Abha Sharma Roche Molecular Systems May 2015 cobas KRAS mutation test Overview of the Presentation 2 Background Approach for follow on Diagnostic Test NDMC Assumption Bridge 1 NDMC ID: 683866
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Slide1
Demonstrating Clinical Effectiveness of a Follow-On Companion Diagnostic Test When a New Clinical Trial is Unfeasible
Abha Sharma, Roche Molecular Systems, May 2015
cobas
® KRAS mutation testSlide2
Overview of the Presentation
2
Background
Approach for follow- on Diagnostic Test
NDMC Assumption
Bridge 1
: NDMC
Criteria for
cobas
Test
Bridge 2
: NDMC
Criterion for FDA-approved
test
Bridge 3: Influence Criteria evaluation
Bridge 4: Covariate assessment
Bridge 5: Sensitivity and Robustness AnalysisSlide3
BackgroundDesign(s) to demonstrate clinical utility of the
first companion diagnostic test Using the final In-Vitro Diagnostic (IVD) version of the test to select patients
Bridging
from Clinical Trial Assay (CTA) or Lab
Developed Test (LDT
) to the
final
IVD Test
Follow on companion diagnostic test : Re-test samples from a previously conducted trial for first companion Diagnostic -samples may not be availableConduct a new prospective trial with the same drug with a placebo arm - unethical to give placebo to patients while an effective approved drug is available.
3Slide4
Approach for Follow on Diagnostic Test and NDMC Assumption
Test Samples from another clinical study cohort by The First companion Diagnostic Test the follow on companion diagnostic test, and the reference method (A sequencing m
ethod)
Calculate agreement between
follow on companion diagnostic
test and the other two tests.
“Transport” Results of drug efficacy from the
pivotal study for the first companion diagnostic test to the follow on companion diagnostic test assuming Non-differential Misclassification (NDMC).4Slide5
Background: Cetuximab for mCRC patients
Pivotal Clinical Study: KRAS Mutation
5
572 Patients with Advanced Colorectal Cancer
Cetuximab
+ BSC
Best Supportive Care (BSC)
Tested by Sanger Sequencing
KRAS Mutation Detected(MD or POS)
KRAS Wild-Type (WT or NEG)
HR- 0.98 (0.70, 1.37)
No Effect of Treatment
HR – 0.55 (0.41,0.74) Treatment Effective
*
Karpetis
et. al. NEJM
2008Slide6
NDMC Assumption: Given the comparator method result, clinical efficacy is assumed not to depend on the cobas
® KRAS Mutation Test result
Sanger Sequencing
cobas
®
KRAS Test
S
= 0 (
Neg)S = 1(Pos)
R = 0 (
Neg
)
δ
00
δ
01
R =
1
(
Pos)
δ10
δ11δ.0
δ.16
Sanger Sequencing
cobas® KRAS TestS = 0 (Neg)S = 1
(Pos)R = 0 (
Neg)δ.0
δ.1R = 1(Pos)
δ.0
δ.1When Clinical outcome is available
Applying NDMC Assumption
δ
r
.
