u.s. food and drug administration
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U.S. Food and Drug Administration. Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated. . Colorectal Cancer Endpoints Workshop November 12, 2003. - PowerPoint PPT PresentationTRANSCRIPT
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U.S. Food and Drug Administration
Notice: Archived DocumentThe content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.
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Colorectal Cancer Endpoints WorkshopNovember 12, 2003
A Case for Time to Tumor Progression as a Clinical Benefit Endpoint in the First-line Therapy of Metastatic Colorectal Cancer
Langdon L Miller, MDChief Medical Officer
PTC Therapeutics
Gary L Elfring, MSStatistical Consultant
Pfizer Corporation
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Acknowledgements
Pfizer Corporation
Sumant Ramachandra, MDGroup Leader
US Medical Oncology
Gabriela Gruia, MD Full-Development Team Leader
Camptosar®
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Premise (1)
An objective, non-survival clinical benefit endpoint is needed as the basis for
full regulatory approval of new therapies for metastatic colorectal cancer
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Why the Need Now?
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An Increasing Number of Treatments Has Added Therapeutic Complexity
0
1
2
3
4
5
6
7
1960 1965 1970 1975 1980 1985 1990 1995 2000 2005
Year
Dru
gs A
vaila
ble
Cituximab (Erbitux)*
Bevacizumab (Avastin)*
Oxaliplatin (Eloxatin)
Capecitabine (Xeloda)
Irinotecan/CPT-11 (Camptosar)
Leucovorin (Leucovorin)
5-fluorouracil (Adrucil)
*Not yet FDA approved
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An Increasing Number of TherapiesHas Prolonged Survival
13 mo
0
5
10
15
20
5-FU/LV (capecitabine) 5-FU/LV (capecitabine)CPT-11
5-FU/LV (capecitabine)CPT-11
OxaliplatinFDA-Approved Therapies
Med
ian
Surv
ival
16 mo
19 mo
Saltz LB et al. Proc Amer Soc Clin Oncol 19:#938, 2000; Tournigand C et al. Proc Amer Soc Clin Oncol 20:#494, 2001Grothey A et al. Proc Amer Soc Clin Oncol 20:#496, 2001; Goldberg RM et al. Proc Amer Soc Clin Oncol 22:#1009, 2003
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Multiple Therapies
Confound relationship between early tumor control effects and long-term survival effects
Disconnect early tumor control effects and long-term survival effects
Reduce likelihood that survival benefit will be seen
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90 5 10 15 20 25 30
Time (mo)
Original Therapy (A) New Therapy (B) Alternative Therapy (C) Palliative Care
Subsequent Therapies Confound Relationship Between Early Tumor Control
and Overall Survival
Tumor Control HR = 1.75Survival HR = 1.00
4
7
9
9
3AB
A+B
16
16
7
7 3
9
9
A+C
A+BC
Tumor Control HR = 1.00Survival HR = 1.14
16
19
Trea
tmen
ts
4
4 3
9
9
A
A+B
Tumor Control HR = 1.75Survival HR = 1.23
13
167
Is B inefficacious?
Is A+B more efficacious than A+C?
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0 5 10 15 20 25 30
Trea
tmen
ts
Time (mo)
Original Therapy New Therapy Later Therapy Later Therapy Later Therapy Palliative Care
Subsequent Therapies Disconnect Early Tumor Control and Long-Term Survival
Tumor Control HR = 1.75Survival HR = 1.14
4
7
3
3
3
3
3
3
9
9
ACDE
A+BCDE
21
25
18 mo
18 mo
4
7
9
9
A
A+B
Tumor Control HR = 1.75Survival HR = 1.23
13
16
9 mo
9 mo
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Prolonged Survival
Increases sample sizes Prolongs accrual time Delays time until final analysis Increases costs
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Sample Size Requirements for a Study Increase
TherapeuticPlatform
Median Survival (mo)Required Sample Size*
PlatformAlone
Platform+
Investigational
5-FU/LV No therapy 13 16 1100
CPT-11/5-FU/LV No therapy 16 19 1600
CPT-11/5-FU/LV Oxali/5-FU/LV 19 22 2200
*Assumes 2-sided =0.05; =0.20; accrual = 100 patients/mo; follow-up = largest hypothesized median + 4 months
Superiority Survival Study
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Sample Size Requirements for a Study Increase
TherapeuticPlatform
Median Survival (mo)Required Sample Size*Existing Investigational
5-FU/LV No therapy 13 11.5 2600
CPT-11/5-FU/LV No therapy 16 14.5 4000
