Article

Analysis of 2-Year Data From the EVEREST II and PLANET Trials

Key differences affect outcomes for PCV.

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Polypoidal choroidal vasculopathy (PCV) is characterized by aneurysmal polypoidal dilatations and branching vascular network, and it is a common form of exudative neovascular age-related macular degeneration (nAMD) in the Asian population.1,2 Photodynamic therapy using verteporfin (vPDT) has remained the standard of practice during the last decade to treat patients with PCV. Several publications in the past decade have focused on the combination therapy of PDT and anti-VEGF.3-7 However, the side-effect profile and high cost of vPDT, as well as the advent of anti VEGF agents, have led to receding interest in usage of vPDT as a standalone modality. The EVEREST II and PLANET studies are major landmark trials focusing on the monotherapy of the anti-VEGF agents ranibizumab (RBZ, Lucentis; Genentech) and aflibercept (AFL, Eylea; Regeneron) respectively compared with combination vPDT therapy.8,9

The 12-month results of EVEREST II showed better outcomes with vPDT+RBZ, while the PLANET study results at 12 months reflect comparable outcome with both monotherapy of AFL and vPDT+AFL. In a previous Retinal Physician article, we reported the differences between the 2 landmark trials and the treatment outcomes at 12 months.10 Here, we analyze the 24-month results of the 2 studies, presented at the Asia-Pacific Vitreo-Retina Congress held in Kuala Lumpur in December 2017.11,12

STUDY DESIGN AND METHODOLOGY

Both studies were multicenter, randomized controlled trials with a follow-up period of 2 years. The PLANET study included patients from the Asia-Pacific and European regions, while EVEREST II included patients only from Asia. The sample size was >300 in each study (PLANET, 318; EVEREST II, 322). The treatment protocols varied significantly in the 2 studies. The PLANET study involved 3 monthly AFL injections (2 mg/0.05 mL) followed by injections every 8 weeks until week 52 and then treat-and-extend (T&E) protocol until week 96. Rescue therapy as vPDT or sham PDT along with AFL every 4 weeks was considered when certain criteria were satisfied, including best corrected visual acuity (BCVA) ≤73 ETDRS letters, <5 letter visual gain, optical coherence tomography (OCT) showing new or persisting fluid, and indocyanine angiography (ICGA) showing active polyps.

On the other hand, EVEREST II involved administration of sham PDT or vPDT at baseline and 3 monthly injections of RBZ. Subsequent RBZ injections were given on a pro-re-nata (PRN) basis to 24 months. Retreatment criteria were defined based on loss of visual acuity, activity on OCT, and ICGA. It also included PDT, which was administered from 3 months onwards with a minimal interval of 3 months between 2 treatment sessions. After 16 months, 41 patients in the RBZ monotherapy group were eligible to be switched to combination therapy. However, finally only 14 patients received vPDT, because the switch was made after 21 months in most of the patients.

BASELINE CHARACTERISTICS

The mean (±SD) age of patients in the PLANET study was 70.8±8.4 and 70.4±8.0 years in the monotherapy and combination groups, respectively. In the EVEREST II study, the mean age in the combination and monotherapy groups were 68.0±8.54 and 68.2±9.02, respectively. Both studies had male preponderance (69.9% in EVEREST II; 69.8% in PLANET) in their study population. The mean BCVA in the PLANET study was 57.7±11.3 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the monotherapy arm and 59.0±11.5 ETDRS letters in the combination arm. Patients in EVEREST II had better visual acuity in both groups, with mean BCVA of 61.2±13.9 ETDRS letters in monotherapy and 61.1±12.6 ETDRS letters in the combination arm. Therefore, patients in PLANET had worse visual acuity (a difference of 2-3 letters) compared to EVEREST II.

VISUAL ACUITY RESULTS

The BCVA gain at 52 weeks in the AFL monotherapy group in the PLANET study was 10.7, which was maintained at 96 weeks. However, the combination AFL+vPDT group had a reduction in BCVA gain from 10.8 letters ETDRS letters at 52 weeks to 9.1 letters at week 96. The difference in BCVA in the 2 groups at week 96 was not significantly different (P=.48). At 96 weeks, 5.6% and 3.2% patients, in the combination and AFL monotherapy respectively, had ≥15 letters loss of visual acuity (P=.37). In EVEREST II, at 24 months, visual gain in the RBZ monotherapy and combination (RBZ+vPDT) groups were 5.6 and 9.7 letters, respectively (P=.005). The corresponding visual gains at 12 months were 5.7 and 9.5 letters in the 2 groups (P=.002). The percentage of patients with ≥15 letters gain was higher (30.8%) in the combination group compared to RBZ monotherapy (24.2%), while the percentage of patients with loss of ≥15 letters was higher in the monotherapy group (5.5%) than the RBZ+vPDT group (4.8%).

