Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Study of Aflibercept, Bevacizumab, or Ranibizumab for DME Supported through a cooperative agreement from the National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 1
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Diabetic Retinopathy Clinical Research Network
Diabetic Retinopathy Clinical Research Network
Comparative Effectiveness Study of Aflibercept, Bevacizumab, or
Ranibizumab for DMESupported through a cooperative agreement from the
National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817
1
Disclosure Disclosure Funding/Support: Cooperative Agreement with NEI and
NIDDK of NIH, U.S. Department of Health and Human Services.
Additional Contributions: Regeneron Pharmaceuticals, Inc. provided the aflibercept; Genentech Inc. provided the ranibizumab. Genentech Inc. also provided funding for blood pressure cuffs and collection of plasma and urine that are not part of the main study reported herein.
A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net.
Diabetic macular edema (DME) affects ~750,000 people in the U.S.
Intravitreous anti-vascular endothelial growth factor (anti-VEGF) injections of either aflibercept (Eylea), bevacizumab (Avastin), or ranibizumab (Lucentis) are effective in treating DME.
The relative efficacy and safety of these agents within a head-to-head study were unknown prior to the results of this trial
Background Background
4
Aflibercept and ranibizumab are FDA approved for DME treatment.
Bevacizumab is not FDA approved for intraocular use, used “off-label” for DME treatment and repackaged into aliquots ~1/500 of
systemic dose in cancer treatments. Medicare allowable charges:
Mean visual acuity letter score (~Snellen Equivalent)
69(20/40)
69(20/40)
68(20/50)
Mean OCT CST (µm) 387 376 390
Any Prior Focal/Grid Laser
36% 39% 37%
Any Prior Treatment with anti-VEGF
11% 14% 13%
Phakic 74% 73% 79%
Treatment for Diabetic Macular Edema
Treatment for Diabetic Macular Edema
13
14
DME Treatment Through 1 Year: anti-VEGF and Laser
DME Treatment Through 1 Year: anti-VEGF and Laser
AfliberceptN = 208
BevacizumabN = 206
RanibizumabN = 206
P-Value
# of Injections (Max = 13)
Mean 9.2 9.7 9.4
Median (25th, 75th percentile)
9 (8, 11) 10 (8, 12) 10 (8, 11) 0.045†
At least one focal/grid laser
37% 56% 46% <0.001‡
†Global (overall 3 group comparison) P-value. Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P = 0.045, aflibercept-ranibizumab: P = 0.19, bevacizumab-ranibizumab: P = 0.22.
‡Global (overall 3 group comparison) P-value. Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P<0.001, aflibercept-ranibizumab: P = 0.058, bevacizumab-ranibizumab: P = 0.061.
15
EfficacyEfficacy
16
0 4 8 12 16 20 24 28 32 36 40 44 48 5202468
101214161820
Aflibercept Bevacizumab Ranibizumab
Weeks
Me
an
Ch
an
ge
in V
isu
al A
cu
ity
Le
tte
r S
co
re 52 Week Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P<0.001• Aflibercept vs. Ranibizumab P = 0.034 • Ranibizumab vs. Bevacizumab P = 0.12
* P-values adjusted for baseline visual acuity and multiple comparisons
+13
+11
+10
Mean Change in Visual Acuity Letter Score, Full Cohort
Mean Change in Visual Acuity Letter Score, Full Cohort
Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/32 to 20/40
Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/32 to 20/40
17
0 4 8 12 16 20 24 28 32 36 40 44 48 5202468
101214161820
Aflibercept Bevacizumab RanibizumabWeeks
Mea
n Ch
ange
in V
isua
l Acu
ity
Lett
er S
core
~+8
~50% of Cohort
Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/50 or Worse
Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/50 or Worse
18
0 4 8 12 16 20 24 28 32 36 40 44 48 5202468
101214161820
Aflibercept Bevacizumab RanibizumabWeeks
Me
an
Ch
an
ge
in V
isu
al A
cu
ity
Le
tte
r S
co
re
1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P<0.001• Aflibercept vs. Ranibizumab P = 0.0031• Ranibizumab vs. Bevacizumab P = 0.21
* P-values adjusted for baseline visual acuity and multiple comparisons
1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P < 0.001• Aflibercept vs. Ranibizumab P = 0.036• Ranibizumab vs. Bevacizumab P = <0.001
