quantifying the value of volumetric

image analysis to pharma

Mozley PD, et al.
Merck Research Laboratories
Problem Statement: General

estimated costs $0.8 – 1.7BB

www.inovation.org
Problem Statement: Specific

 paucity of evidence
that CT imaging
adds value
 gap: signal
processing
– signals are becoming
progressively brilliant
– analysis lags behind
Volumetric Image Analysis (VIA)

 hypothesis: better quantification techniques

will add value
• improve patient care
• decrease number of subjects per trial
• shorten time-on-study per subject
• reduce development times
• speed delivery of new treatments
pharma’s qualification process

 assess feasibility, time & effort; if go, then

 characterize precision & accuracy; if go, then

 estimate value

– retrospectively
– prospectively
• small studies at a few premier centers
• options in mega, multi-national settings
value

 definedas the ability to have a unique

impact on patient management
precision: Methods

 sample: 2 phantom sets + 10 clinical cases

 target lesions: measurable lung tumors

 CT scans:  5 mm RI ( QIBA UPICT

protocol)
 image analysts: 7 independent teams

– provided with one screenshot per tumor on

one slice
accuracy: Results +/- 2.7 to 12% @ 5 mm

volumes  spheres with diameters of 40, 20, & 10 mm

corresponding volumes = 33.5, 4.2, and 0.5 mL. Courtesy of Petrick N, et al. FDA
precision: Results
 image sets per subject: mean = 7.2 +/- 1.5
 target lesion volumes: mean = 117 +/- 136 mL

 time on trial: mean = 283 +/- 72 days

Left Panel: largest = 413 mL; Right: smallest = 1.8 mL

precision: Results for Merck clinical only

volume
mean median max
Merck & 90%CI 95% CI
%relvar %relvar discord
partners

intra-
5.0 4.3 10.3 12.5 17.0
rater
inter-
5.3 4.4 10.8 15.7 19.1
rater
precision: Results for 7 teams
agreement between 7 teams

CV 95% CI
absolute values 25% 59%

% change 12.4% 20%

precision for change: iota values

auto-SLD VIA
overall 0.73 0.95
minimum 0.58 0.86
maximum 0.96 0.99

Conclusion: agreement is higher for volume

than for SLD
Conclusions:

• biases between teams seem highly

consistent for both volume & SLD
• CV for absolute volume too high in this
setting
• CV for change OK
• CV higher for SLD than for volume
• Therefore, GO to next step
Response Rate: volume versus SLD
100

SLD.Average
vol.Average
80
% Survival (PR endpoint)

60

p=0.002, log rank test

40
20
0

42 84 126 168 210 252 294 336 378

Time on Trial [days]

PFS: volume versus SLD
100

SLD.Average
vol.Average
80
% Survival (PD endpoint)

60

p=0.039, log rank test

40
20
0

42 84 126 168 210 252 294 336 378

Time on Trial [days]

Conclusions: precision

 volumes might be
– more precise than SLDs as a basis for
RECIST
– more sensitive indicators of response
– cost effective
 Therefore, GO to next step
next step: retrospective analysis Phase III

R + placebo p.o. x 14 d
A n = 123
N
D
SOC drug 1
O SOC = q 21 d
MI SOC drug 2
Z
E + MK p.o. x 14 d
n = 125
Can VIA add value?

 Reduce the number of subjects who never meet

criteria for PR or PD?
 Decrease the number of subjects who come off
trial because of New Lesions?
 Bring trials to closure faster?
Methods: image re-analysis
 selection of target lesions by independent
radiologists
 automatic edge detection algorithm
 manual revision of edges
 certification of final boundaries by radiologists
 automatic computation:
– 3D tumor volume [mm3]
– 1D longest diameter  greatest distance [mm]
between any two in-plane pixels on any slice in the
stack of tomographic images representing the target
Methods (continued)