POLYP REGRESSION RESULTS

The polyp regression or inactivity as determined by ICGA has been studied in greater detail in cases of PCV because it is one of the most important predictors of recurrence of disease activity.5 Complete polyp regression at 96 weeks in the PLANET study was seen in 33.1% and 29.1% of patients in the AFL monotherapy and AFL+vPDT combination therapy arms, respectively. In contrast, at 52 weeks 38.9% patients in the AFL group and 44.8% in the combination group showed complete regression. EVEREST II results show that 56.6% and 26.7% of patients with combination therapy and RBZ monotherapy achieved complete polyp regression at 24 months (P=.0001) while at 12 months in the respective groups, 69.7% and 33.8% patients had complete polyp regression (P=.0001). The receding effect of PDT with time, especially 2 years and beyond, has been previously shown.13 ICGA was needed when decisions regarding rescue treatment were made, as was seen in 17% of the study population in the PLANET study at 96 weeks, whereas 13% qualified to be considered for rescue treatment at 12 months.

REDUCTION IN CENTRAL MACULAR THICKNESS

The AFL monotherapy group had a better reduction in central macular thickness (CMT; 140 µ vs 135.4 µ, P=.19) in the PLANET study at 96 weeks, while in EVEREST II, RBZ monotherapy had a lesser reduction in CMT compared to vPDT+RBZ combination at 2 years, which was statistically not significant (109.3 µ vs 152.9 µ).

NUMBER OF INJECTIONS OR INTERVENTIONS

In the PLANET study, the mean number of AFL injections in both treatment arms was 8.1. During week 52 through week 96, the mean number of AFL injections was 4.6 in both treatment arms. This reduction was due to the T&E regimen in the second year as compared to fixed-dose schedule during the initial year. Similarly, the total number of interventions including AFL + sham PDT was 8.4 (first year) and 4.7 (second year) in the monotherapy arm. The AFL+vPDT combination arm received a mean of 8.3 and 4.7 interventions during the first and second years, respectively. The importance of a T&E regimen in the PLANET study lies in the fact that the number of injections reduced from 8.1 in the first year to 4.6 in the second year. The number of injections in the second year reflects real-life situations where monthly injections may be difficult and cost prohibitive.

In EVEREST II, the combination group had a mean of 8.1 RBZ injections and 2.2 vPDT treatment sessions whereas the monotherapy group received a mean of 12.5 injections during the 24 months. The number of RBZ injections during the second year were 3 and 5.1 in the combination and monotherapy group, respectively. One important difference is that while the combination arm showed a reduction in the number of anti-VEGF injections in EVEREST II, the PLANET study did not show any such difference. The explanation may lie in the fact that vPDT was used as a rescue therapy in the PLANET study, while PDT was performed at baseline in the EVERST II study.

SAFETY PROFILE

The side-effect profiles of AFL, RBZ, and vPDT were similar to the previously reported ocular or systemic side effects, with no new safety signals reported.14-16 The serious ocular side effects were vitreous hemorrhage, retinal hemorrhage, macular hole, and unaccounted blindness. The total number of deaths during the study period of 24 months was 4 in PLANET and 3 in EVEREST II.

CONCLUSION

The basic differences between the 2 studies must be analyzed to understand the difference in the treatment outcomes. The diagnosis and rescue treatment criteria were made using the support of a central reading center (CRC) in EVEREST II, which made the EVEREST II study more robust compared to PLANET, in which rescue was based on physician discretion. The inclusion of vPDT at baseline in EVEREST II is in contrast to rescue vPDT in PLANET study. Considering the fact that in PLANET, at 96 weeks, 86.8% and 83% of patients in the AFL and AFL+vPDT groups, respectively, did not require rescue therapy suggest that vPDT may be an overtreatment in these AFL-treated eyes. However, 41 eyes (26.6%) in the RBZ monotherapy arm in EVEREST II satisfied the criteria for switch to combination therapy, thus making vPDT a necessary treatment modality in RBZ-treated eyes.

The differences in polyp regression pattern reveal variable results in both studies. While 56.6% of patients in the RBZ+vPDT group showed complete polyp regression, only one-third of patients in RBZ monotherapy, AFL, or AFL+vPDT groups showed polyps regression. The explanation could be found in the conservative ICGA criteria or a synergistic effect of RBZ with PDT. However, the question remains unanswered whether polyp regression is a treatment goal in these eyes or not. The number of AFL injections in PLANET dropped significantly from a mean of 8.1 at 1 year to a mean of 4.6 at 2 years, which has significant cost implications. The anatomical and visual outcomes in the form of BCVA gain, CMT reduction, or polyp regression were best achieved at 6 months, which was maintained at 24 months. In short, while the PLANET study showed the efficacy and good safety outcomes of AFL monotherapy, EVEREST II showed better outcomes with combination as compared to RBZ monotherapy. Comparing the results of 2 different studies has certain limitations; however, this paves the way for a future study featuring head-to-head comparison of the 2 drugs and their combination with PDT. RP

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