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons
Mean (µm) Change in OCT CSTBaseline visual acuity 20/32 to 20/40
Mean (µm) Change in OCT CSTBaseline visual acuity 20/32 to 20/40
30
0 4 8 12 16 20 24 28 32 36 40 44 48 52-250
-200
-150
-100
-50
0
Aflibercept Bevacizumab RanibizumabVisit Week
Mea
n I
mp
rove
men
t in
OC
T C
SF
T
hic
knes
s fr
om
Bas
elin
e (µ
m)
Thinner is decreased DME
1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P <0.001• Aflibercept vs. Ranibizumab P = 0.057• Ranibizumab vs. Bevacizumab P = <0.001
-67
-129
-119
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons
Mean (µm) Change in OCT CSTBaseline visual acuity 20/50 or Worse
Mean (µm) Change in OCT CSTBaseline visual acuity 20/50 or Worse
31
0 4 8 12 16 20 24 28 32 36 40 44 48 52-250
-200
-150
-100
-50
0
Aflibercept Bevacizumab Ranibizumab
Visit Week
Me
an
Imp
rov
em
en
t in
OC
T C
SF
Th
ick
ne
ss
fr
om
Ba
se
line
(µ
m)
Thinner is decreased DME
1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P < 0.001• Aflibercept vs. Ranibizumab P = 0.22• Ranibizumab vs. Bevacizumab P = <0.001
-135
-176
-210
* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons
32
-129
-67
-119
Observed Data
Mea
n O
CT
CS
F C
han
ge
Treatment Group Comparisons
Difference CI P- Value
Aflibercept vs
Bevacizumab-55.8
-78.3 to -32.9 <0.001
Aflibercept vs
Ranibizumab-18.2 -36.9 to
+0.6 0.057
Ranibizumab vs
Bevacizumab-37.7 -59.3 to
-16.1 <0.001
OCT CSF OutcomesBaseline = 20/32-20/40
OCT CSF OutcomesBaseline = 20/32-20/40
Visual Acuity OutcomesBaseline = 20/32-20/40
Visual Acuity OutcomesBaseline = 20/32-20/40
33Afli
berce
pt
Bevac
izum
ab
Ranib
izum
ab
62%
34%
60%
Observed Data
Per
cen
t
Treatment Group Comparisons
Difference CIP-
Value
Aflibercept vs
Bevacizumab+31%
+16% to +45% <0.001
Aflibercept vs
Ranibizumab-2% -16% to
+12% 0.79
Ranibizumabvs
Bevacizumab+33% +17% to
+48% 0.001
CSF <250 µm
34
-210
-135
-176
Observed Data
Mea
n O
CT
CS
F C
han
ge
Treatment Group Comparisons
Difference CIP-
Value
Aflibercept vs
Bevacizumab-85.8
-121.9 to -49.7 <0.001
Aflibercept vs
Ranibizumab-18.5 -48.2 to
+11.2 0.22
Ranibizumab vs
Bevacizumab-67.3 -101.4 to
-33.1 <0.001
OCT CSF OutcomesBaseline = 20/50 or WorseOCT CSF Outcomes
Baseline = 20/50 or Worse
Visual Acuity OutcomesBaseline = 20/50 or Worse
Visual Acuity OutcomesBaseline = 20/50 or Worse
35Afli
berce
pt
Bevac
izum
ab
Ranib
izum
ab
70.00
39
56
Observed Data
Per
cen
t
Treatment Group Comparisons
Difference CIP-
Value
Aflibercept vs
Bevacizumab +32%+16%
to +48% <0.001
Aflibercept vs
Ranibizumab+16% +3% to
+30% 0.025
Ranibizumab vs
Bevacizumab+16% +2% to
+29% 0.025
CSF <250 µm
SafetySafety
36
Ocular Adverse Events through 1 Year (Study Eye)
Ocular Adverse Events through 1 Year (Study Eye)
37
Aflibercept(N = 224)
Bevacizumab(N = 218)
Ranibizumab(N = 218)
P-Value
No. of injections prior to 1 year
1991 2055 2011
Endophthalmitis 0 0 0
Inflammation† <1% <1% <1% 1.0
Retinal detachment/tear
0 <1% <1% 0.55
Vitreous hemorrhage
2% 4% 3% 0.35
Injection related cataract
<1% <1% 0 0.55
IOP elevation‡ 14% 9% 11% 0.18
†Includes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreous cells.‡Includes intraocular pressure increase ≥10mmHg from baseline at any visit, intraocular pressure ≥30 mmHg at any visit, or initiation of intraocular pressure-lowering medications not in use at baseline. There were no glaucoma surgeries.IOP= Intraocular Pressure
ǁIncludes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreal cells.‡Includes intraocular pressure increase ≥10mmHg from baseline at any visit, intraocular pressure ≥30 mmHg at any visit, or initiation of intraocular pressure-lowering medications not in use at baseline. There were no glaucoma surgeries.
Systemic Adverse Events APTC* through 1-Year
Systemic Adverse Events APTC* through 1-Year
39
Aflibercept(N = 224)
Bevacizumab(N = 218)
Ranibizumab(N = 218)
Non-fatal MI 2% <1% 1%
Non-fatal stroke 0 2% 2%
Vascular death <1% 2% 1%
Any APTC Event 3% 4% 5%Global P = 0.56
* Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994;308:81-106.
