New Insights from ARVO

Exploring patient outcomes when switching anti-VEGF therapies.

Dr. Kaiser: At the 2013 ARVO meeting, researchers presented numerous papers, describing outcomes after patients were switched from other anti-VEGF agents to aflibercept (Eylea, Regeneron). Dr. Hariprasad, what are your impressions of the data presented?

Dr. Hariprasad: Some 15 presentations dealt with switching anti-VEGF agents (one of which was from our group at the University of Chicago). I found wide variability in these studies — their definitions of suboptimal responders, inclusion/exclusion criteria, types of imaging used — but all of them studied suboptimal responders to ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech). This is what I took away from those studies:

• 1 study showed that vision and OCT didn’t change.

• 3 studies showed that vision didn’t change, but OCT improved.

• 1 study showed that vision improved, but OCT stayed the same.

• 10 of 15 studies showed that vision and OCT improved.

The key message is that no patient lost vision or showed anatomic worsening on OCT. This leads me to believe we can safely switch to aflibercept from older-generation anti-VEGF agents, and a distinct population of patients will respond and may even benefit in terms of dosing regimen.

Dr. Ehlers: Most of these studies were retrospective, and interpreting findings and drawing significant conclusions from them is difficult. I did note, however, that anatomic improvement seemed to be fairly universal, while vision was somewhat variable. For example, Barbazetto and colleagues looked at 80 eyes and then a subset of 12 eyes that lost vision when they were switched to aflibercept.⁷ Of those 12 eyes, seven returned to baseline vision with continued therapy, while all 12 improved from an anatomic standpoint.

Dr. Kaiser: In a study led by Rishi Singh at the Cleveland Clinic, we are prospectively following about 26 patients, who had three injections of aflibercept after switching and then an injection every 8 weeks. At 6 months, these patients had gained about seven letters of vision. I didn’t expect to see such a large improvement in such a short period. (There is preliminary, unpublished data addressing this in the ASSESS study.)

Dr. Hariprasad: Especially in the hardest-to-treat patients.

Dr. Slakter: And in chronically treated patients.

Dr. Kaiser: Why do you think this is, Dr. Slakter?

Dr. Slakter: In considering possible reasons for aflibercept showing a better treatment response, we might consider tachyphylaxis for patients who have been receiving chronic therapy. However, I have seen patients who received only one or two doses of ranibizumab or bevacizumab respond dramatically after being switched to aflibercept, so I can’t consider that a tachyphylaxis issue.

The ability of aflibercept to bind placental growth factor (PIGF) is something to consider. In my practice, we found that a majority of chronically treated patients with sub-optimal response have features of either a thick choroid that might suggest underlying central serous chorioretinopathy (CSC) or have patterns on indocyanine green angiography suggesting PCV. Many of the patients whom we are considering poor responders have these other features. Some researchers have studied some of the growth factors or angiogenic factors in AMD, and PlGF never seems to be on the list, but that’s in “typical” AMD. The question is: what about cases with central serous or polypoidal components? Maybe PlGF does play a role.

The tight binding affinity of aflibercept may be part of the answer. If the binding affinity is tighter and longer, it will hold the VEGF and prevent it from hitting its receptor. Most poor responders have RPE elevations. Most of them have occult-type CNV on fluorescein. Most of them have at least some degree of sub-RPE fluid. From the moment we inject any of the anti-VEGF drugs, regardless of the size of the molecule, the lowest concentration of drug from day 1 is under the RPE, so that would be the area where binding affinity might play the biggest role. The driving factor may be as simple as the affinity of the aflibercept for VEGF.

Evidence on Switching

Dr. Kaiser: As we’ve seen at ARVO 2013, research into the efficacy of switching anti-VEGF agents to treat AMD continues to mount. Two recently published papers are representative of the data being reported. Let’s discuss our own clinical experiences in comparison with the findings of these researchers.

