Transcript Roche Template

Demonstrating Clinical Effectiveness of a Follow-On
Companion Diagnostic Test When a New Clinical Trial is
Unfeasible
cobas® KRAS mutation test
Abha Sharma, Roche Molecular Systems, May 2015
Overview of the Presentation
 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 Analysis
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Background
• Design(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 available
 Conduct 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.
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Approach for Follow on Diagnostic Test and
NDMC Assumption
1. 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 method)
2. Calculate agreement between follow on companion diagnostic test
and the other two tests.
3. “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).
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Background: Cetuximab for mCRC patients
Pivotal Clinical Study: KRAS Mutation
572 Patients with
Advanced Colorectal
Cancer
Cetuximab + BSC
Best Supportive Care
(BSC)
Tested by Sanger
Sequencing
KRAS Mutation
Detected(MD or
POS)
HR- 0.98 (0.70, 1.37)
No Effect of Treatment
*Karpetis et. al. NEJM 2008
KRAS WildType (WT or
NEG)
HR – 0.55 (0.41,0.74)
Treatment Effective
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NDMC Assumption:
Given the comparator method result, clinical efficacy is assumed not
to depend on the cobas® KRAS Mutation Test result
Sanger Sequencing
S = 0 (Neg)
cobas®
KRAS
Test
S=1
(Pos)
R = 0 (Neg)
δ00
δ01
R=1
(Pos)
δ10
δ11
δ.0
δ.1
When Clinical
outcome is
available
Sanger Sequencing
cobas®
KRAS
Test
S=0
(Neg)
S=1
(Pos)
R=0
(Neg)
δ.0
δ.1
R=1
(Pos)
δ.0
δ.1
Applying
NDMC
Assumption
δr. = δr0 (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 )
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Background: Cetuximab Study and FDA-Approved KRAS
Test
572 Patients with
Advanced Colorectal
Cancer
Best Supportive Care
(BSC)
Cetuximab + BSC
Tested by FDAApproved KRAS test
KRAS Mutation
Detected(MD)
HR- 0.91 (0.67, 1.24)
No Effect of Treatment
KRAS WildType (WT)
HR – 0.63 (0.47,0.84)
Treatment Effective
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NDMC Assumption Implication and Analysis
(Criterion 1 and 2)
•
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)
XELOXA Samples +
supplemental mCRC
samples (n=461)
Sanger Sequencing
FDA Approved Test
Calculate
NPV+PPV-1
cobas® KRAS Test
Calculate
NPV+PPV-1
cobas® KRAS Test
NPV+PPV-1 is defined as the “attenuation factor”
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Attenuation Factor (NPV+ PPV-1) calculations
Here, τ is the prevalence of Pr(S=1) in the Pivotal Study, and
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Comparison of the cobas® KRAS Mutation Test with
Comparator Methods for Detection of KRAS Mutations in
Codon 12/13
Comparator Method
cobas®
KRAS
Mutation
Test
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)
NPA
(95% CI)
96.9% (92.2%, 98.8%)
93.3% (88.1%, 96.3%)
88.7% (84.7%, 91.8%)
96.5% (93.5%, 98.1%)
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Attenuation Factor (NPV+ PPV-1) calculations
for cobas® test and FDA Approved Test
Table 1: Attenuation Factors for cobas® KRAS mutation
test
Comparator
Sanger
Sequencing
PPV
NPV
(95% CI)
(95% CI)
0.975
0.858
(0.811, 0.902)
(0.946,
0.994)
Attenuation Factor
(95% CI)
83.3%
(77.7, 88.3)
Table 2: Attenuation Factor for FDA Approved test
Comparator
Sanger
Sequencing
PPV
NPV
(95% CI)
0.840
(95% CI)
0.956
Attenuation Factor
(95% CI)
79.5%
(0.918,
(73.4, 85.2)
0.986)
Table 3: Attenuation Factor with
respect to FDA Approved
test
Comparator
FDA
Approved
Test
(0.790, 0.888)
PPV
NPV
(95% CI)
0.957
(95% CI)
0.945
(0.927, 0.981)
(0.909,
0.978)
Attenuation Factor
(95% CI)
90.2%
(85.6, 94.4)
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Five Criteria to Establish Clinical Utility of
cobas® KRAS Test
1. NDMC (Non-Differential Misclassification) criterion for cobas® Test
2. NDMC (Non-Differential Misclassification) criterion for FDA Approved
Test
3. Influence Condition Evaluation
4. Covariate Assessment
5. Sensitivity Analysis
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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.
