Reviewing visual and anatomic outcomes in 2 clinical trials
A recent report found that individualised faricimab (Vabysmo, Roche) dosing up to every 16 weeks maintains robust anatomic and visual outcomes through 2 years in patients with neovascular age-related macular degeneration (AMD). Varun Chaudhary, MD, professor and head of ophthalmology, McMaster University, Hamilton, and chair of Retina Evidence and Trials INternational Alliance (RETINA), presented his dosing pearls at the 2023 meeting of the Association for Research in Vision and Ophthalmology in New Orleans, Louisiana.
The presentation looked at the personalised treat-and-extend algorithm that was used in the TENAYA (NCT03823287) and LUCERNE (NCT03823300) clinical trials to identify pragmatic learning points that clinicians can apply to patients in clinical practice.
He pointed out 3 key takeaways from the clinical trial protocols, the first being that the control arm with aflibercept (Eylea, Regeneron Pharmaceuticals) 2 mg was not a treat-and-extend arm but rather was fixed dosing.
“This is important because in noninferiority trials we must ensure that we meet the constancy assumption, which means that the control arm should give us the best results we would expect in day-to-day clinical practice. When this clinical trial was designed, fixed-dosing aflibercept met that assumption,”
Dr Chaudhary said.
The second take-home message was that the faricimab arm used a modified treat-and-extend protocol. That is, in year 1, the goal with faricimab was to inhibit angiotensin II (Ang2) and VEGFA to stabilise the choroidal neovascular membrane. This was accomplished with a modified fixed-dosing regimen.
After week 60, when the choroidal neovascular membrane was stabilised, the goal was to significantly reduce the treatment burden and move to a personalised treat-and-extend algorithm. In year 1, the patients received 4 monthly faricimab treatments. Then, based on disease activity, they were moved either to the every-8-week, every-12-week, or every 16-week arm, where they remained until week 60. At that point, patients converted to a treat-and-extend algorithm in all arms.
The third take-home message was the pragmatic retreatment criteria by which disease activity was defined as active disease either on central subfield thickness (CST) or visual acuity (VA) or the presence of a new hemorrhage.
Dr Chaudhary explained that in the presence of any of the 3 criteria, “active” indicated active disease and the treatment level was reduced.
Patients were transferred to an extended regimen when all 3 parameters were stable, which is similar to how most clinical treat-and-extend trials have been designed and how many clinicians use treat-and-extend regimens in clinical practice.
Patients treated with faricimab and aflibercept obtained rapid visual gains. Faricimab administered up to every 16 weeks showed noninferiority in the VA outcomes compared with fixed-dosing aflibercept.
The number of treatments administered was interesting, Dr Chaudhary commented. The median number of faricimab treatments over the 112 weeks was 10 vs 15 with aflibercept, with the consideration that aflibercept was fixed dosing and faricimab was treat-and-extend dosing.
Both treatment arms showed a rapid reduction in CST that was maintained out to week 112. The patient status, he noted, was important after week 60 when the early disease stability with faricimab significantly reduced the need for treatment when patients were moved to a personalised treat-and-extend regimen. In year 2, a median of 3 treatments was administered after week 60 with faricimab compared to a median of 6 treatments with
aflibercept, again with the caveat that treatment algorithms differed.
A deeper dive into the combined effects of faricimab, both Ang2 and VEGF inhibition, may be telling. During the first 3 months of treatment, this was a head-to-head matching of monthly aflibercept vs monthly faricimab. Dr Chaudary said, “We know from previous clinical trials that monthly aflibercept is a very robust anti-VEGF agent that significantly reduces fluid. However, compared to faricimab with its dual inhibitory effects, at weeks 4, 8 and 12, there was greater CST reduction with the faricimab arm compared to aflibercept. In addition, considering the absence of subretinal and intraretinal fluid [SRF, IRF] the patients in the faricimab arm were more likely to not have SRF and IRF during each of these matched-dosing phases. This is clinically relevant, because we typically wait for retinas to be dry before we start extending the treatment regimens.”
Seventy-five percent of patients on faricimab had no IRF and SRF at week 8 after 2 treatments compared with aflibercept when patients were fluid-free at week 12 after 3 injections. Looking past 12 weeks, at each time point, more patients on faricimab were fluid-free faster than those on aflibercept.
Regarding treatment durability, almost 80% of patients receiving faricimab achieved 12-week or longer dosing during years 1 and 2. About 45% of patients achieved every-16-week dosing during year 1, which increased to 63% during year 2.
The combined inhibitory effect of faricimab seemed to contribute to the longer dosing interval. An analysis of the cytokine data from some patients showed a rapid reduction in the Ang2 and VEGF 8 levels in the aqueous, but then the VEGF 8 levels started to increase and reached the baseline level at week 16. The Ang2 levels remained suppressed out to week 16. “The suppression up to week 16 correlated nicely with the durability signal, which shows that 63% of patients could be kept on every-16-week intervals in year 2 or week 112,” he said. Further studies and validation are needed to understand the role of Ang2 and durability in these outcomes.
When considering treat-and-extend results, he emphasised that outcomes can change depending on the algorithm or treatment criteria used. In the TENAYA and LUCERNE trials, treatment activity was defined based on best-corrected VA or CST or new hemorrhage, any of which can be defined as active disease. Using those criteria at week 20, 78% of patients were extended to every-12-week dosing weeks or longer intervals. However, when using retreatment criteria requiring worsening of vision and CST to define active disease, if we repeated this hypothetical exercise at week 20, 96% of patients would have reached every-12-week or longer dosing.
It can be challenging to appreciate these extension intervals. Considering this, Dr Chaudhary and his colleagues focused on individual patients throughout the study. At week 60, all patients were switched to a treat-and-extend algorithm and the decisions were made every time a patient returned to the clinic. In the TENAYA and LUCERNE studies, over 2500 decisions were made at patient visits during the treat-and-extend phase. “We found that 74.7% of these treatment decisions allowed patients to be maintained at the treatment interval, 15% of the treatment decisions allowed patient to be extended by 4-week intervals, and in about 10% of visits, the treatment interval was decreased,” he said. The decision to reduce the interval was mostly driven by the CST, not VA or visual loss. In the trials, a new macular hemorrhage in the faricimab arm developed in approximately 0.9% of patients.
Moving from fixed to treat-and-extend dosing
Analysis showed that 69% of patients on every-16-week treatment at week 60 remained there during the treat-and-extend phase; 71% of patients on every-12-week dosing coming into the treat-and-extend regimen remained on equal to or greater than every-12-week dosing during the treat-and-extend phase.
With patients on every-12-week dosing, 59% were extended to every-16-week dosing during the treat-and-extend phase, 56% of patients on every-8-week dosing were extended to every-12 or every-16-week dosing at week 112. About 32% of patients receiving every-8-week dosing had to remain at that treatment interval, he summarised.
Varun Chaudhary, MD
Chaudhary is professor and head of ophthalmology, McMaster University, Hamilton, and chair of Retina Evidence and Trials INternational Alliance (RETINA). He has no financial interest in this subject matter.