Gefitinib decreased lung fibrosis, but worsened inflammation, in rats

The early study suggested that TGF-α overexpression caused pulmonary fibrosis in transgenic mice [ref1], whereas TGF-α deficiency reduced pulmonary fibrosis in TGF-α knockout mice [ref2]. Therefore, it is plausible to treat patients with IPF by inhibition of TGF-α/EGF signaling. In a bleomycin-induced lung fibrosis model in mice,  it was shown that EGFR tyrosine kinase inhibitors, gefitinib and AG1478. Both inhibitors attenuated lung fibrosis [ref3].

Recently, Dr. Sone group examined the effect of gefitinib in a radiation induced injury model in rats. The new study found that gefitinib attenuated fibrotic lung remodeling, but exaggerated lung inflammation [ref4].



References

Hardie WD, Le Cras TD, Jiang K, Tichelaar JW, Azhar M, Korfhagen TR. Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2004;286:L741–L749.


Madtes DK, Elston AL, Hackman RC, Dunn AR, Clark JG. Transforming growth factor-alpha deficiency reduces pulmonary fibrosis in transgenic mice. Am J Respir Cell Mol Biol 1999;20:924–934.

Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycin-induced lung
fibrosis in mice. Am J Respir Crit Care Med. 2006 Sep 1;174(5):550-6. Epub 2006
Jun 1. PubMed PMID: 16741154.

Miyake K, Tani K, Kakiuchi S, Suzuka C, Toyoda Y, Kishi J, Tezuka T, Yuasa S,
Hanibuchi M, Aono Y, Nishioka Y, Sone S. Epidermal growth factor
receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but
attenuates lung fibrosis in response to radiation injury in rats. J Med Invest.
2012;59(1-2):174-85. PubMed PMID: 22450006.

PANTHER-IPF trial failed

The PANTHER-IPF trial results were published recently in NEJM. The trial was to test the three-drug regimen (prednisone, azathioprine, and NAC) against NAC alone (plus matched identified placebos for prednisone and azathioprine), as compared with matched placebos for each of the active therapies, in patients with idiopathic pulmonary fibrosis who had mild-to-moderate impairment in pulmonary function.

Unfortunately, the three-drug regimen was stopped on October 14, 2011, when interim assessment found the increased deaths, hospitalizations, and serious adverse events among patients with the 3-drug regimen.
































Clearly the benefit to the 3-drug regimen was lacking. Because of the combination group was stopped early, there was no assessment on the primary outcome at the end of the study. Interim analysis showed no difference in the change in FVC.

 The NAC only arm is now continued.

Reference:
Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012 May 24;366(21):1968-77. Epub 2012 May 20. PubMed PMID: 22607134.


http://www.nejm.org/doi/full/10.1056/NEJMoa1113354