Ranibizumab Equivalent to Bevacizumab for Treating Wet AMD

Laurie Barclay

May 07, 2012

May 7, 2012 — Ranibizumab (Lucentis, Genentech) is equivalent to bevacizumab (Avastin, Genentech) for treating neovascular age-related macular degeneration (AMD), according to 2-year results from the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) reported online May 2 in the May issue of Ophthalmology.

"[Ranibizumab] and [bevacizumab] are equally effective for the treatment of neovascular AMD," lead author and CATT chairman Daniel F. Martin MD, chairman of the Cole Eye Institute at the Cleveland Clinic in Ohio, told Medscape Medical News in an email interview. "Monthly dosing results in a small increase in visual gain over and above as needed dosing, [but] the difference was small and was not that evident in the broader measures of visual function (20/40 or better, 3 line loss of gain), so patients and docs will have to ask if 10 more injections over two years is worth it. For some patients the answer will be yes, and for others, no."

The goals of the multicenter, randomized CATT study were to evaluate the effects of ranibizumab and bevacizumab when given monthly or as needed for 2 years, and to assess the effect of switching to as-needed treatment after 1 year of monthly treatment.

CATT is the first study to compare the 2 drugs head-to-head for AMD, which is the leading cause of vision loss and blindness in older Americans. Neovascular or wet AMD is associated with growth of abnormal blood vessels, which leak fluid and blood into the macula and obscure central vision. Both drugs inhibit vascular endothelial growth factor (VEGF), thereby blocking angiogenesis and leakage of fluid from abnormal blood vessels.

Of 1185 patients with neovascular AMD who were enrolled in CATT, 1107 were followed up during year 2. At enrollment, participants were randomly assigned to 1 of 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). During the second year of the study, participants continued receiving the same drug, but those initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment.

The primary study endpoint was mean change in visual acuity. For participants who had been receiving the same regimen for 2 years, both drugs were associated with a similar mean gain in visual acuity (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8 letters; P = .21). Compared with as-needed treatment, monthly treatment was associated with greater mean gain in visual acuity (difference, -2.4 letters; 95% CI, -4.8 to -0.1 letters; P = .046).

At 2 years, two thirds of patients had visual acuity of 20/40 or better, which is suitable for driving. Only about 15% of patients achieved this result with previously available treatments.

The proportion of participants without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = .0003; regimen, P < .0001).

"The additional injections with monthly treatment, particularly for Lucentis, dry out the retina better but are also associated with a higher risk of geographic atrophy," Dr. Martin said. "And more injections are associated with more risk for infection."

Participants who switched from monthly to as-needed treatment had a greater mean reduction in vision during year 2 (-2.2 letters; P = .03) and a lower proportion without fluid (-19%; P < .0001).

"It is clear that if patients do decide to do monthly injections for the small potential benefit, you have to do it for a full two years," Dr. Martin noted. "As soon as patients switched to as-needed (PRN) treatment, they wound up in the same place for every visual acuity and anatomical metric as PRN-always patients, as if they had never had a year of monthly treatment."

When asked for independent comment, Philip J. Rosenfeld, MD, PhD, professor of ophthalmology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine in Florida, told Medscape Medical News that "the most profound outcome from the CATT was the higher incidence of geographic atrophy in the monthly dosing arm."

"[Ranibizumab] may dry the macula better, but with a higher risk of geographic atrophy," Dr. Rosenfeld said in an email interview. "Suddenly, monthly dosing doesn't look so attractive, and the idea that drier and thinner is better may not be true. This really should make everyone stop and think about the trade-off between drying short-term and atrophy long-term, [and it] makes treat-and-extend an even more attractive treatment paradigm."

Adverse Events

The drugs were associated with similar rates of mortality, myocardial infarction, and stroke (P > .60), which were the major safety areas of concern. Compared with ranibizumab treatment, bevacizumab treatment was associated with a higher proportion of patients with 1 or more systemic serious adverse events (39.9% vs 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07 - 1.57; P = .009). Most of these were hospitalizations for nonspecific causes.

"[The adverse events] were distributed across many different conditions, most of which were not associated with bevacizumab when evaluated in cancer clinical trials, in which the drug was administered at 500 times the dose used for AMD," Dr. Martin said. "Fewer doses were associated with a higher rate of serious adverse events, which is not a typical dose-response relationship. CATT was not capable of determining whether there is an association between a particular adverse event and treatment."

The investigators note that it is difficult to interpret the persistence of higher rates of serious adverse events with bevacizumab because of the lack of specificity to conditions associated with VEGF inhibition.

"Adverse events indicate development or worsening of a medical condition," Dr. Martin said. "The events may or may not be causally associated with the clinical trial treatment, but they are always monitored and reported in any clinical trial. The median age of patients in CATT was over 80 years, and a high rate of hospitalizations would be anticipated as a result of chronic or acute medical conditions more common to older populations."

Study Strengths and Limitations

A study strength noted by Dr. Martin is that CATT is a randomized clinical trial conducted at 43 sites across the United States with a large number of patients.

"For a full assessment of safety, you would have to conduct a much larger study ( > 10,000 patients), which is not feasible," he said. "There are 5 ongoing clinical trials worldwide that are evaluating the same questions. Some will report their results very soon."

Dr. Rosenfeld added that LUCAS (Lucentis Compared to Avastin Study) in Norway should help resolve the debate over the merits of the treat-and-extend strategy. Still unanswered is the question of whether the risk for geographic atrophy seen with ranibizumab also applies to aflibercept (Eylea, Regeneron Pharmaceuticals).

"The major limitation of [CATT] is that the safety issues could not be fully explored because of the number of patients enrolled and the imbalance in comorbidities at baseline that led to imbalances in serious adverse events throughout the study," Dr. Rosenfeld said. "I find it highly unlikely that CATT suddenly identified risk factors from [bevacizumab] that were not recognized at the time of high-dose oncology studies."

"CATT is the first study to show that monthly dosing results in equivalent visual acuity outcomes with both [bevacizumab] and [ranibizumab] over two years," Dr. Rosenfeld concluded. "While there was a small difference in visual acuity outcomes between monthly and PRN dosing, the CATT results confirm to me that our current clinical practice of using a treat-and-extend treatment paradigm, in which the number of injections are more than a pure PRN regimen and slightly fewer than a pure monthly regimen, is probably an acceptable compromise for patients who want fewer visits and slightly fewer injections compared with monthly dosing. I believe PRN is just as good as monthly dosing, but PRN dosing requires attention to detail and compliance with re-treatment guidelines that just can't be rigorously enforced in a multicenter clinical trial."

The National Eye Institute, National Institutes of Health, Department of Health and Human Services, funded this study. Some of the study authors report various financial relationships with Heidelberg Engineering, Regeneron, Physical Sciences Incorporated, Genentech, Bioptigen, and/or Alcon Laboratories. One of the study authors has a patent pending for optical coherence tomography analysis technology related to analysis for AMD. Dr. Rosenfeld has disclosed no relevant financial relationships.

Ophthalmology. Published online May 2, 2012. Abstract

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