=
δ
r0
(1-
πr ) + δr1 πr = (NDMC) δ.0 (1- πr ) + δ.1 πr Here , π1 = PPV and π0 = 1-NPV; δ1. = Log Hazard Ratio in R=1(Pos); δ0. = Log Hazard Ratio in R=0 (Neg )Slide7
Background: Cetuximab Study and FDA-Approved KRAS Test
7
572 Patients with Advanced Colorectal Cancer
Cetuximab
+ BSC
Best Supportive Care (BSC)
Tested by FDA-Approved KRAS test
KRAS Mutation Detected(MD)
KRAS Wild-Type (WT)
HR- 0.91 (0.67, 1.24)
No Effect of Treatment
HR – 0.63 (0.47,0.84) Treatment EffectiveSlide8
8
XELOXA Samples + supplemental mCRC samples (n=461)
Sanger Sequencing
cobas
®
KRAS Test
Calculate NPV+PPV-1
Calculate NPV+PPV-1
Under NDMC: E(
h|R
=0) –E(
h|R
=1) = [E(
h|S
=0) – E(
h|S
=1)( NPV+PPV-1)
difference in log-hazard ratio for
cobas
test = difference in log-hazard ratio for
Sanger ×(NPV+PPV-1)NDMC Assumption Implication and Analysis (Criterion 1 and 2)NPV+PPV-1 is defined as the “attenuation factor”
FDA Approved Test
cobas
®
KRAS TestSlide9
Attenuation Factor (NPV+ PPV-1) calculations
9
Here,
τ
is the prevalence of
Pr
(S=1) in the Pivotal Study, and Slide10
Comparison of the cobas® KRAS Mutation Test with Comparator Methods for Detection of KRAS Mutations in Codon 12/13
cobas
®
KRAS Mutation Test
Comparator Method
Sanger Sequencing
FDA-approved IVD test
MD
NMD
Invalid
Total
MD
NMD
Invalid
Total
MD
124
34
5
163
139
9
15
163
NMD
4
268
2
274
10
248
16
274
Invalid
0
19
5
24
0
5
19
24
Total
128
321
12
461
149
262
50
461
PPA
(95% CI)
96.9% (92.2%, 98.8%)
93.3% (88.1%, 96.3%)
NPA
(95% CI)
88.7% (84.7%, 91.8%)
96.5% (93.5%, 98.1%)
10Slide11
Attenuation Factor (NPV+ PPV-1) calculations for cobas
® test and FDA Approved Test11
Comparator
PPV
(95% CI)
NPV
(95% CI)
Attenuation Factor (95% CI)
Sanger Sequencing
0.858
(0.811, 0.902)
0.975
(0.946, 0.994)
83.3%
(77.7, 88.3)
Table 1: Attenuation Factors for
cobas
®
KRAS mutation test
Table 2: Attenuation Factor for FDA Approved test
Comparator
PPV
(95% CI)
NPV
(95% CI)Attenuation Factor (95% CI)
Sanger Sequencing
0.840 (0.790, 0.888)
0.956 (0.918, 0.986)
79.5% (73.4, 85.2)
Comparator
PPV
(95% CI)
NPV
(95% CI)
Attenuation Factor (95% CI)
FDA Approved Test
0.957
(0.927, 0.981)
0.945 (0.909, 0.978)90.2%(85.6, 94.4)
Table 3: Attenuation Factor with respect to FDA Approved test Slide12
Five Criteria to Establish Clinical Utility of cobas® KRAS Test
NDMC (Non-Differential Misclassification) criterion for cobas®
Test
NDMC
(Non-Differential Misclassification)
criterion
for
FDA Approved Test
Influence Condition EvaluationCovariate AssessmentSensitivity Analysis12Slide13
Influence Condition Evaluation: (3)
Evaluate Influence Condition: To enable Overall population labeling, the beneficial effect of the drug must not be limited to only the predefined subpopulation Our Objective is to show that for this study overall Population labeling does not apply; Influence condition is false
i.e. 95% CI for the hazard ratio in the Mutation positive subset
includes
1, and
the 95% CI for the hazard ratio in the Mutation Negative subset
excludes
1.
13Slide14
Influence Condition Evaluation:
Log Hazard Ratios for cobas® test can be calculated using following
relationships between hazard ratios based on NDMC assumption
-
For
Mutation Negative subset
δ
0.
