Post hoc analysis of Protocol I demonstrates predictive value of early nonresponse to anti-VEGF

Early detection of nonresponders will allow an early switch to alternative therapies.

A post hoc analysis of the DRCR.net Protocol I study demonstrated that the long-term outcomes of anti-VEGF treatment for diabetic macular edema can be predicted as early as after three monthly injections.

“We are very happy to know that we can predict the long-term outcome and make an early decision to move patients to another therapeutic strategy if they do not respond well to anti-VEGF therapy,” Albert J. Augustin, MD, told Ocular Surgery News.

Protocol I evaluated the effects of Lucentis (ranibizumab, Genentech) with prompt or deferred laser vs. triamcinolone with prompt laser in patients with DME. The post hoc analysis was carried out in the two ranibizumab groups, pooling together the anatomical and functional outcome data at 3 months, 1 year and 3 years.

“In this way, we had quite a large number of patients, and it turned out that, by looking at VA changes and OCT central retinal thickness changes at 3 months, we can predict the long-term outcome of anti-VEGF therapy,” Augustin said.

Also, the area under curve, anatomic and functional results were quite similar and closely correlated.

“This is a good step in the direction of finding biomarkers of response to therapy,” Augustin said.

Albert J. Augustin

Further investigation

Further analysis was performed by grouping patients according to duration of edema. Patients with resolution of edema at 3 months were classified as good responders, while persistence up to 6, 9 and 12 months was graded as an increasingly poorer response and eventually no response.

“This way of grouping the patients is another way to predict how they will perform in the second and third year. Patients who had remained wet for the first year and had not shown significant response despite monthly ranibizumab injections also had poor outcomes on VA. In other words, edema duration inversely correlated with VA increase: The longer the duration of the edema, the lesser was the VA increase,” Augustin said.

“We have extracted most of the information we could get from Protocol I. One drawback was that at the time of Protocol I, we did not have spectral domain but only time domain OCT. In Protocol T, SD-OCT was used, allowing us to focus much more on the anatomy. That’s why the Protocol T population will be even more interesting,” he said.

In Protocol T, ranibizumab, Avastin (bevacizumab, Genentech) and Eylea (aflibercept, Regeneron) were compared. With all three agents, a post hoc analysis will show whether the early response can be a predictor of the later response. Thus, an evaluation of the Protocol T data should be able to confirm the Protocol I post hoc analysis and make the current conclusions even more robust.

Advantages of an early switch

Meanwhile, other studies have come to similar conclusions, and there is increasing consent that the results after three injections should be considered as a threshold to decide whether to continue with anti-VEGF or switch to another therapy.

“The switch may be to steroids or to a combination of steroids and laser. There are no recommendations available at the moment, but it is quite clear that we can predict the long-term outcomes after a short period of time and that we should indeed try a different strategy as soon as we realize that the patient does not respond adequately to anti-VEGF injections,” Augustin said.

The positive consequences of identifying nonresponders early in the course of therapy and making an early switch to another therapy are uncountable, Augustin said.

“We will be able to reduce the workload coming from so many anti-VEGF injections and have more efficient schedules for those who can truly benefit from them. We will be able to reduce the burden to the patients and their families, who need to come once a month or even more if anti-VEGF injections are performed in both eyes,” he said. “If we use steroids as a switch or even as first-line therapy in the cases where they are better indicated, the burden of frequent injections will be considerably reduced, leading also to consistent saving for the health care system because such a strategy is less costly.” – by Michela Cimberle

Disclosure: Augustin reports he is a consultant to Allergan.

A post hoc analysis of the DRCR.net Protocol I study demonstrated that the long-term outcomes of anti-VEGF treatment for diabetic macular edema can be predicted as early as after three monthly injections.

“We are very happy to know that we can predict the long-term outcome and make an early decision to move patients to another therapeutic strategy if they do not respond well to anti-VEGF therapy,” Albert J. Augustin, MD, told Ocular Surgery News.

Protocol I evaluated the effects of Lucentis (ranibizumab, Genentech) with prompt or deferred laser vs. triamcinolone with prompt laser in patients with DME. The post hoc analysis was carried out in the two ranibizumab groups, pooling together the anatomical and functional outcome data at 3 months, 1 year and 3 years.

“In this way, we had quite a large number of patients, and it turned out that, by looking at VA changes and OCT central retinal thickness changes at 3 months, we can predict the long-term outcome of anti-VEGF therapy,” Augustin said.

Also, the area under curve, anatomic and functional results were quite similar and closely correlated.

“This is a good step in the direction of finding biomarkers of response to therapy,” Augustin said.

Albert J. Augustin

Further investigation

Further analysis was performed by grouping patients according to duration of edema. Patients with resolution of edema at 3 months were classified as good responders, while persistence up to 6, 9 and 12 months was graded as an increasingly poorer response and eventually no response.

“This way of grouping the patients is another way to predict how they will perform in the second and third year. Patients who had remained wet for the first year and had not shown significant response despite monthly ranibizumab injections also had poor outcomes on VA. In other words, edema duration inversely correlated with VA increase: The longer the duration of the edema, the lesser was the VA increase,” Augustin said.

“We have extracted most of the information we could get from Protocol I. One drawback was that at the time of Protocol I, we did not have spectral domain but only time domain OCT. In Protocol T, SD-OCT was used, allowing us to focus much more on the anatomy. That’s why the Protocol T population will be even more interesting,” he said.

In Protocol T, ranibizumab, Avastin (bevacizumab, Genentech) and Eylea (aflibercept, Regeneron) were compared. With all three agents, a post hoc analysis will show whether the early response can be a predictor of the later response. Thus, an evaluation of the Protocol T data should be able to confirm the Protocol I post hoc analysis and make the current conclusions even more robust.

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Advantages of an early switch

Meanwhile, other studies have come to similar conclusions, and there is increasing consent that the results after three injections should be considered as a threshold to decide whether to continue with anti-VEGF or switch to another therapy.

“The switch may be to steroids or to a combination of steroids and laser. There are no recommendations available at the moment, but it is quite clear that we can predict the long-term outcomes after a short period of time and that we should indeed try a different strategy as soon as we realize that the patient does not respond adequately to anti-VEGF injections,” Augustin said.

The positive consequences of identifying nonresponders early in the course of therapy and making an early switch to another therapy are uncountable, Augustin said.

“We will be able to reduce the workload coming from so many anti-VEGF injections and have more efficient schedules for those who can truly benefit from them. We will be able to reduce the burden to the patients and their families, who need to come once a month or even more if anti-VEGF injections are performed in both eyes,” he said. “If we use steroids as a switch or even as first-line therapy in the cases where they are better indicated, the burden of frequent injections will be considerably reduced, leading also to consistent saving for the health care system because such a strategy is less costly.” – by Michela Cimberle

Disclosure: Augustin reports he is a consultant to Allergan.