 outcome measures
– auto-SLD  sum of longest diameters of all target lesions
– volume  sum of corresponding tumor volumes
 endpoints
– Objective Response Rate (ORR)  number of subjects
with a Best Overall Response (BOR) of PR or CR
divided by the total number of subjects
– Progression Free Survival (PFS)  time from first drug
dose until PD based on change in tumor mass or the
appearance of new metastases
Methods (continued)

 statistical analysis
– 3D versus 1D in all subjects
– MK arm versus placebo arm
 categorical variables: RECIST versus “Enhanced
RECIST”
– Partial Response (PR) = decrease of >30% from baseline
– Progressive Disease (PD) = increase of >20% from nadir
 continuous variables
– median change in auto-SLD or volume at each time-point
for whole groups
 Results: Objective Response Rates
Survival
allPlot
184 patients
1.0 SLD
Tests Between Groups
Volumetric
% Reaching Partial Response

0.8 Test ChiSquare DF Prob>ChiSq

Log-Rank 22.6529 1 <.0001*
0.6 Wilcoxon 26.5519 1 <.0001*

0.4 Survival Plot

1.0 SLD
0.2 Volumetric
% Reaching Partial Response

0.8
0.0
0 0.6 42 84 126 168 210 252 294 336 378
Time on Trial (days)
0.4

Kaplan-Meier
0.2 analysis shows that VIA is more sensitive than
auto-SLD
0.0 for detecting PR
0 100 200 300 400
BRR (days)
Results: Objective Response Rates

auto-SLD 23.9%

VIA 41.8%
time to Partial Response (PR)

  MK (n = 87) Placebo (n = 97)

auto-SLD VIA auto-SLD VIA
[days] [days] [days] [days]
mean 92.2 69.9 104.8 75.3
median 83.0 49.0 86.0 47.0

 Results: VIA detects PR sooner than auto-SLD

– MK-arm: 22.2 days, p-value = 0.0002
– placebo-arm: 29.5 days, p-value < 0.0001
Conclusions: Response Rates

 VIA is more sensitive than auto-SLD

 VIA confirms favorable responses sooner
than auto-SLD
 the differences are potentially meaningful?
Results
Survival Plot
for PFS: auto-SLD v VIA
1.0 SLD
% Reaching Progressive Disease

Volumetric

0.8 Tests Between Groups

Test ChiSquare DF Prob>ChiSq
0.6 Log-Rank 11.5214 1 0.0007*
Wilcoxon 7.3709 1 0.0066*
Survival Plot
0.4
1.0 SLD
Volumetric
% Reaching Partial Response

0.2 0.8

0.6
0.0
0.4
0 42 84 126 168 210 252 294 336 378
0.2
Time on Trial (days)
 VIA is more sensitive
0.0
than auto-SLD for patients with
longer times on trial
0 100 200
BRR (days)
300 400
Stable Disease as Best Overall Response

 auto-SLD: 71.2% of all subjects came off trial

without target lesions ever meeting radiological
criteria for PR or PD
– 35.1% were re-categorized by VIA
 VIA: 50.5%

– 8.8% were re-categorized by auto-SLD

 Conclusion: VIA results in fewer patients being
right-censored
change = PD before new lesions?

 
auto-SLD VIA conclusion
<20% before new loss for
lesions 6.0% 9.2% quants
>20% before new win for
lesions 16.8% 38.0% quants
ties between quants & no added
new lesions 10.3% 5.4% value
no new lesions AND no no
>20% 68.3% 48.9% information
extrapolation to a successful trial

 decrease sample size by ~20%

 save ~ US$2 MM in external cash burn for
conventional image management & analysis
services
 cost ~$300,000 to $500,000 USD in extra cash
burn for VIA
 speed the conclusion of clinical trials
Conclusions

 VIA is more sensitive than auto-SLD in some

contexts
 quantification is sometimes more sensitive
than new lesions for assessing PD
 VIA could shorten trials
 advanced NSCLC is a context in which VIA
could add value
– to clinical trials
– to a few, highly selected patients
 ¿ Questions ?
 P. David Mozley, M.D.
 mozley@merck.com

 (+1) 215 353 8958 (mobile)