= δ00 (1- π0 ) + δ01 π0 = (NDMC) δ.0 (1- π0 ) + δ.1 π0
Here
,
π
0
= 1-NPV
-For Mutation
Positive
subsetδ1. = δ10 (1-
π1 ) + δ11 π1
= (NDMC) δ.0 (1- π1 ) + δ.1
π1 Here , π1 = PPV14Slide15
Influence Condition Evaluation Results
Drug Efficacy
cobas
®
KRAS
Mutation Test
Status
Samples
Tested
(N)
Hazard Ratio (HR)
Estimate
95% CI
Overall Survival (OS)
No
Mutation Detected
272
0.558
(0.422, 0.752)
Mutation Detected
158
0.908
(0.670, 1.209)
Progression Free Survival
(
PFS)
No
Mutation Detected
272
0.413
(0.304, 0.550)
Mutation Detected
158
0.869
(0.670, 1.138)
15Slide16
Covariates Comparison between the two studies: Patient Characteristics (4)
Characteristic
Study Cohort (N=437)
Pivotal
Clinical study
(N=453)
P-value
*
Sex
N
437
453
Female
204 (46.7%)
153 (33.8%)
P
1
<0.0001
Male
233 (53.3%)
300 (66.2%) Race
N437
453
White391 (89.5%)414 (91.4%)
P1=0.151
Non-White
46 (10.5%)
39 (8.6%)
Baseline ECOG
N
421453
0
285 (67.7%)
110 (24.3%)
P
1
<0.0001
1
125 (29.7%)
245 (54.1%)
2
11 (2.6%)
98 (21.6%)
Age
N
437
453
Median
61.0
63.2
P
2
=0.004
Min - Max
26.0 - 89.0
28.6 – 88.1
BSA
N
361
453
Median
1.9
1.8
P
2
<0.0001
Min - Max
1.3 - 2.8
1.3 – 2.5
*
P
1
=p-value from Chi-Square Goodness-of-Fit Test; P
2
=p-value from 2-sided one sample Sign Test.
Note: ECOG=Eastern Cooperative Oncology Group; BSA= Body surface area BSA=[(height in cm*weight in Kg)/3600]
1/2
16Slide17
Covariates Comparison between the two studiesDisease Characteristics (4)
Disease Characteristics
Study Cohort (N=437)
Therascreen (N=453)
P-value
a
Disease Stage
Duke’s Stage Total
430
59
A
0 (0.0%)
1 (1.7%)
P
1
<0.0001
B
0 (0.0%)
16 (27.1%)
C
363 (84.4%)
38 (64.4%)
D67 (15.6%)
4 (6.8%)
Tumor Type
N
432
448
Primary
420 (97.2%)
410 (91.5%)
P1<0.0001
Metastatic12 (2.8%)38 (8.5%)
a
; P
1
=p-value from Chi-Square Goodness-of-Fit Test.
17Slide18
Covariates Comparison between the two studiesSample Characteristics (4)
Study Cohort (N=437)
Pivotal Clinical study
(N=453)
P-value
a
Tumor Content in Sample
N
437
453
Median
35.00
47.25
P
2
<0.0001
Min - Max
5.0 - 90.0
1.0 – 100.0
Macro Dissection of Samples
N437453
Tumor Content ≤20
98 (22.4%)39 (8.6%)
P1<0.0001
Tumor Content >20
339 (77.6%)
414 (91.4%)
Necrosis Score Within Tumor Area
N437
453
0 - < 10%
304 (69.6%)
346 (76.4%)
P
1
<0.0001
10 - 50%
131 (30.0%)
86 (19.0%)
>50%
2 (0.5%)
21 (4.6%)
KRAS Mutation Type
N
149
208
12ALA
12 (8.1%)
14 (6.7%)
P
1
=0.317
12ARG
2 (1.3%)
2 (0.9%)
12ASP
42 (28.2%)
71 (34.1%)
12CYS
15 (10.1%)
16 (7.7%)
12SER
13 (8.7%)
11 (5.3%)
12VAL
35 (23.5%)
54 (25.9%)
13ASP
30 (20.1%)
40 (19.2%)
a
; P
1
=p-value from Chi-Square Goodness-of-Fit Test; P
2
=p-value from 2-sided one sample Sign Test..