In a retrospective study, Ho and colleagues looked at 96 eyes of 85 patients who had been treated with bevacizumab, ranibizumab or both and then were switched to aflibercept.⁸ After 4 months, the researchers found most eyes demonstrated stable visual acuity and anatomic improvements.

What clinical features would lead you to switch anti-VEGF therapies?

Dr. Hariprasad: Suboptimal resolution of macular fluid and inability to stabilize or improve vision leads me to try a different drug. I also consider switching to aflibercept if the patient has a too-frequent treat-and-extend schedule on an older generation therapy.

Dr. Ehlers: Switching may be warranted if fluid persists, or if fluid recurs rapidly on a p.r.n. or a treat-and-extend regimen.

Dr. Jain: The main reasons I switch drugs are the following: 1) incomplete response to therapy; 2) inability to extend to greater than 6 to 8 weeks on current therapy; 3) a patient’s desire to use an FDA-approved medication.

Dr. Slakter: I switch from other anti-VEGF agents to aflibercept in several situations. One is when an ongoing monthly regimen of the original agent fails to dry the macula in spite of at least four injections. In some cases, I have patients who have received injections as close as every 2 weeks without resolution of exudation. Another indication for switching therapy is when I’m unable to extend the treatment interval beyond 4 to 5 weeks without recurrent exudation. If this happens, I try aflibercept to get a longer treatment interval.

Dr. Kaiser: What treatment regimen do you follow when you switch to aflibercept?

Dr. Hariprasad: I treat monthly, and then, depending on the clinical response, I conservatively treat and extend.

Dr. Ehlers: My regimen varies based on the clinical scenario or the patient’s desires and priorities. Typically, I treat monthly until the macula is dry or a plateau is reached, and then I switch to treat-and-extend or p.r.n.

Dr. Slakter: I initiate treatment with the standard three loading doses used with treatment-naïve patients, followed by a slow treat-and-extend strategy. Given that many switched patients have chronic exudation, I plan for several monthly treatments before extending.

Dr. Jain: For a patient who has had an incomplete response, I load with three aflibercept injections. For transition patients who have had a complete response to previous anti-VEGF therapy, I give a single injection of aflibercept, have them return in 6 weeks, re-treat and extend to 8 weeks if the macula is dry.

Dr. Kaiser: How many cases do not respond to switching to aflibercept?

Dr. Ehlers: A significant proportion of patients respond from an anatomic standpoint with less predictable functional improvement.

Dr. Slakter: About 80% to 90% of my patients show some or major reduction in leakage or extension of treatment interval. About 10% show no significant difference using aflibercept.

Dr. Jain: It depends on how you define “respond.” I tend to base my decision less on OCT findings and more on visual acuity and subjective changes that patients report to me. The bottom line in my experience of switching patients to aflibercept is that we can increase the interval of treatment by 2 weeks compared with other anti-VEGF agents and maintain or slightly gain some visual acuity.

Dr. Kaiser: Does your experience mirror the Ho article?

Dr. Hariprasad: Yes. In fact, my resident Dr. Khushboo Agrawal and I presented our research at this ARVO meeting. We looked at 35 patients whom we were unable to treat and extend beyond 6 weeks with ranibizumab or bevacizumab, and we switched them to aflibercept. They showed an improvement in vision and drying on OCT. We also administered the Visual Function Questionnaire (VFQ-25) and found an improvement in the patients’ perceptions of their disease, mainly driven by fewer visits.⁹

Dr. Ehlers: I believe my experience mirrors the findings of Ho and colleagues fairly closely, but I do think I have seen a higher percentage of anatomic and vision improvement.

Dr. Slakter: I see similar anatomic benefits, but in many patients, I see a significant visual benefit, as well, beyond what Ho reported. I believe the major limitation in vision gain is related to the extent of chronic damage already present when we change treatment. If therapy is switched sooner, there’s more potential for improvement.

Dr. Jain: I have found a slight improvement in visual acuity at the 6-month mark, otherwise my outcomes are similar to those reported by Ho.

