (NSCLC) and other solid tumors 3, 4, 5, 6, 7.
• Entrectinib has been shown to be effective in treating NSCLC with ROS1 rearrangements, with a favorable toxicity profile 6, 7.
• The most common adverse events associated with entrectinib are fatigue, nausea, diarrhea, and constipation, but lung toxicity is not specifically mentioned as a common adverse event 4, 7.
• Further studies would be needed to determine the potential risk of lung toxicity associated with entrectinib treatment.