What is the role of Ofev (nintedanib) in treating radiation-induced pulmonary fibrosis?

Use of Nintedanib (Ofev) in Radiation-Induced Pulmonary Fibrosis

Nintedanib can be considered for radiation-induced pulmonary fibrosis based on preclinical evidence showing reduction in microscopic lung fibrosis, though it lacks direct clinical trial data in this specific population and is not formally approved for this indication. 1

Evidence Base and Mechanism

The rationale for using nintedanib in radiation-induced pulmonary fibrosis stems from its mechanism as an intracellular inhibitor of multiple tyrosine kinases (VEGF, FGF, and PDGF receptors) that are involved in fibrotic processes. 2 While nintedanib has strong evidence in idiopathic pulmonary fibrosis and progressive pulmonary fibrosis from other causes, the evidence specific to radiation-induced fibrosis is limited to preclinical studies.

Preclinical Evidence

• A mouse model of partial lung irradiation demonstrated that nintedanib (30-60 mg/kg daily) significantly reduced microscopic fibrotic changes including interstitial edema, interstitial and perivascular fibrosis, inflammation, and vasculitis when started one week post-irradiation. 1
• The anti-fibrotic effect was confirmed histologically but notably could not be detected by CT density measurements, meaning standard radiographic monitoring may not capture treatment response. 1
• No adverse effects were observed in the preclinical model. 1

Extrapolation from Progressive Pulmonary Fibrosis Guidelines

The 2022 ATS/ERS/JRS/ALAT guidelines conditionally recommend nintedanib for progressive pulmonary fibrosis (PPF) from various causes, which could theoretically include radiation-induced fibrosis if it meets PPF criteria. 3

Defining Progressive Disease

Radiation-induced pulmonary fibrosis would need to demonstrate progression defined by:

• Decline in FVC ≥10% predicted within 24 months, OR
• Decline in FVC 5-10% predicted plus worsening respiratory symptoms or increased fibrosis on imaging within 24 months 3

Expected Benefits in PPF

• Nintedanib reduces annual FVC decline by approximately 107 ml compared to placebo in PPF patients. 3, 2
• It decreases the risk of ILD progression 2.4-fold. 3, 4
• The effect on mortality was not statistically significant in the INBUILD trial. 3
• Quality of evidence is rated as low to moderate, meaning effects should be interpreted with caution. 3, 4

Practical Treatment Algorithm

If considering nintedanib for radiation-induced pulmonary fibrosis:

1. Confirm progressive fibrosis with serial pulmonary function tests showing FVC decline and/or worsening symptoms with radiographic progression 3

2. Initiate at standard dosing: 150 mg twice daily 2, 4

3. Anticipate gastrointestinal side effects which are the most common adverse events:

   • Diarrhea occurs in approximately 62% of patients (versus 18% on placebo) 2
   • Abdominal pain is 4.2 times more frequent 3, 4
   • Nausea is 3.1 times more frequent 3, 4
   • Vomiting is 3.6 times more frequent 3, 4
   • Weight loss is 3.7 times more frequent 3, 4

4. Manage adverse effects proactively:

   • For persistent diarrhea or intolerance, reduce to 100 mg twice daily 2, 4
   • Adverse events lead to permanent dose reduction 7.9 times more frequently than placebo 3, 4
   • Treatment discontinuation occurs 1.9 times more frequently 3, 4

5. Monitor liver enzymes regularly:

   • AST elevation is 3.2 times more frequent 3, 4
   • ALT elevation is 3.6 times more frequent 3, 4

Critical Caveats

• CT imaging cannot reliably monitor treatment response in radiation-induced fibrosis, as preclinical data showed histologic improvement without corresponding CT density changes. 1 Serial pulmonary function testing is essential for monitoring.

• No human clinical trial data exists specifically for radiation-induced pulmonary fibrosis—the recommendation is extrapolated from PPF data and preclinical models. 1

• Early initiation may be important, as the preclinical model started treatment one week post-irradiation. 1 Waiting for established fibrosis may reduce efficacy.

• The drug slows progression but does not reverse existing fibrosis, so expectations should be set accordingly. 4