CPT-11/5-FU/LV Oxali/5-FU/LV 19 17.5 5700
*Assumes retention of 50% of survival benefit relative to prior therapy,1-sided =0.025; =0.20; accrual = 100 patients/mo; follow-up = longest hypothesized median + 4 months
Non-inferiority Survival Study
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Time to Accrue Sufficient Number of Patients Increases
TherapeuticPlatform
Sample Size Time to Accrue (mo)
Superiority Non-inferiority Superiority Non-
inferiority
5-FU/LV No therapy 1100 2600 11 26
CPT-11/5-FU/LV No therapy 1600 4000 16 40
CPT-11/5-FU/LV Oxali/5-FU/LV 2100 5700 21 57
*Assumes accrual = 100 patients/mo
Survival Study
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Time to Acquisition of Mature Data is Prolonged
ExistingTherapy
Number of Events* Time to Analysis (mo)
Superiority Non-inferiority Superiority Non-
inferiority
5-FU/LV No therapy 728 2062 31 43
CPT-11/5-FU/LV No therapy 1076 3212 39 60
CPT-11/5-FU/LV Oxali/5-FU/LV 1448 4726 47 80
*Based on assumptions from prior slides
Survival Study
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Cost to Conduct A Study Increases
ExistingTherapy
Sample Size Trial Cost*
Superiority Non-inferiority Superiority Non-
inferiority
5-FU/LV No therapy 1100 2600 $44M $104M
CPT-11/5-FU/LV No therapy 1600 4000 $64M $160M
CPT-11/5-FU/LV Oxali/5-FU/LV 2200 5700 $88M $228M
*Assumes fully loaded internal and external costs of $40,000/patient
Survival Study
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Implications for Evaluation of Survival as the Primary Measure of Clinical Benefit
Value of survival as an endpoint is reduced Development in colorectal cancer takes on
added risk, time, and expense Conduct of noninferiority studies or multiple
studies becomes impractical NDA submissions are delayed Antitumor therapies may not be studied
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Why Not Evaluate Symptom Control Instead?
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Issues with Symptom Control
Symptom severity is subjective Disparate types of symptoms in metastatic
colorectal cancer complicate interpretation– Fatigue vs pain vs anorexia vs dyspnea vs ascites
Symptoms are not uniformly present at diagnosis and are often not severe
Treatment and disease may induce the same symptoms (eg, nausea, diarrhea)
Relevant symptoms may be missed
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20Combined EORTC QLQ C-30 from all patients with baseline data enrolled in Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
Baseline Symptom* % of Patients(N=849)
AverageSymptom
Score(Max 100)
Fatigue 86 35Physical dysfunction 64 31Pain 54 20Appetite Loss 38 18Dyspnea 34 15Nausea/Vomiting 28 9Diarrhea 37 15Abdominal swelling Not collected Not collected
Baseline Symptoms in Patients with Untreated Metastatic Colorectal Cancer
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Issues with Symptom Control
Instruments may be insensitive to important changes in tumor size
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Subjective Measures of Quality of Life May Not Change Despite
Objective Tumor Shrinkage
Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
Response Rates
39
21
01020304050
CPT-115-FU/LV
5-FU/LV
%
35
22
01020304050
5-FU/LV
%
CPT-115-FU/LV
p<0.001 p<0.005
EORTC QLQ C-30 Global Health Status
-20-15-10-505
101520
0 4 8 12 16 20 24 28 32Weeks
Better
Worse
Mea
n C
hang
e (
se)
CPT-11/5-FU/LV 5-FU/LV
-20-15-10-505
101520
0 4 8 12 16 20 24 28 32Weeks
Better
Worse
Mea
n C
hang
e (
se)
CPT-11/5-FU/LV 5-FU/LV
P=NS P=NS
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Issues with Symptom Control
Symptom progression analyses are often not useful because symptom progression usually occurs after tumor progression (when patient is off study)
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00.10.20.30.40.50.60.70.80.9
1
0 10 20 30 40Months
Prob
abili
ty
Weight Loss 5%
Time to Tumor Progression
Weight Loss Most Often Occurs after Tumor Progression
*Definitive weight loss (last time weight was <5% from baseline)Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
N=1015
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00.10.20.30.40.50.60.70.80.9
1
0 10 20 30 40Months
Prob
abili
ty
Role Functioning
Global Health
Social FunctioningCognitive Functioning
