Ranibizumab Combined With Low-Dose Sorafenib for Exudative Age-Related Macular Degeneration

Abstract

Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered. Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered. Age-related macular degeneration (AMD) is the principal cause of severe vision loss in the elderly. The most common cause is choroidal neovascularization, also called exudative AMD. Because angiogenesis is a common factor in both cancer and exudative AMD, angiogenesis inhibition has been developed as a therapeutic strategy for both. Many clinical studies have supported use of the vascular endothelial growth factor (VEGF) antagonist bevacizumab for AMD and for cancer; the studies using bevacizumab for AMD were initially clinical observations and then nonrandomized trials. Thus far, results have been so overwhelmingly favorable that bevacizumab is commonly used for treatment of AMD, even though a randomized trial has not been performed.1Avery RL Pieramici DJ Rabena MD Castellarin AA Nasir MA Giust MJ Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.Ophthalmology. 2006; 113 (e5. Epub 2006 Feb 3.): 363-372Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar Sunitib and sorafenib have recently been approved as therapy for cancer.2Cabebe E Wakelee H Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEFGR tyrosine kinase inhibitors.Curr Treat Options Oncol. 2007; 8: 15-27Crossref PubMed Scopus (120) Google Scholar These oral tyrosine kinase inhibitors strongly diminish VEGF signaling by inhibiting VEGF receptor (VEGFR) function.3Stein MN Flaherty KT Sorafenib and sutinib in renal cell carcinoma.Clin Cancer Res. 2007; 13: 3765-3770Crossref PubMed Scopus (57) Google Scholar Studies show that very low doses of sorafenib inhibit VEGFR. When orally administered, 200 mg of sorafenib has a serum half-life of 29.5 hours; the maximum concentration of 1700 nM is 18 times higher than the 50% inhibitory concentration (IC50) for VEGFR2 and 65 times higher than the IC50 for VEGFR1.4Strumberg D Richly H Hilger RA et al.Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.J Clin Oncol. 2005 Feb 10; 23 (Epub 2004 Dec 21.): 965-972Crossref PubMed Scopus (799) Google Scholar, 5Strumberg D Clark JW Awada A et al.Safety, pharmacokinetics and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.Oncologist. 2007; 12: 426-437Crossref PubMed Scopus (370) Google Scholar We describe 2 patients with exudative AMD who needed multiple ranibizumab injections and who elected to have off-label sorafenib added to their standard treatment in an attempt to decrease the number of intraocular injections. The Mayo Clinic Institutional Review Board approved this study of 2 patients with exudative AMD in whom ranibizumab therapy was combined with sorafenib. An 83-year-old man was followed up for recurrent exudative AMD in his right eye (his left eye had a disciform scar with 20/600 vision). He had undergone multiple intraocular injections of bevacizumab and ranibizumab during the past 2 years (Figure 1, A). An initial fluorescein angiogram showed leakage consistent with a mainly occult neovascular membrane (Figure 1, B). His visual acuity was 20/70. Fundoscopy showed intraretinal fluid with cystoid changes. Optical coherence tomography (OCT) revealed retinal thickening with cystic changes (Figure 1, C). Because the patient wanted to decrease the number of intraocular injections, he elected to undergo an injection of intraocular ranibizumab in conjunction with oral sorafenib, 200 mg, 3 times a week for 5 weeks. At 5-week follow-up, his visual acuity had improved to 20/60, and OCT showed 1 small residual cystoid space (Figure 1, D). One month after the patient discontinued sorafenib therapy, his vision decreased to 20/70, and OCT showed a recurrence of obvious intraretinal fluid (Figure 1, E). The patient elected to use oral sorafenib alone. After 1 month, the patient's vision improved to 20/50, and OCT showed a marked diminution in the intraretinal fluid (Figure 2, F). The patient stated that after the initial dose of sorafenib, he had mild acral dermatitis, but it resolved spontaneously. Hehas had no other problems and continues to take low-dose sorafenib therapy.FIGURE 2Case 2. Timeline of treatment with ranibizumab and/or sorafenib from September 2005 to September 2007. B, Initial fluorescein angiogram shows leakage consistent with a neovascular membrane. C, Optical coherence tomogram confirms presence of intraretinal fluid (arrow) 2 months after ranibizumab injection. D, Optical coherence tomogram shows intraretinal fluid (arrow) 1 month after ranibizumab injection. E, Optical coherence tomogram shows no intraretinal fluid 1 month after administration of sorafenib.View Large Image Figure ViewerDownload (PPT) An 81-year-old man with recurrent exudative AMD in his left eye had undergone 8 injections of ranibizumab during the past year (Figure 2, A). His visual acuity was 20/30 in his left eye and 20/20 in his right eye. Initial fluorescein angiography had confirmed leakage consistent with a neovascular membrane (Figure 2, B). Fundoscopy showed confluent