Dr. Kaiser: Are patients generally accepting of a switch to a different anti-VEGF agent?

Dr. Hariprasad: Patients definitely have questions about my decision-making process and the reasoning behind my recommendation to switch therapies. Billing issues sometimes arise; however, acceptance is high.

Dr. Kaiser: What OCT features do you monitor to see if switching was beneficial?

Dr. Slakter: Initially, I was observing only for reduced subretinal fluid and retinal cystic changes. Over time, however, I have found many instances when a chronic PED that was not changing or was even worsening when treated with other anti-VEGF agents now shows reduced height or total resolution with aflibercept. Therefore, I’ve now added RPE elevation to the parameters I monitor to determine the effect of the change in medication.

Dr. Jain: I also look for PED height and volume, as well as cystoid macular edema volume and subretinal fluid volume.

Dr. Ehlers: I look for evidence of exudation or disease activity, including intraretinal fluid, subretinal fluid, sub-RPE fluid and extent of pigment epithelial elevation.

Dr. Kaiser: Why do you think patients who are switched to aflibercept have anatomic improvement?

Dr. Hariprasad: I can only theorize that the anatomic improvement is related to aflibercept’s higher affinity to VEGF and its inhibition of PlGF, or the patient may have experienced tachyphylaxis to the previous anti-VEGF agent.

Dr. Ehlers: At this point, we don’t know why one patient may respond to one anti-VEGF agent versus another. Responses may be patient-specific or related to the various VEGF inhibitors. There’s likely a difference between true nonresponders and those with incomplete response or early recurrence with other anti-VEGF agents. I agree that tachyphylaxis may play a role in some patients. The additional blocking of PlGF may be important, as well as differences in drug potency or binding affinity.

Refractory and Recurrent AMD

Dr. Kaiser: Yonekawa and colleagues recently published a retrospective chart review of 102 eyes of 94 patients with chronic refractory or recurrent neovascular AMD.¹⁰ They found converting these patients to aflibercept resulted in stabilized vision and improved anatomic outcomes, while allowing injection intervals to be extended. Are the clinical features that Yonekawa and colleagues used to decide to switch agents similar to those used by Ho and colleagues? Are they similar to what you use in your practice?

Dr. Ehlers: As with any retrospective study, assessing what factors prompted a change in therapy is difficult. In general, patients who are refractory or rapidly recurrent are those whom I most frequently consider switching.

Dr. Slakter: In the Yonekawa paper, there are no clearly defined criteria for switching. Patients were switched for a variety of reasons and with various prior treatment histories. In Ho’s paper, there seems to be a somewhat better definition of the switch criteria but again this was retrospective in nature. The descriptions generally apply to what I do in practice.

Dr. Kaiser: Do you switch patients who are recurrent or only those who are refractory?

Dr. Hariprasad: Both.

Dr. Ehlers: I consider possible alternative therapies for either of these types of patients.

Dr. Slakter: I switch when a patient is not showing an adequate response to treatment, or when a regular schedule of frequent injections is required to control the exudation, or if it becomes necessary to shorten the interval to control the exudative process. For example, if a patient has been stable on every-6-week treatment and suddenly develops new exudative activity requiring more frequent injections, I consider switching drugs.

Dr. Jain: I switch all types of patients — recurrent, refractory and complete responders who cannot be extended.

Dr. Kaiser: How many injections do you consider adequate to determine if a switch is required?

Dr. Hariprasad: This is a difficult question to answer. Suboptimal responders can occur in year 1 or even year 2 of therapy. In most cases, we can identify suboptimal responders before the end of 1 year.

Dr. Ehlers: It’s impossible to know what’s “adequate.” Generally, if I detect no anatomic response after three injections, I start to discuss the possibility of switching drugs.

Dr. Jain: Typically, I consider switching after three injections.

Dr. Slakter: I prefer to give a minimum of four injections to see if an anti-VEGF treatment is working. This is one injection beyond the usual loading dose and will typically be sufficient to determine if there is a beneficial response. If I observe slow but gradual improvement on each examination, I continue the same medication until no further improvement is noted. Therefore, in some cases, more than four injections may be required to determine if a change in medication is needed.

