ranibizumab combined with low-dose sorafenib for exudative age-related macular degeneration

Mayo Clin Proc. • February 2008;83(2):231-234 • www.mayoclinicproceedings.com 231

RANIBIZUMAB AND SORAFENIB FOR MACULAR DEGENERATION

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

CASE REPORT

From the Department of Ophthalmology (T.D., J.S.P., L.C.C., T.P.L.) andDepartment of Oncology (J.R.M.), Mayo Clinic. Rochester, MN; and Vitreo-Retinal Surgery, PA. Edina, MN (E.H.R.).

Individual reprints of this article are not available. Address correspondence toJose S. Pulido, MD, Department of Ophthalmology, Mayo Clinic, 200 First StSW, Rochester, MN ([email protected]).

© 2008 Mayo Foundation for Medical Education and Research

Ranibizumab Combined With Low-Dose Sorafenib forExudative Age-Related Macular Degeneration

TERESA DIAGO, MD; JOSE S. PULIDO, MD, MPH, MS; JULIAN R. MOLINA, MD, PHD; LUCIENNE C. COLLET, MD;THOMAS P. LINK, CRA; AND EDWIN H. RYAN JR, MD

Angiogenesis is a common factor in the pathogenesis of cancerand in exudative age-related macular degeneration (AMD).Therefore, angiogenesis inhibition has been developed as atherapeutic strategy. We report 2 cases of recurrent exudativeAMD in which oral sorafenib, a tyrosine kinase inhibitor approvedfor cancer, was added to intravitreal ranibizumab, an antibody tovascular endothelial growth factor. These 2 patients werefollowed up by determination of visual acuity, fluorescein angiog-raphy, fundoscopy, and optical coherence tomography. The visualacuity of 1 patient improved from 20/70 to 20/60 while he wasreceiving sorafenib therapy; that of the other did not. Markedimprovement was noted in both patients on optical coherencetomography. Additionally, both patients appeared to receive somebenefit when low-dose oral sorafenib was used as monotherapyafter its initial addition to ranibizumab therapy. Randomized trialsof adding sorafenib to standard therapy for patients with neo-vascular AMD should be considered.

Mayo Clin Proc. 2008;83(2):231-234

AMD = age-related macular degeneration; IC50 = 50% inhibitoryconcentration; OCT = optical coherence tomography; PED = pigmentepithelial detachment; VEGF = vascular endothelial growth factor;VEGFR = VEGF receptor

Age-related macular degeneration (AMD) is theprincipal cause of severe vision loss in the elderly.

The most common cause is choroidal neovascularization,also called exudative AMD. Because angiogenesis is acommon factor in both cancer and exudative AMD, angio-genesis inhibition has been developed as a therapeuticstrategy for both. Many clinical studies have supported useof the vascular endothelial growth factor (VEGF) antag-onist bevacizumab for AMD and for cancer; the studiesusing bevacizumab for AMD were initially clinical obser-vations and then nonrandomized trials. Thus far, resultshave been so overwhelmingly favorable that bevacizumabis commonly used for treatment of AMD, even though arandomized trial has not been performed.1

Sunitib and sorafenib have recently been approved astherapy for cancer.2 These oral tyrosine kinase inhibitorsstrongly diminish VEGF signaling by inhibiting VEGFreceptor (VEGFR) function.3 Studies show that very lowdoses of sorafenib inhibit VEGFR. When orally admin-istered, 200 mg of sorafenib has a serum half-life of 29.5hours; the maximum concentration of 1700 nM is 18 timeshigher than the 50% inhibitory concentration (IC50) forVEGFR2 and 65 times higher t han the I C50 fo r VEGFR1.4,5

We describe 2 patients with exudative AMD who neededmultiple ranibizumab injections and who elected to have off-label sorafenib added to their standard treatment in anattempt to decrease the number of intraocular injections.

REPORT OF CASES

The Mayo Clinic Institutional Review Board approved thisstudy of 2 patients with exudative AMD in whom ran-ibizumab therapy was combined with sorafenib.