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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
δ0. = δ00 (1- π0 ) + δ01 π0 = (NDMC) δ.0 (1- π0 ) + δ.1 π0
Here , π0 = 1-NPV
-For Mutation Positive subset
δ1. = δ10 (1- π1 ) + δ11 π1 = (NDMC) δ.0 (1- π1 ) + δ.1 π1
Here , π1 = PPV
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Influence Condition Evaluation Results
Drug Efficacy
cobas®
KRAS
Mutation Test
Status
Hazard Ratio (HR)
Samples
Tested
(N)
Estimate
95% CI
No Mutation
Detected
272
0.558
(0.422, 0.752)
Mutation Detected
158
0.908
(0.670, 1.209)
No Mutation
Detected
272
0.413
(0.304, 0.550)
Mutation Detected
158
0.869
(0.670, 1.138)
Overall Survival (OS)
Progression Free Survival
(PFS)
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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%)
P1<0.0001
Male
233 (53.3%)
300 (66.2%)
Race
N
437
453
White
391 (89.5%)
414 (91.4%)
P1=0.151
Non-White
46 (10.5%)
39 (8.6%)
Baseline ECOG
N
421
453
0
285 (67.7%)
110 (24.3%)
P1<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
P2=0.004
Min - Max
26.0 - 89.0
28.6 – 88.1
BSA
N
361
453
Median
1.9
1.8
P2<0.0001
Min - Max
1.3 - 2.8
1.3 – 2.5
* P =p-value from Chi-Square Goodness-of-Fit Test; P =p-value from 21
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
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Covariates Comparison between the two
studies
Disease Characteristics (4)
Disease Characteristics
Study Cohort
(N=437)
Therascreen
(N=453)
Disease Stage
Duke’s Stage Total
430
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A
0 (0.0%)
1 (1.7%)
B
0 (0.0%)
16 (27.1%)
C
363 (84.4%)
38 (64.4%)
D
67 (15.6%)
4 (6.8%)
Tumor Type
N
432
448
Primary
420 (97.2%) 410 (91.5%)
Metastatic
12 (2.8%)
38 (8.5%)
a; P =p-value from Chi-Square Goodness-of-Fit Test.
1
P-valuea
P1<0.0001
P1<0.0001
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Covariates Comparison between the two studies
Sample Characteristics (4)
Study Cohort
(N=437)
Pivotal Clinical
study (N=453)
Tumor Content in Sample
N
437
453
Median
35.00
47.25
Min - Max
5.0 - 90.0
1.0 – 100.0
Macro Dissection of Samples
N
437
453
Tumor Content ≤20
98 (22.4%)
39 (8.6%)
Tumor Content >20
339 (77.6%)
414 (91.4%)
Necrosis Score Within Tumor
Area
N
437
453
0 - < 10%
304 (69.6%)
346 (76.4%)
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%)
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 =p-value from Chi-Square Goodness-of-Fit Test; P =p-value from 21
2
sided one sample Sign Test..
P-valuea
P2<0.0001
P1<0.0001
P1<0.0001
P1=0.317
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Hazard ratio Estimates for Significant Covariates
If the covariate distribution was similar to observed in the original study
Covariates
Age
BSA
Duke’s Stage (<=C, >C)
Baseline ECOG
Necrosis
(0 - <10%, 10 – 50%,
>50%)
Sex
Tumor Type
Tumor content (<=20 or
>20)
Tumor content (Num)
Drug Efficacy
OS
PFS
OS
PFS
OS
PFS
OS
PFS
OS
PFS
OS
PFS
OS
PFS
OS
PFS
OS
PFS
Hazard Ratio (HR)
Wild Type
Mutation Detected
Estimate
95% CI
Estimate
95% CI
0.554
(0.426,0.730)
0.907
(0.667,1.207)
0.413
(0.308,0.555)
0.872
(0.660,1.156)
0.563
(0.416,0.760)
0.902
(0.681,1.202)
0.416
(0.313,0.560)
0.874
(0.667,1.142)
0.559
(0.422,0.757)
0.903
(0.678,1.217)
0.412
(0.311,0.552)
0.866
(0.656,1.131)
0.563
(0.414,0.771)
0.904
(0.675,1.214)
0.407
(0.302,0.551)
0.860
(0.646,1.137)
0.562
(0.420,0.753)
0.890
(0.686,1.180)
0.408
(0.303,0.545)
0.844
(0.659,1.117)
0.552
0.408
0.549
0.401
0.563
0.416
0.556
0.408
(0.428,0.734)
(0.311,0.545)
(0.419,0.726)
(0.299,0.531)
(0.425,0.755)
(0.308,0.554)
(0.405,0.734)
(0.306,0.541)
0.898
0.867
0.980
0.972
0.912
0.889
0.901
0.877
(0.662,1.195)
(0.662,1.141)
(0.699,1.335)
(0.726,1.326)
(0.677,1.214)
(0.665,1.187)
(0.673,1.221)
(0.668,1.149)
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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.
Sanger Sequencing
cobas®
KRAS Test
Pos
Neg
k
Pos
Neg
a
b
c
d
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 Research
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OS (HR) Changes by KRAS Status as Determined by the
cobas® KRAS Mutation Test by Moving Subjects from
Concordance to Discordance (Criterion 5)
when k = 45, which corresponds to 21% more discordance between the
cobas® KRAS Mutation Test and Sanger sequencing for Mutation Positive
subset
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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 subset
Five Bridges to Demonstrate Clinical Utility
NPV+PPV-1 for
cobas® test >83%
NPV+PPV-1 for cobas® test >
NPV+PPV-1 for FDA Approved
Test
XELOXA
+
Supplemental
samples
Influence condition is
false
Cetuximab CO.17
Trial results
Covariate
Assessment
Sensitivity Analysis
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Acknowledgements
• Interactions with FDA
John Palma, Lesley Farrington, Allison Gannon, Tori Brophy, Sung
Lee
• Clinical 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
team
COBAS is a trademark of Roche.
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