Dr. Kaiser: Why do you think there’s a disconnect between the visual and anatomic results in the Yonekawa study?

Dr. Ehlers: Determining the specific etiology of the vision/anatomy disconnect is difficult. The chronicity of lesions may influence the visual outcomes in these cases. In addition, the short follow-up may also influence the overall functional outcome.

Dr. Slakter: As in the Ho study, many anatomic reasons relate to damage of the retina or RPE that will limit visual outcome in spite of a positive anatomic response. Also, there was a mean of just over three injections in this study, suggesting limited follow-up. Perhaps the vision would have improved with ongoing therapy and time.

Dr. Jain: There has always been a disconnect between OCT findings and visual acuity outcomes. This shows us that we cannot use a single method to determine how best to treat our patients. All aspects are important: visual acuity, anatomy, clinical examination and the patient’s subjective experience.

Dr. Kaiser: Is the treatment regimen after the switch to aflibercept, as described in the Yonekawa paper, similar to what you follow in your practices?

Dr. Ehlers: The treatment regimen is not particularly clear in the manuscript. The multi-clinician and retrospective nature of the study make identifying specific regimens difficult. Generally, my approach is to switch to a fairly consistent dosing regimen (e.g., monthly) until the macula is dry or a plateau is reached. Once that is achieved, I try a treat-and-extend or p.r.n. regimen, based on the patient’s preference and the clinical features.

Dr. Kaiser: Do you have any concerns about switching anti-VEGF agents?

Dr. Slakter: No.

Dr. Jain: None to date.

Dr. Hariprasad: Further research is necessary, but evidence showing benefit is mounting in the literature. I have no concerns, except that we need to give patients realistic expectations when switching. We should explain that there may be no benefit or only anatomical benefit and no vision gain. Hopefully, both vision and OCT will improve, but this isn’t always the case.

Dr. Kaiser: We’ve talked at length about the diagnosis and treatment of macular degeneration, particularly in light of multiple anti-VEGF agents from which to choose. We look forward to receiving new data from continuing research on these and other therapies to guide our clinical decisions. ■

References

1. Martin DF, Maguire MG, Fine SL, et al. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119:1388-1398.

2. Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537-2548. Erratum in: Ophthalmology. 2013;120:209-210.

3. Busbee BG, Ho AC, Brown DM, et al; HARBOR Study Group. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120:1045-1056.

4. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration. One-year findings from the IVAN randomized trial. Ophthalmology. 2012;119:1399-1411.

5. Krebs I, Schmetterer L, Boltz A, et al; MANTA Research Group A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol. 2013;97:266-271.

6. Wykoff CC, Brown DM, Chen E, et al: SAVE Study Group. SAVE (Super-dose anti-VEGF) trial: 2.0 mg ranibizumab for recalcitrant neovascular age-related macular degeneration: 1-year results. Ophthalmic Surg Lasers Imaging Retina. 2013;44:121-126.

7. Barbazetto IA, Gallego-Pinazo R, Engelbert M. Short-term vision changes after switch to aflibercept therapy for age-related macular degeneration previously treated with other anti-VEGF agents. Invest Ophthalmol Vis Sci 2013;54: E-Abstract 3796.

8. Ho VY, Yeh S, Olsen TW, et al. Short-term outcomes of aflibercept for neovascular age-related macular degeneration in eyes previously treated with other vascular endothelial growth factor inhibitors. Am J Ophthalmol. 2013;156:23-28.

9. Agrawal R, Chen S, Ittiara R, Patel D, Hariprasad SM. Comparison of the relative efficacy of aflibercept in the treatment of neovascular age related macular degeneration in patients previously treated with alternative vascular endothelial growth factor inhibitors: Invest Ophthalmol Vis Sci 2013;54: E-Abstract 3828.

10. Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol. 2013;156:29-35.