Late Intervention with Radiation-Induced Lung Fibrosis - Comparing Pamrevlumab Anti-CTGF Therapy vs. Pirfenidone vs. Nintedanib as Mono-, Dual- and Triple-therapy Combinations

Abstract

Radiation-induced lung fibrosis (RILF) is a major late side effect of radiotherapy of thoracic malignancies. The severity of RILF depends on irradiated lung volume and prescribed dose/fractionation scheme. In contrast to acute and subacute pneumonitis that are responsive to steroids, RILF is a dose-limiting factor for curative treatment of tumors and is an unmet medical need for potential anti-fibrosis therapy. We investigated the impact of pamrevlumab (FG-3019), an anti-CTGF antibody, and compared it to approved IPF (idiopathic pulmonary fibrosis) drugs, pirfenidone and nintedanib, or to their combinations. Late intervention, after fibrosis begins (15-16-week post radiation in mice), is challenging for anti-fibrotic treatment. Therefore, we evaluated if dual or triple combinations of the antifibrotic drugs may elicit superior effects. C57Bl/6 mice received single dose 14.5 Gy whole thoracic irradiation (RT) and the antifibrotic treatments started 16 weeks after RT, when lung remodeling was evident by CT, for 8 weeks. Pamrevlumab or placebo IgG were administered IP 2/wk at 40 mg/kg. Pirfenidone or nintedanib were administered PO at a daily target dose of 300 or 100 mg/kg, either formulated into chow or by gavage. Lung density changes were assessed by CT, and lung function was assessed by blood gas analysis. Gene expression changes were assessed by RNAseq. Pamrevlumab was the only monotherapy to inhibit lung remodeling and to normalize a substantial number of RT-altered transcripts when the IPF drugs were administered in chow. Interestingly, pirfenidone appeared to antagonize some of the benefits of pamrevlumab, which was also supported by transcriptome analysis. Based on the known short plasma half-life of pirfenidone and nintedanib and their possible insufficient exposure in chow, both drugs were administered by gavage for the next experiments to ensure that mice received a full daily dose. Neither drug was tolerable at the full dose, so the daily doses were divided into two parts and administered 2/d. With gavage administration, both pirfenidone and nintedanib inhibited lung remodeling measured by CT (p< 0.05), but pamrevlumab remained the superior monotherapy (p< 0.001). Combining pirfenidone with pamrevlumab did not appear to alter the benefit of pamrevlumab, but the combination of nintedanib with pamrevlumab significantly decreased lung remodeling at 24 weeks after RT compared to pamrevlumab alone (p< 0.01). Pamrevlumab was the only monotherapy to significantly increase median survival (p< 0.01). Addition of pirfenidone or nintedanib to pamrevlumab resulted in non-significant changes of median survival. At late stage RILF development, pamrevlumab monotherapy exhibits potent antifibrotic activity that warrants further clinical evaluation.