CASE 1An 83-year-old man was followed up for recurrentexudative AMD in his right eye (his left eye had adisciform scar with 20/600 vision). He had undergonemultiple intraocular injections of bevacizumab and ran-ibizumab during the past 2 years (Figure 1, A). An initialfluorescein angiogram showed leakage consistent with amainly occult neovascular membrane (Figure 1, B). Hisvisual acuity was 20/70. Fundoscopy showed intraretinalfluid with cystoid changes. Optical coherence tomography(OCT) revealed retinal thickening with cystic changes(Figure 1, C). Because the patient wanted to decrease thenumber of intraocular injections, he elected to undergo aninjection of intraocular ranibizumab in conjunction withoral 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 sorafenibtherapy, his vision decreased to 20/70, and OCT showed arecurrence of obvious intraretinal fluid (Figure 1, E). Thepatient elected to use oral sorafenib alone. After 1 month,the patient’s vision improved to 20/50, and OCT showed amarked diminution in the intraretinal fluid (Figure 2, F).The patient stated that after the initial dose of sorafenib, hehad mild acral dermatitis, but it resolved spontaneously. He

Mayo Clin Proc. • February 2008;83(2):231-234 • www.mayoclinicproceedings.com232



Jul 2007

FIGURE 1. Case 1. A, Timeline of treatment with ranibizumab and/or sorafenib from September 2005 to September2007. B, Initial fluorescein angiogram reveals leakage consistent with a neovascular membrane. C, Opticalcoherence tomogram confirms the presence of intraretinal fluid (arrow) before combined therapy was given. D,Optical coherence tomogram shows no intraretinal fluid 1 month after combined therapy. E, Recurrence ofintraretinal fluid (arrow) 2 months after discontinuation of sorafenib. F, Optical coherence tomogram shows nointraretinal fluid 1 month after reinstitution of sorafenib.

Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep

RanibizumabSorafenib

A

Aug 2007

Sep 2005

Sep 2007

Oct 2007

D E

F

B C

Mayo Clin Proc. • February 2008;83(2):231-234 • www.mayoclinicproceedings.com 233



has had no other problems and continues to take low-dosesorafenib therapy.

CASE 2An 81-year-old man with recurrent exudative AMD in hisleft eye had undergone 8 injections of ranibizumab duringthe past year (Figure 2, A). His visual acuity was 20/30 inhis left eye and 20/20 in his right eye. Initial fluoresceinangiography had confirmed leakage consistent with aneovascular membrane (Figure 2, B).

Fundoscopy showed confluent soft drusen, intraretinalhemorrhage, and pigment epithelial detachment (PED)

FIGURE 2. Case 2. Timeline of treatment with ranibizumab and/or sorafenib from September 2005 toSeptember 2007. B, Initial fluorescein angiogram shows leakage consistent with a neovascularmembrane. C, Optical coherence tomogram confirms presence of intraretinal fluid (arrow) 2 monthsafter ranibizumab injection. D, Optical coherence tomogram shows intraretinal fluid (arrow) 1 monthafter ranibizumab injection. E, Optical coherence tomogram shows no intraretinal fluid 1 month afteradministration of sorafenib.

with an occult choroidal neovascular membrane in-volving the fovea. Additionally, OCT revealed PED andintraretinal cystoid spaces (Figure 2, C). The patientwas given an injection of ranibizumab and returned 1month later. Cystoid spaces were still evident, and hisvision had decreased to 20/40 (Figure 2, D). He optedto take sorafenib, 200 mg, 3 times a week for a monthbecause he wanted to avoid further intraocular injec-tions. One month later, his visual acuity remained stable,and OCT showed improvement with resolution of theintraretinal fluid and a decrease in the size of the PED(Figure 2, E).

Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep

RanibizumabSorafenib

A

Jul 2007Feb 2007

Aug 2007 Sep 2007

D E

B C

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REFERENCES1. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust

MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related maculardegeneration. Ophthalmology. 2006;113(3):363-372.e5. Epub 2006 Feb 3.2. Cabebe E, Wakelee H. Role of anti-angiogenesis agents in treating

NSCLC: focus on bevacizumab and VEFGR tyrosine kinase inhibitors. CurrTreat Options Oncol. 2007;8(1):15-27.3. Stein MN, Flaherty KT. Sorafenib and sutinib in renal cell carcinoma. Clin

Cancer Res. 2007;13(13):3765-3770.4. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and

pharmacokinetic study of the novel Raf kinase and vascular endothelial growthfactor receptor inhibitor BAY 43-9006 in patients with advanced refractorysolid tumors. J Clin Oncol. 2005 Feb 10;23(5):965-972. Epub 2004 Dec 21.5. Strumberg D, Clark JW, Awada A, et al. Safety, pharmacokinetics and

preliminary antitumor activity of sorafenib: a review of four phase I trials inpatients with advanced refractory solid tumors. Oncologist. 2007;12(4):426-437.6. Bressler NM, Bressler SB, Fine SL. Neovascular (exudative) age-related

macular degeneration. In: Stephen J. Ryan, ed. Retina. Philadelphia, PA:Elsevier Mosby; 2006:1075-1113.7. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and

therapy. Pharmacol Rep. 2006;58(3):353-363.8. Ho QT, Kuo CJ. Vascular endothelial growth factor: biology and thera-

peutic applications. Int J Biochem Cell Biol. 2007;39(7-8):1349-1357. Epub2007 Apr 22.9. Kernt M, Staehler M, Christian S, Kampik A, Neubauer AS. Resolution of

macular oedema in occult choroidal neovascularization under oral sorafenibtreatment [published online ahead of print October 1, 2007]. Acta OphthalmolScand. doi:10.1111/j.1600-0420.2007.01014.x.

DISCUSSION

Vascular endothelial growth factor is implicated in thedevelopment of choroidal neovascularization and someforms of cancer.6,7 On the basis of this observation, VEGFantagonists are used as treatment of angiogenic diseases.8

Currently, only pegaptanib and ranibizumab have beenapproved by the Food and Drug Administration for treatingneovascular AMD, but intravitreal bevacizumab has alsobeen used off label with reported success.1 Sorafenib andother tyrosine kinase inhibitors have been approved fortreatment of certain cancers. Because sorafenib is a stronginhibitor of VEGFR signaling and has a long half-life, wediscussed the off-label use of sorafenib with these patientswho wanted to undergo fewer intraocular injections.

The 200-mg dosage of sorafenib 3 times a week is muchlower than the dosage of 800 mg/d used in patients withcancer. We chose this dosage because very low dosesinhibit VEGFR. An oral dose of 200 mg of sorafenib has ahalf-life of 29.5 hours and a maximum concentration of1700 nM. This concentration is 18 times higher than theIC50 for VEGFR2 and 65 times higher than the IC50 forVEGFR1; thus, 1 dose should have sufficient inhibitoryeffect on VEGFR2 for 2 or 3 days.4,5

Both our patients experienced stability or improvementin vision and a marked improvement on OCT after sora-fenib therapy was added to the regimen. Case 1 revealed amarked improvement in intraretinal edema 1 month aftertaking sorafenib. After this patient discontinued sorafenibtherapy, intraretinal fluid recurred, and his vision de-creased. One month after sorafenib was resumed, his visionand OCT findings improved. Case 2 showed resolution ofthe intraretinal fluid after sorafenib had been administeredfor 1 month. Neither patient developed serious adverseevents. Case 1 stated that after the initial dose of sorafenib,he had mild acral dermatitis; this condition resolvedspontaneously, and he continued the medication. No otheradverse events were noted.

The limitations of this study are the short follow-up ofthe 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 reflectedthe natural history of exudatve AMD. However, theapparent increase in macular edema in 1 patient after dis-continuation of sorafenib and the reduced macular edemaafter reinitiation of sorafenib in both patients suggest amonotherapeutic effect.

Kernt et al9 described a patient with renal cell carcinomawho had exudative AMD. This patient experienced improve-ment of his exudative AMD after use of a standard dose ofsorafenib for his renal cell cancer. Although the case reportby Kernt et al supports our findings, their patient receivedmuch higher doses of sorafenib than what we thought wasneeded for VEGFR inhibition for AMD. Adding low-dosesorafenib to standard therapy for refractory or recurrentexudative AMD, as well as trials for use as a single agent inpatients with neovascular AMD, should be considered.

ranibizumab combined with low-dose sorafenib for exudative age-related macular degeneration

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