U.S. Food and Drug Administration

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 It was current when produced, but is no longer maintained and may be outdated.

2

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

3

Acknowledgements

Pfizer Corporation

Sumant Ramachandra, MDGroup Leader

US Medical Oncology

Gabriela Gruia, MD Full-Development Team Leader

Camptosar®

4

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

5

Why the Need Now?

6

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

7

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

8

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

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


16

19

Trea

tmen

ts

4

4 3

9

9

A

A+B


13

167

Is B inefficacious?

Is A+B more efficacious than A+C?

10

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


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


13

16

9 mo

9 mo

11

Prolonged Survival

Increases sample sizes Prolongs accrual time Delays time until final analysis Increases costs

12

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

13

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

14

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

15

Time to Acquisition of Mature Data is Prolonged

ExistingTherapy

Number of Events* Time to Analysis (mo)


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

16

Cost to Conduct A Study Increases

ExistingTherapy

Sample Size Trial Cost*


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

17

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

18

Why Not Evaluate Symptom Control Instead?

19

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

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

21


Instruments may be insensitive to important changes in tumor size

22

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

23


Symptom progression analyses are often not useful because symptom progression usually occurs after tumor progression (when patient is off study)

24

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

25

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


*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

26


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

27

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

28

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

29

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])

30

Why Consider TTP as an Endpoint?

31


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

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

33

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

34

It’s Only Logical That Halting Tumor Progression is Clinically Beneficial

Cancer Burden over Time

Healthy Adenoma

.

. . . .. .

. . .

PrimaryDiagnosis

MetastaticCarcinoma

35

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

36


Correlates with survival in metastatic colorectal cancer

37

Equation: y = ax + b

Changes in Median Endpoint Values Suggest that TTP Appears to Correlate with Survival


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

38

Equation: Survival = 1TTP + 9 mo

Changes in Median Endpoint Values Suggest Hypothetical Equation Correlating TTP with Survival


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

39

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


40

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


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

42

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


43

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

44


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

45

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



13

16

16

TTP Provides an Accurate and Direct Reflection of Drug Activity,

Unaffected by Subsequent Therapies


16

16

19

7

46

Reduces sample sizes Shortens accrual time Speeds time until final analysis Decrease costs Makes first-line development

in colorectal cancer practical


47

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

48

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

49

Time to Accrue Sufficient Number of Patients

TherapeuticPlatform

Sample Size Time to Accrue (mo)


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

50

Time to Acquisition of Mature Data

ExistingTherapy

Number of Events Time to Analysis (mo)


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

51

Cost to Conduct A Study

ExistingTherapy

Sample Size Trial Cost*


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

52


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

53

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

54

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

55

Primary Data Can be Collected, Stored and Saved for Later Audit

56

Central, Independent, Blinded Radiographic Review Can Enhance Confidence in Results

57

Provides a clear method of presentation and interpretation


Offers straightforward analysis that incorporates all available data

Can be supported by secondary analyses

58

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

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*

60

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

61

What Caveats Must be Considered in Assessing TTP?

62

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

63

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

64

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

65

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

66

Conservative censoring rules should

limit TTP to time on study therapy

Time to Tumor Progression Measurement Considerations

67

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

68

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

69

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

70

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

71

Summary

72

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:

73

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

74

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)

75

It’s Time to Move to TTP As the Primary Regulatory Endpoint

in Metastatic Colorectal Cancer

Conclusion

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