My name is Zachary Moore, and I will be presenting the results of a phase 2 randomized controlled trial and an intentative for the treatment of radiation pneumonitis. I do not have any financial relationships to disclose. Radiation pneumonitis is a common toxicity of radiation treatment with rates of occurrence after definitive radiotherapy of around 20%. The clinical symptoms of radiation pneumonitis range from a dry cough and fever to shortness of breath and severe respiratory insufficiency. About 50% of patients with an initial episode of radiation pneumonitis have subsequent acute pulmonary exacerbations, and many eventually develop pulmonary fibrosis. There is no level 1 evidence for a therapeutic intervention that's effective in the treatment of acute radiation pneumonitis or the prevention of long-term effects of fibrosis. Typically a long, gradual taper of steroids is used for treatment. Nintendonib is a multiple tyrosine kinase inhibitor that blocks FGFR, PDGFR, and VEGFR. It's FDA approved for the treatment of idiopathic pulmonary fibrosis, and it has been shown to slow the progression of this disease in large phase 3 clinical trials by reducing the decline in forced vital capacity. Since the pathophysiology of idiopathic pulmonary fibrosis involves some of the same signaling pathways as radiation pneumonitis and the development of radiation fibrosis, we wish to determine whether Nintendonib would be effective in this setting. We completed a multi-institution phase 2 randomized double-blinded study comparing Nintendonib versus placebo in combination with a standard prednisone taper for the treatment of radiation pneumonitis. Our hypothesis was that the use of Nintendonib would decrease the incidence of acute exacerbations, long-term pulmonary function decline with fibrosis, and improve patient-reported outcomes in patients with grade 2 or higher radiation pneumonitis. The primary endpoint was to determine whether 12 weeks of Nintendonib in combination with oral prednisone decreased acute pulmonary exacerbations by improving freedom from exacerbations within one year, compared to placebo plus prednisone, with an acute exacerbation defined as a new or worsening cough, dyspnea, hypoxia, or pneumonitis lasting more than 4 days without an alternative cause. The secondary endpoints were the total number of acute exacerbations within one year and others that are going to be reported subsequently, including pulmonary function tests, assessment of radiographic fibrosis, hospitalizations, and patient-reported outcomes. All patients had a primary thoracic malignancy or lung metastasis that was treated with radiation greater than 4 weeks prior to enrollment, and was diagnosed with grade 2 or higher radiation pneumonitis. Patients were randomized one-to-one to Nintendonib for 12 weeks plus prednisone taper or prednisone taper alone. Follow-ups were scheduled with CT scans, pulmonary function tests, quality-of-life questionnaires, and biomarker studies. The planned enrollment was 68 patients. However, the study was closed early due to slow accrual after enrolling 34 patients. 30 patients were eligible for inclusion in the analysis. Baseline patient characteristics are shown here. Freedom from pulmonary exacerbations is shown here. At one year, an estimated 72% of patients in the Nintendonib group and 40% of patients in the placebo group were free from pulmonary exacerbations. This difference was not statistically significant with a p-value of 0.074. The total exacerbations in each group was compared by determining the probability of zero exacerbations using a Poisson model. The incidence rate ratio was not significant comparing the two treatment arms. Overall, the estimated median freedom from exacerbations was not reached in the Nintendonib arm in 193 days in the placebo group. This table shows grade 2 or higher adverse events that were rated as possibly and probably or definitely related to the study drug. There were 17 such events in the Nintendonib group and 5 in the placebo group. Two deaths occurred in the Nintendonib group but are not likely to have been caused by the study intervention. Additionally, uncomplicated venous thrombosis resulted in discontinuation of treatment for one patient and the Nintendonib group. In conclusion, this study showed no statistically significant difference in pulmonary exacerbations in patients treated with Nintendonib plus prednisone. However, there was a trend towards greater freedom from pulmonary exacerbations. Additionally, the study was limited by low accrual, reducing its power. Given the trend towards an improvement in pulmonary exacerbations with Nintendonib and some other recent studies that suggest a potential benefit of this drug for radiation pneumonitis, additional evaluation of Nintendonib is warranted. Secondary endpoints from this study, including patient-recorded outcomes, serum biomarkers, and radiographic findings will be reported in the future.

phase 2

randomized controlled trial

Nintendonib

radiation pneumonitis

tyrosine kinase inhibitor