Physical Functioning
Emotional Functioning
Time to Tumor Progression
*Definitive EORTC QLQ C-30 score worsening (last time score was no worse than baseline)Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
Declines in Functional Scores Most Often Occur After Tumor Progression
N800
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Time to Tumor Progression
00.10.20.30.40.50.60.70.80.9
1
0 10 20 30 40Months
Prob
abili
ty
Nausea/Vomiting
PainDiarrhea
DyspneaAppetite LossFatigue
Declines in Symptom Scores Most Often Occur After Tumor Progression
*Definitive EORTC QLQ C-30 score worsening (last time score was no worse than baseline)Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
N800
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0 3 6 9 12
CPT-11/5-FU/LV
CT scans No PDNo PD No PDBaseline
Discontinuation due to tumor progression
Oxali/5-FU/LV
Months
PD
Symptom Progression When Patient is Off Study and is Receiving Second-Line Therapy
Confounds Interpretation of Results
Worsened symptoms; decline in weight and
functional status
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Implications for Evaluation of Symptoms as the Primary Measure of Clinical Benefit
Problems with complexity, subjectivity, reliability, and interpretability make study design and analysis difficult
Development in colorectal cancer takes on added risk and expense
Antitumor therapies may not be studied
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Premise (2)
Time to tumor progression (TTP) offers an objective, reliable, and practical alternative to survival and symptom-control endpoints
* Time from randomization to the first of either objective tumor progression or death (where tumor progression is a >20% increase in sum of longest dimensions of measured tumors from nadir or the appearance of 1 new tumor [RECIST])
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Why Consider TTP as an Endpoint?
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Time to Tumor Progression
Represents the most common cause of treatment failure
Incorporates the value of time Offers direct assessment of disease
burden that logically correlates with symptom progression and survival
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32Combined data from all treated patients who discontinued therapy. Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
Reason for Treatment Discontinuation
% of Patients(N=1001)
Tumor Progression 70Patient Request 10Adverse Events 8On-Treatment Death 4Other 4Improvement 3Noncompliance/lost to follow-up 1
Tumor Progression is the Most Common Cause of Treatment Failure in Patients
with Metastatic Colorectal Cancer
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Response
PD at 18 wks
By Incorporating the Value of Time, TTP Better Categorizes Tumor Control
Than Response RateProgressive Disease
PD at 6 wks
01020304050607080
0 6 12 18 24 30 36 42 48 54
Time (weeks)
Tota
l Tar
get T
umor
Len
gth
(cm
)
Response Status Stable Disease
PD at 54 wks
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It’s Only Logical That Halting Tumor Progression is Clinically Beneficial
Cancer Burden over Time
Healthy Adenoma
.
. . . .. .
. . .
PrimaryDiagnosis
MetastaticCarcinoma
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It’s Only Logical That Halting Tumor Progression is Clinically Beneficial
Cancer Burden over Time
Healthy Adenoma
.
. . . .. .
. . .
PrimaryDiagnosis
MetastaticCarcinoma
Symptoms None None Fatigue, Fatigue, anorexia obstruction pain, dyspnea,
DVTascites,
obstructionSurvival Decades Decade Years Months
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Time to Tumor Progression
Correlates with survival in metastatic colorectal cancer
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Equation: y = ax + b
Changes in Median Endpoint Values Suggest that TTP Appears to Correlate with Survival
Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
0 5 10 15 20
Time (mo)
4
7
9
9
5-FU/LV
CPT-11/5-FU/LV
13
16
4 9CPT-11 13
3 mo 3 mo
N=1068
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Equation: Survival = 1TTP + 9 mo
Changes in Median Endpoint Values Suggest Hypothetical Equation Correlating TTP with Survival
Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
0 5 10 15 20
Time (mo)
4
7
9
9
5-FU/LV