18Slide19
Hazard ratio Estimates for Significant CovariatesIf the covariate distribution was similar to observed in the original study
19
Hazard Ratio (HR)
Wild Type
Mutation Detected
Covariates
Drug Efficacy
Estimate
95% CI
Estimate
95% CI
Age
OS
0.554
(0.426,0.730)
0.907
(0.667,1.207)
PFS
0.413
(0.308,0.555)
0.872
(0.660,1.156)
BSA
OS
0.563
(0.416,0.760)
0.902
(0.681,1.202)
PFS
0.416
(0.313,0.560)
0.874
(0.667,1.142)
Duke’s
Stage (<=C, >C)
OS
0.559
(0.422,0.757)
0.903
(0.678,1.217)
PFS
0.412
(0.311,0.552)
0.866
(0.656,1.131)
Baseline ECOG
OS
0.563
(0.414,0.771)
0.904
(0.675,1.214)
PFS
0.407
(0.302,0.551)
0.860
(0.646,1.137)
Necrosis
(0 - <10%, 10 – 50%, >50%)
OS
0.562
(0.420,0.753)
0.890
(0.686,1.180)
PFS
0.408
(0.303,0.545)
0.844
(0.659,1.117)
Sex
OS
0.552
(0.428,0.734)
0.898
(0.662,1.195)
PFS
0.408
(0.311,0.545)
0.867
(0.662,1.141)
Tumor Type
OS
0.549
(0.419,0.726)
0.980
(0.699,1.335)
PFS
0.401
(0.299,0.531)
0.972
(0.726,1.326)
Tumor content (<=20 or >20)
OS
0.563
(0.425,0.755)
0.912
(0.677,1.214)
PFS
0.416
(0.308,0.554)
0.889
(0.665,1.187)
Tumor content (Num)
OS
0.556
(0.405,0.734)
0.901
(0.673,1.221)
PFS
0.408
(0.306,0.541)
0.877
(0.668,1.149)Slide20
Sensitivity Analysis* (5)
Sensitivity analysis was conducted to consider the robustness of the study results to the assumptions by simulating how many agreements between cobas
®
test
and Sanger sequencing would have to be changed to disagreements before the study fails to show clinical effectiveness.
20
Sanger Sequencing
cobas
®
KRAS Test
Pos
Neg
Pos
a
b
Neg
c
d
k
k
‘k’ patients will be randomly selected from ‘a’ cell and their status will be changed to Sanger
Pos
,
cobas
test Negative, similarly k’ patients will be randomly selected from ‘d’ cell and their status will be changed to Sanger Negative cobas test Positive. Estimate of Log Hazard ratio calculated for each value of ‘k
’.The highest value of k at which the hazard ratio is still statistically significant will be determined.
*Denne, Pennello et al. 2014, Statistics in Biopharmaceutical ResearchSlide21
OS (HR) Changes by KRAS Status as Determined by the cobas® KRAS Mutation Test by Moving Subjects from Concordance to
Discordance (Criterion 5)21
when
k
= 45, which corresponds to 21% more discordance between the
cobas
®
KRAS Mutation Test and Sanger
sequencing for Mutation Positive subsetSlide22
PFS (HR) Changes by KRAS Status as Determined by the cobas® KRAS Mutation Test by Moving Subjects from Concordance to Discordance (5)
when k = 27, which corresponds to 12.6% more discordance between the
cobas
®
KRAS Mutation Test and Sanger
sequencing
in Mutation Positive subsetSlide23
Five Bridges to Demonstrate Clinical Utility
23
XELOXA
+
Supplemental samples
Cetuximab
CO.17
Trial results
NPV+PPV-1
for
cobas
®
test >83%
NPV+PPV-1 for
cobas
®
test >
NPV+PPV-1 for FDA Approved Test
Influence condition is false
Covariate Assessment
Sensitivity AnalysisSlide24
AcknowledgementsInteractions with FDA
John Palma, Lesley Farrington, Allison Gannon, Tori Brophy, Sung LeeClinical Study Coordination , conduct, Karen Yu, Melody Chee, Sim
Truong
Clinical Study decisions, CSR and research
Sid
Scudder
Statistical Analysis
Guili Zhang, Shagufta Aslam, Ranga Yerram and SAS programming teamCOBAS is a trademark of Roche. 24Slide25
Doing now what patients need next
25