soft drusen, intraretinal hemorrhage, and pigment epithelial detachment (PED) with an occult choroidal neovascular membrane involving the fovea. Additionally, OCT revealed PED and intraretinal cystoid spaces (Figure 2, C). The patient was given an injection of ranibizumab and returned 1 month later. Cystoid spaces were still evident, and his vision had decreased to 20/40 (Figure 2, D). He opted to take sorafenib, 200 mg, 3 times a week for a month because he wanted to avoid further intraocular injections. One month later, his visual acuity remained stable, and OCT showed improvement with resolution of the intraretinal fluid and a decrease in the size of the PED (Figure 2, E). Vascular endothelial growth factor is implicated in the development of choroidal neovascularization and some forms of cancer.6Bressler NM Bressler SB Fine SL Neovascular (exudative) age-related macular degeneration.in: Ryan Stephen J. Retina. Elsevier Mosby, Philadelphia, PA2006: 1075-1113Google Scholar, 7Nowak JZ Age-related macular degeneration (AMD): pathogenesis and therapy.Pharmacol Rep. 2006; 58: 353-363PubMed Google Scholar On the basis of this observation, VEGF antagonists are used as treatment of angiogenic diseases.8Ho QT Kuo CJ Vascular endothelial growth factor: biology and therapeutic applications.Int J Biochem Cell Biol. 2007; 39 (Epub 2007 Apr 22.): 1349-1357Crossref PubMed Scopus (144) Google Scholar Currently, only pegaptanib and ranibizumab have been approved by the Food and Drug Administration for treating neovascular AMD, but intravitreal bevacizumab has also been used off label with reported success.1Avery RL Pieramici DJ Rabena MD Castellarin AA Nasir MA Giust MJ Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.Ophthalmology. 2006; 113 (e5. Epub 2006 Feb 3.): 363-372Abstract Full Text Full Text PDF PubMed Scopus (1082) Google Scholar Sorafenib and other tyrosine kinase inhibitors have been approved for treatment of certain cancers. Because sorafenib is a strong inhibitor of VEGFR signaling and has a long half-life, we discussed the off-label use of sorafenib with these patients who wanted to undergo fewer intraocular injections. The 200-mg dosage of sorafenib 3 times a week is much lower than the dosage of 800 mg/d used in patients with cancer. We chose this dosage because very low doses inhibit VEGFR. An oral dose of 200 mg of sorafenib has a half-life of 29.5 hours and a maximum concentration of 1700 nM. This concentration is 18 times higher than the IC50 for VEGFR2 and 65 times higher than the IC50 for VEGFR1; thus, 1 dose should have sufficient inhibitory effect on VEGFR2 for 2 or 3 days.4Strumberg D Richly H Hilger RA et al.Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.J Clin Oncol. 2005 Feb 10; 23 (Epub 2004 Dec 21.): 965-972Crossref PubMed Scopus (799) Google Scholar, 5Strumberg D Clark JW Awada A et al.Safety, pharmacokinetics and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.Oncologist. 2007; 12: 426-437Crossref PubMed Scopus (370) Google Scholar Both our patients experienced stability or improvement in vision and a marked improvement on OCT after sorafenib therapy was added to the regimen. Case 1 revealed a marked improvement in intraretinal edema 1 month after taking sorafenib. After this patient discontinued sorafenib therapy, intraretinal fluid recurred, and his vision decreased. One month after sorafenib was resumed, his vision and OCT findings improved. Case 2 showed resolution of the intraretinal fluid after sorafenib had been administered for 1 month. Neither patient developed serious adverse events. Case 1 stated that after the initial dose of sorafenib, he had mild acral dermatitis; this condition resolved spontaneously, and he continued the medication. No other adverse events were noted. The limitations of this study are the short follow-up of the patients, the small number of treated patients, and the overlap between use of ranibizumab and sorafenib therapy. Additionally, it could be that the patients' courses reflected the natural history of exudatve AMD. However, the apparent increase in macular edema in 1 patient after discontinuation of sorafenib and the reduced macular edema after reinitiation of sorafenib in both patients suggest a monotherapeutic effect. Kernt et al9Kernt M, Staehler M, Christian S, Kampik A, Neubauer AS. Resolution of macular oedema in occult choroidal neovascularization under oral sorafenib treatment [published online ahead of print October 1, 2007]. Acta Ophthalmol Scand. doi:10.1111/j.1600-0420.2007.01014.x.Google Scholar described a patient with renal cell carcinoma who had exudative AMD. This patient experienced improvement of his exudative AMD after use of a standard dose of sorafenib for his renal cell cancer. Although the case report by Kernt et al supports our findings, their patient received much higher doses of sorafenib than what we thought was needed for VEGFR inhibition for AMD. Adding low-dose sorafenib to standard therapy for refractory or recurrent exudative AMD, as well as trials for use as a single agent in patients with neovascular AMD, should be considered.