CPT-11/5-FU/LV
13
16
4 9CPT-11 13
3 mo 3 mo
N=1068
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Both Hypothetical and Actual Equation Correlate TTP with Survival
0
5
10
15
20
25
30
0 2 4 6 8 10 12 14 16Time to Tumor Progression (mo)
Surv
ival
(mo)
Hypothetical equation: Survival = 1TTP + 9 mo
Actual equation: Survival = 1.17TTP + 8.33 mo; r=.56
N=1068
Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
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One-One TTP-Survival Relationship is Constant Independent of
Treatment, Performance Status, or LDH
Factor Value Slope Intercept
Overall All 1.2 8.3
TreatmentCPT-115-FU/LV
CPT-11/5-FU/LV
1.11.21.2
8.78.28.1
PS0 12
0.91.21.3
11.8 7.23.1
LDH UNL>UNL
1.01.3
11.26.1
*UNL=upper normal limit
Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
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41*TTP assessed at 6-week intervals through Week 36 and then at 12-week intervalsData from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
TTP Correlation with Survival
0
5
10
15
20
25
30
0-9n=321
9-15n=170
15-21n=135
21-27n=116
27-33n=73
33-39n=96
39-51n=99
>51n=58
TTP (wks)
Med
ian
Surv
ival
(mo)
9
5% C
I
N=1068
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TTP is Highly Correlated with Survival in Cox Regression Analysis
Factor Value Hazard Ratio 2 p-value
TTP <6 mo vs 6 mo 0.31 [0.26-0.37] 157 <0.0001
PS 0 vs 1 0.47[0.40-0.55] 109 <0.0001
LDH UNL vs >UNL 0.51[0.44-0.60] 97 <0.0001
*UNL=upper normal limit
Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000
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Results Are Corroborated by a Publication Analysis of Correlation Between TTP and Survival*
Output Input Slope Intercept r† p†
Survival(mo)
TTP(mo) 0.68 8.74 0.481 <0.0001
*Includes published summary data from 29 phase III studies in 13,500 patients receiving first-line therapy (5-FU, 5-FU/LV, CPT-11, CPT-11/5-FU/LV, oxaliplatin/5-FU/LV) for metastatic colorectal cancer , with studies reported in years 1990 through 2000
† Spearman correlation coefficients/tests
Louvet C et al. Cancer 91:2033, 2000
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Time to Tumor Progression
Provides a direct reflection of drug activity
Is not confounded by subsequent (eg, 2nd-line) therapies
Offers utility as an endpoint in non-inferiority trials
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4
4
4
7
7
7
3
3
9
9
9
9
9
9
3
0 5 10 15 20 25 30
A
A+B
AB
A+B
A+C
A+BC
Trea
tmen
ts
Time (mo)
Original Therapy (A) New Therapy (B) Alternative Therapy (C) Palliative Care
Tumor Control HR = 1.75Survival HR = 1.23
Tumor Control HR = 1.00Survival HR = 1.14
13
16
16
TTP Provides an Accurate and Direct Reflection of Drug Activity,
Unaffected by Subsequent Therapies
Tumor Control HR = 1.75Survival HR = 1.00
16
16
19
7
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Reduces sample sizes Shortens accrual time Speeds time until final analysis Decrease costs Makes first-line development
in colorectal cancer practical
Time to Tumor Progression
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Sample Size Requirements for a Study
TherapeuticPlatform
Median TTP (mo)Required Sample Size*
PlatformAlone
Platform+
Investigational
5-FU/LV No therapy 4 7 150
CPT-11/5-FU/LV No therapy 7 10 400
CPT-11/5-FU/LV Oxali/5-FU/LV 7 10 400
*Assumes 2-sided =0.05; =0.20; accrual = 100 patients/mo; follow-up = longest median + 2 months
Superiority TTP Study
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Sample Size Requirements for a Study
TherapeuticPlatform
Median TTP (mo)Required Sample Size*Existing Investigational
5-FU/LV No therapy 4 2.5 200
CPT-11/5-FU/LV No therapy 7 5.5 750
CPT-11/5-FU/LV Oxali/5-FU/LV 7 5.5 750
*Assumes retention of 50% of survival benefit relative to prior therapy,1-sided =0.025; =0.20; accrual = 100 patients/mo; follow-up = longest median + 2 months
Non-inferiority TTP Study
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Time to Accrue Sufficient Number of Patients
TherapeuticPlatform
Sample Size Time to Accrue (mo)
Superiority Non-inferiority Superiority Non-
inferiority
5-FU/LV No therapy 150 200 1.5 2.0
CPT-11/5-FU/LV No therapy 400 750 4.0 7.5
CPT-11/5-FU/LV Oxali/5-FU/LV 400 750 4.0 7.5
*Assumes accrual = 100 patients/mo
TTP Study