Systemic Adverse Events Through 1 Year
Pre-specified (Per Participant)
Systemic Adverse Events Through 1 Year
Pre-specified (Per Participant)
40
Aflibercept(N = 224)
Bevacizumab(N = 218)
Ranibizumab(N = 218)
P-Value*
Death (any cause) 1% 2% 2% 0.72
Hospitalization 21% 18% 22% 0.51
SAEs 26% 21% 25% 0.40
Gastrointestinal † 20% 18% 17% 0.84
Kidney Events‡ 13% 11% 11% 0.81
Hypertension Events
12% 7% 12% 0.20
*Global (overall 3 group comparison) P-value from Fisher’s Exact Test. †Includes events with a Medical Dictionary for Regulatory Activities system organ class of gastrointestinal disorders‡Includes a subset of Medical Dictionary for Regulatory Activities system organ class of renal and urinary disorders events indicative of intrinsic kidney disease, plus increased/abnormal blood creatinine or renal transplant from other system organ classesSAEs = Serious adverse events
Post Hoc Analysis: Cardiovascular Events Through 1 Year
Post Hoc Analysis: Cardiovascular Events Through 1 Year
41
Aflibercept(N = 224)
Bevacizumab(N = 218)
Ranibizumab(N = 218)
Global P-Value unadjusted/
adjusted*
Any Cardiovascular Event,† excluding Hypertension
9% 9% 17% 0.0121
0.0242
Any Cardiovascular Event†
19% 16% 26% 0.0383
0.0814
* Adjusted for potential confounders: gender, age at baseline, Hemoglobin A1c at baseline, diabetes type, diabetes duration at baseline, insulin use, prior coronary artery disease, prior myocardial infarction, prior stroke, prior transient ischemic attack, prior hypertension, smoking status
† Events with a MedDRA system organ class of cardiac disorder or vascular disorder OR considered by the medical monitor as related to a cardiac or vascular event (cardiac murmur, cardiac pacemaker insertion/replacement, coronary arterial stent insertion, heart rate irregular, and stent placement)
Pairwise comparisons (adjusted for multiple comparisons): 1. A-B: P=1.0, A-R: P=0.015, B-R: P = 0.014 2. A-B: P=0.68, A-R: P=0.040, B-R: P = 0.0243. A-B: P=0.53, A-R: P=0.087, B-R: P = 0.0384. A-B: P=0.37, A-R: P=0.19, B-R: P = 0.081
DiscussionDiscussion All three anti-VEGF agents, on average, produced
substantial visual acuity improvement by 1 month, sustained through 1 year.
On average, greater improvement occurred with aflibercept, but relative effect varied by initial visual acuity. Mild initial vision loss (20/32-20/40, 50% of study eyes):
little difference in mean visual acuity at 1 year Worse initial vision loss: aflibercept had an advantage
over the other agents• Statistically significant: Mean improvement of 18.9 for aflibercept vs.
11.8 for bevacizumab (P<0.001) and vs. 14.2 with ranibizumab (P = 0.003)• Clinically meaningful: For example, relative improvement ≥15 letters (>3
Snellen lines) in 63% more aflibercept-treated eyes than bevacizumab-treated eyes, and 34% more than ranibizumab-treated eyes
43
Discussion Discussion Bevacizumab had a lesser effect on reducing
macular edema than the other two agents, regardless of starting acuity.
Few eyes in any group had substantial visual acuity loss.
Median number of injections: 9 to 10 in all three groups.
Fewer eyes in the aflibercept group received focal/grid laser for DME after 24 weeks, presumably because a greater % of eyes in the aflibercept group had resolution of central DME (which drives decision to apply laser).
44
DiscussionDiscussion Serious adverse event, death, and
hospitalization rates appeared similar among treatment groups.
Significant differences in frequencies of major cardiovascular events were not identified • However, post-hoc analysis combining MedDRA
system organ classes of cardiac and vascular resulted in more participants in the ranibizumab group reporting these adverse events.
• This is inconsistent with prior studies and may be due to chance.
Endophthalmitis was rare: 0.02% of injections.No differences in intraocular inflammation.
45
Bevacizumab: Note: a central pharmacy repackaged into single use
vials• Testing was completed for sterility, purity, and
potency, a standard that may not be available in a clinical practice setting
Results may not apply to eyes with persistent or recurrent DME already receiving anti-VEGF
46
DiscussionDiscussion
Conclusion Conclusion
All three anti-VEGF agents are effective treatments for DME causing vision impairment.
When initial visual acuity loss is mild, on average there is little difference in visual acuity at 1-year.
At worse levels of initial visual acuity aflibercept is more effective at improving vision.
47
Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
48
A complete list of all DRCR.net investigator financial disclosures and these slides can be found at www.drcr.net.
Full protocol available on clinicalTrials.gov (NCT01627249)
Reference: DOI: 10.1056/NEJMoa1414264
Diabetic Retinopathy Clinical Research Network. Aflibercept, ranibizumab, or bevacizumab for diabetic macular edema. NEJM 2015;372:xxx-xxx.