AMD: Continued Anti-VEGF Treatment May Induce Response

Pam Harrison

October 09, 2015

Patients with neovascular age-related macular degeneration (AMD) who have a poor initial response to an antivascular endothelial growth factor (anti-VEGF) agent may still respond to treatment with the same drug over time, without being switched to an alternative agent, the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) study suggests.

The study was published online September 14 in Ophthalmology.

Gui-shuang Ying, PhD, from the University of Pennsylvania, Philadelphia, and colleagues found that the 126 patients who met their hypothetical drug-switching criteria at week 12, but who continued receiving the same initial anti-VEGF agent, achieved a mean gain of 2.8 letters between week 12 and year 1 and a mean gain of 2.9 letters at year 2 (P = .11).

In addition, total retinal thickness decreased from week 12, with a mean decrease of 53 μm at year 1 (P < .0001) and 54 μm at year 2 (P = .0004). Also, fluid at the foveal center resolved in one third of eyes at year 1, and more than half of eyes at year 2.

Further, the authors found that even among the 83 patients who still met the groups' hypothetical drug-switching criteria at week 24, staying on the same anti-VEGF drug resulted in significant improvements over time. Specifically, the patients showed a mean gain of 3.3 letters at year 1 (P = .03), and a mean gain of 4.9 letters at year 2 (P = .008).

Also, total retinal thickness decreased between week 24 and year 1 by a mean of 26 μm (P = .04), and by year 2, the mean decrease was 36 μm (P = .02). After week 24, fluid at the foveal center again resolved in about one third of patients at year 1, and in about half of eyes at year 2.

"I think one of the key findings from this study is that if a patient responds to anti-VEGF treatment after the first three injections — in other words, by week 12 — they will most likely continue to respond with further treatment, and treatment should continue," Dr Ying told Medscape Medical News.

"On the other hand, if a patient does not respond well by week 12, they should still be given an opportunity to continue with treatment, as they have a reasonably good opportunity to gain visual acuity by year 2 with continued treatment, using the same drug."

CATT Study

The CATT study involved 1185 participants with choroidal neovascularization secondary to AMD with a baseline visual acuity of 20/25 to 20/320.The mean visual acuity at baseline was 61 letters. The study eye had not yet received treatment for active choroidal neovascularization, and patients received either ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech) in one of three dosing regimens.

Overall, mean visual acuity improved by 3.6 letters at week 4, by 5.8 letters at week 12, and by 6.4 letters at week 24, after which they stabilized at about six to seven letters gained through to the end of year 2.

Approximately 30% of patients had a gain of three lines or more by week 36, and fewer than 10% of the cohort experienced a loss of three lines or more at the end of the second year.

"The strongest predictor of vision outcome at years 1 or 2 in our study was VA response at week 12," Dr Ying and colleagues observe. Specifically, among 176 eyes that showed a gain of three lines or more from baseline, 78% showed a similar gain of three lines or more at year 2, whereas only 5% showed a loss of one line or more at the same endpoint.

Notably, of 113 eyes that had a loss of one line or more at week 12, 27% showed a gain of one line or more at year 2, whereas 52% showed a similar loss of one line or more at year 2.

Baseline predictors for less of a gain in visual acuity at year 2 were the same as the authors had previously reported at 1 year and included older age (P = .02), baseline visual acuity of 20/40 or better in the study eye (P < .0001), larger choroidal neovascularization area (P = .002), and the presence of retinal pigment epithelium elevation (P = .001).

The presence of geographic atrophy at baseline (P = .04) and thicker (>425 μm) and thinner (≤325 μm) total foveal thickness (P = .01) were significant predictors for less visual gain at year 2.

Prospectively Defined Criteria

"To date, there are no widely accepted prospectively defined criteria for switching anti-VEGF drugs," the investigators note.

For the purposes of the CATT study, they devised their own criteria for when patients were hypothetically eligible to switch medications. First, patients had to have a visual acuity of 20/40 or worse. Second, patients had to have gains of less than one line of vision in response to their initial therapy at either 12 or 24 weeks. Third, patients had to have persistent fluid at the center of the fovea on optical coherence tomography. Last, patients had to have received all three initial monthly treatments of either anti-VEG agent up to the time of the hypothetical switch point for switching at week 12, and to have received five of six monthly treatments to be hypothetically switched at week 24.

Dr. Ying and colleagues note that it was "surprising" to learn that the visual acuity response at 12 weeks predicted less than 50% of the variation in visual acuity responses at both years 1 and 2. "This fluctuation of [visual acuity] during the course of ant-VEGF treatment makes it challenging to determine the beneficial effect on [visual acuity] from switching to another treatment," the investigators write.

For example, eyes that had a visual acuity gain of at least one line at 12 weeks generally had a similar gain at years 1 and 2. However, 17% eyes that initially showed a loss of one line or more at the same assessment point gained one line or more at year 1, as did 27% of eyes by year 2.

"This shift from early VA loss to later VA gain contributes to the lower than expected association between early VA response and later VA response at years 1 or 2," the authors write. "In addition, the fact that a meaningful percentage of eyes eventually had VA gain despite early loss is encouraging and should prompt ophthalmologists and patients not to give up anti-VEGF treatment, even if early VA response is not optimal."

Given that there are no guidelines governing the way ophthalmologists should switch patients from one anti-VEGF treatment to another, Dr Ying called for a randomized controlled trial to compare patients who do not appear to be responding well on one anti-VEGF agent and who are switched to a new agent with similar patients who continue receiving the same treatment to see whether switching really does improve visual acuity.

Slow Response

Asked to comment on the study, Winfried Amoaku, MD, from the University of Nottingham in the United Kingdom, told Medscape Medical News he does not completely agree with the conclusions arrived at by Dr Ying and colleagues.

"I accept that some eyes, whether with AMD or diabetic macular edema, show a slow response to treatment with one anti-VEGF or other," he told Medscape Medical News.

"Some of these will improve slowly over an 8-month period," he added. However, as he pointed out in his own review on defining response to anti-VEGF therapies in AMD ( Eye . 2015;29:721-731), there are significant interindividual differences in response to anti-VEGF agents, and these differences are dependent on such factors as the patient's age, lesion characteristics and duration, and baseline visual acuity.

"Furthermore, a proportion of eyes with AMD show a decline in acuity or morphology despite therapy, or require very frequent retreatment," he noted.

"When we didn't have alternative treatments, there was nothing to be done," Dr Amoaku said. "But now that we have alternatives, we know that switching treatment is beneficial for those that respond poorly to one treatment or the other.…And those eyes that had only a three-letter improvement at 12 months could have done much better if response to treatment was good or treatment was switched appropriately."

In his opinion, poor or no response to any anti-VEGF treatment is a signal that physicians need to reevaluate the diagnosis and, if necessary, switch to alternative therapies, including other anti-VEGF agents or photodynamic therapy.

"There are some eyes that will deteriorate from the start," Dr Amoaku emphasized. "And careful observation is required to tease these out."

Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Various coauthors report financial relationships with Janssen, Bioptigen, Genentech, Physical Sciences Inc, Alcon Laboratories, Thrombogenics, Heidelberg Engineering, Neurotech, and Roche. Dr Amoaku has provided consultancy services to Alcon, Allergan, Bayer, Novartis, and Thrombogenics and has received travel grants from Allergan, Bayer, and Novartis as well as honoraria for lectures from Allergan and Novartis.

Ophthalmology. Published online September 14, 2015. Abstract

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