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Time to Acquisition of Mature Data
ExistingTherapy
Number of Events Time to Analysis (mo)
Superiority Non-inferiority Superiority Non-
inferiority
5-FU/LV No therapy 102 112 10.5 8.0
CPT-11/5-FU/LV No therapy 250 426 16.0 16.5
CPT-11/5-FU/LV Oxali/5-FU/LV 250 426 16.0 16.5
*Based on assumptions from prior slides
TTP Study
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Cost to Conduct A Study
ExistingTherapy
Sample Size Trial Cost*
Superiority Non-inferiority Superiority Non-
inferiority
5-FU/LV No therapy 150 200 $6M $8M
CPT-11/5-FU/LV No therapy 400 750 $16M $30M
CPT-11/5-FU/LV Oxali/5-FU/LV 400 750 $16M $30M
*Assumes total fully loaded internal and external costs of $40,000/patient
TTP Study
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Time to Tumor Progression
Is based on simple, standardized, radiographic tumor measurement criteria
Can be physically described and objectively quantified
Is supported by data available in the primary patient record for FDA audit
Can be subjected to central, uniform, blinded review
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RESPONSE EVALUATION CRITERIA IN SOLID TUMORS
(RECIST)
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
P Therasse, SG Arbuck, EA Eisenhauer,J Wanders, RS Kaplan, L Rubinstein,
J Verweij, M Van Glabbeke, AT van Oosterom, MC Christian, SG Gwyther
Journal of the National Cancer Institute 92: 205-216, 2000
TUMOR RESPONSE CRITERIA WORLD HEALTH ORGANIZATION
(WHO)
WHO Handbook for Reporting Results of Cancer Treatment
World Health Organization Offset Publication No. 48
Geneva, Switzerland, 1979————————————————————————————
Reporting Results of Cancer Treatment
AB Miller, B Hogestraeten, M Staquet, A Winkler
Cancer 47:207–14, 1981
Tumor Measurement Criteria Have Been Standardized
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Tumor Measurements Can be Readily Described and Quantified
LesionLongest Target Lesion Diameter (cm)
Baseline Week 6
Week 12
Week 18
Week 24
Right lung #1 3 2 2 2 3Right lung #2 2.5 2 2 2 3Left liver lobe 6 5 3 3 5
Right liver lobe 2.5 2 2 2 2Total Length 14 11 9 9 13% Change -21% -36% -36% +44%*
Disease Status SD PR PR PD*Change from nadir
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Primary Data Can be Collected, Stored and Saved for Later Audit
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Central, Independent, Blinded Radiographic Review Can Enhance Confidence in Results
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Provides a clear method of presentation and interpretation
Time to Tumor Progression
Offers straightforward analysis that incorporates all available data
Can be supported by secondary analyses
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Kaplan-Meier Plotting and Log-Rank Testing Allows Comprehensive Display
and Analysis of All Available Data
0.00.10.20.30.40.50.60.70.80.91.0
0 3 6 9 12 15
Months
Prob
abili
ty
p<0.001(log-rank test)
Time To Tumor Progression
Median Median4.4 mo 6.7 mo
CPT-11/5-FU/LV (N=198)5-FU/LV (N=187)Censored
Douillard et al. Lancet 355:1041, 2000
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59Douillard et al. Lancet 355:1041, 2000
Assessment of Time to Treatment Failure Allows Confirmatory Analysis of
Treatment Effect and Any Censoring Issues Time To Tumor Progression
0 3 6 9 12 15Months
p<0.001*
* log-rank test
4.4 mo 6.7 mo
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
Censored
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Prob
abili
ty
Time To Treatment Failure
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Prob
abili
ty0 3 6 9 12 15
Months* log-rank test
3.8 mo 5.3 mo
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
Censored
p=0.001*
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Hazard Ratio Factor Value [95% CI] p-value
LDH UNL vs >UNL 0.59 0.0001[.49-.71]
PS 0 vs 1 0.79 0.0051 [.67–.93]
Treatment CPT-11/5-FU/LV 0.62 0.0001 vs 5-FU/LV [.53–.73]
*ULN=upper limit of normal
Cox Regression Analysis PermitsConfirmatory Analysis of Treatment Effect in
the Context of Important Prognostic Variables
Saltz LB et al. Proc Amer Soc Clin Oncol 19:242a, 2000
Time To Tumor Progression
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What Caveats Must be Considered in Assessing TTP?
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Tumor assessment frequency should be the same across study arms even when cycles are of different lengths
Time to Tumor Progression Measurement Considerations
Minimum interval between tumor assessments should be less than the expected treatment effect size
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Unequal Tumor Assessment Intervals Between Study Arms Can Bias TTP Assessment
% S
igni
fican
t Fal
se P
ositi
ves
23.7
10
3.40.70.1
0
5
10
15
20
25
1/1 1/1.5 1/2 1/2.5 1/37
8
9
10
Med
ian
TTP
(mo)
Tumor Assessment Intervals (mo)
*Based on 1000 simulations of studies with exponential TTP curves where true median for both Arm A and Arm B is 7 months, N=400 patients/arm, log-rank =0.0025 (0.25%)
Treatment ATreatment B
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Experimental arm: Saltz CPT-11/5-FU/LV in 6-week cycles
0 6 12 18 24 30etc
Weeks 36
CPT-115-FULV
CPT-115-FULV
CPT-115-FULV
CPT-115-FULV
CPT-115-FULV
CPT-115-FULV
CPT-115-FULV
CT scans
Cycles
Control arm: Mayo Clinic 5-FU/LV in 4-week cycles
etcWeeks 12
5-FULV
16
5-FULV
20
5-FULV
24
5-FULV
28
5-FULV
32
5-FULV
36
5-FULV
8
5-FULV
4
5-FULV
0
5-FULV
CT scans
Cycles
Plan for Uniform Tumor Assessment Frequency Despite Discordant Cycle Lengths
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Wee
ks fr
om P
rior A
sses
smen
t
12 Wks
6 Wks
Weeks from Start of Treatment
12 Wks
6 Wks
Actual Investigator Performance in Maintaining Tumor Assessment Frequency
CPT-11/5-FU/LV
5-FU/LV
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Conservative censoring rules should
limit TTP to time on study therapy
Time to Tumor Progression Measurement Considerations
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Conservative Censoring Rules
Situation Date CensoredNo baseline or on-treatment tumor assessment Randomization Yes
Treatment discontinuation for PD Last on-study assessment No
Treatment discontinuation for other than PD or death
Last on-study assessment without PD Yes
New anticancer treatment started Last on-study assessment before start of new treatment Yes
Death before first PD assessment Death No
Death after 1 assessment but before PD
Last on-study assessment without PD Yes
Patients still on treatment Last on-study assessment without PD Yes
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Nonconservative Censoring Rule Includes 2nd-line Therapy and Potential Biases TTP
0 3 6 9 12Months
TTP declared 12 months
Therapy A
Discontinuation due to adverse event
Therapy B
CT scans No PDNo PD No PDBaseline No PD PDNo PD
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TTP censored4.5 months
0 3 6 9 12
Therapy A
CT scans No PDNo PD No PDBaseline No PD
Discontinuation due to adverse event
PD
Therapy B
Months
No PD
Conservative Censoring Rule Confines TTP Determination to 1st-line Study Period
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00.10.20.30.40.50.60.70.80.9
1
0 3 6 9 12 15 18 21 24Months
Prob
abili
ty o
f Pro
gres
sion
Dropout rate (%)
0 5 10 15 20 25 30 35 40 45 50
Median TTP 5.4 5.6 6.2 6.8 7.1 7.4 7.6 8.0 8.2 8.4 8.6
Model of Potential Bias of TTP Due to Nonconservative Censoring Rule
Simulated (100x) TTP curves created by adding 3-month follow-up intervals for various percentages (5% to 40%) of patients who discontinue therapy due to toxicity
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Summary
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TTP Satisfies Critical Requirements as A Regulatory Clinical Benefit Endpoint
Directly evaluates changes in disease burden Correlates with other outcomes (in particular, survival) Is not confounded by subsequent (eg, 2nd-line) therapies Offers utility as an endpoint in non-inferiority trials Can be objectively quantified, reviewed, and audited Offers clear interpretation and straightforward analysis Conserves patient resources and hastens development
When Evaluated Properly, TTP:
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00.10.20.30.40.50.60.70.80.9
1
0 6 12 18 24 30 36Months
Prob
abili
ty
=0.051-=0.80
2200 patients4 years$88M
19 mo 22 mo
Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)
Survival Superiority Study Offers Too Little, Too Late, For Too Much
Survival
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00.10.20.30.40.50.60.70.80.9
1
0 6 12 18 24 30 36Months
Prob
abili
ty
=0.00251-=0.90
800 patients20 months
$32M
Survival
TTP7 mo 10 mo
=0.051-=0.80
2200 patients4 years$88M
19 mo 22 mo
Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)
Single Superiority Study Can Offer Highly Robust TTP Assessment (=0.0025)
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It’s Time to Move to TTP As the Primary Regulatory Endpoint
in Metastatic Colorectal Cancer
Conclusion