Other endpoints in screening Other endpoints in screening studies for Soft Tissue Sarcomasstudies for Soft Tissue Sarcomas

Jaap Verweij MD.PhDJaap Verweij MD.PhD

Dept of Medical OncologyDept of Medical Oncology

Erasmus University Medical CenterErasmus University Medical Center

RotterdamRotterdam

The NetherlandsThe Netherlands

TimeTime

DiseaseDisease

Surrogate

Endpoint

Surrogate

Endpoint

True Clinical

Outcome

True Clinical

Outcome

Time

Time

DiseaseDisease

Surrogate

Endpoint

Surrogate

Endpoint

True Clinical

Outcome

True Clinical

Outcome

Intervention

Question:Question:

If you know of all these ……… (Your Markers!)If you know of all these ……… (Your Markers!)

Would you be able to cure Would you be able to cure metastatic soft tissue sarcoma metastatic soft tissue sarcoma

(your ultimate aim)?(your ultimate aim)?

This is just a random selection of photographs. I apologize to This is just a random selection of photographs. I apologize to anyone who is not listedanyone who is not listed

DiseaseDisease

Surrogate

Endpoint

Surrogate

Endpoint

True Clinical

Outcome

True Clinical

Outcome

Intervention

We Should Desist Using RECISTat Least in GIST

Robert S. Benjamin, M.D.Department of Sarcoma Medical Oncology

The SARCOMA Center

+++++++

++ + +++ + + + + + ++ +++ ++++++++++++++ +++++++ + +++++++ ++

++

++++

+

+++ +

+ + +++ +

Months

Time to Progression - Nonresponders

302724211815129630

1

.9

.8

.7

.6

.5

.4

.3

.2

.1

0 Our Criteria n=17 RECIST n=54

p = 0.02

+ + ++++ +

++++++ +++ +

++++++ +++

++++ +++++++++++ +++

+ + ++++ +++++ ++ + ++++++++++++++ + +++++++++++++++++++++ ++

+++++++++++++++++++++++++ ++++

Months

Time to Progression - Responders

302724211815129630

1

.9

.8

.7

.6

.5

.4

.3

.2

.1

0

Our Criteria n=81 RECIST n=44

It is easier It is easier to splice to splice an atom an atom than a than a

prejudiceprejudice

A.EinsteinA.Einstein

How can we find How can we find the proof of the proof of concept:concept:

earlyearly

when tumors do when tumors do not shrink with not shrink with treatmenttreatment

??

Screening for new drugs in STS

Are we looking Are we looking at the right at the right spot?spot?

Which endpoint to use in Which endpoint to use in screening for new agents?screening for new agents?

Response rateResponse rate

Progression Free RateProgression Free Rate

Progression Arrest RateProgression Arrest Rate

TTP ratioTTP ratio

Response RateResponse Rate Advantage: Advantage:

Response relatively easily measurableResponse relatively easily measurable

Disadvantage: Disadvantage: Does not take duration into account (DTIC 17%, Does not take duration into account (DTIC 17%,

duration 10 weeks)duration 10 weeks) Several cytotoxics discarded for response rate, Several cytotoxics discarded for response rate,

but high SD ratebut high SD rate May not be appropriate for new cytostatic agentsMay not be appropriate for new cytostatic agents

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9

time (months)

tum

ors

ize

SD

PR

Hypothetical tumor Hypothetical tumor evolution during treatmentevolution during treatment

Is stable disease a Is stable disease a relevant achievement?relevant achievement?

i.e: CR+PR+i.e: CR+PR+SDSD

vs vs

PDPD

(months)0 3 6 9 12 15

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :

221 234 47 16 5 1

136 146 55 18 14 11

Inactive agents

Active agents

Progression free rateProgression free rate(2(2ndnd line treatment) line treatment)

Van Glabbeke et al, EJC 38:543-549,2002Van Glabbeke et al, EJC 38:543-549,2002

Progression free rates (2Progression free rates (2ndnd line) line)

2 %2 %10 %10 %3 %3 %28 %28 %380380All patientsAll patients

33 %%1414 %%44 % %3939 %%146146ActiveActive

2 %2 %8 %8 %3 %3 %21 %21 %234234InactiveInactive

SESEEstim.Estim.SESEEstim.Estim.

6 months6 months3 months3 monthsNNType of drugType of drug

Van Glabbeke et al, EJC 38:543-549,2002Van Glabbeke et al, EJC 38:543-549,2002

0

5

10

15

20

25

30

0 1 2 3 4 5

time (AU)

tum

ors

ize

Hypothetical tumor Hypothetical tumor evolution during evolution during

treatmenttreatmentTTP1TTP1

TTP2TTP2

If TTP2/TTP1 If TTP2/TTP1 >> 1.33: potentially active 1.33: potentially active agent*agent*

* Mick et al, Contr.Clin.Trials 21:343-359. 2000* Mick et al, Contr.Clin.Trials 21:343-359. 2000

ET-743 as 3rd line ET-743 as 3rd line treatment inj soft tissue treatment inj soft tissue

sarcomasarcoma

Total populationTotal population Patients without tumor Patients without tumor regression but long regression but long

lasting stable diseaselasting stable disease

ASCO 2003, # ASCO 2003, # 32933293

It could take long to assessIt could take long to assess

And in screening studies we would like And in screening studies we would like to know earlyto know early

The problem of durationThe problem of duration

Using progression rateUsing progression rate

Set maximum PD rate Set maximum PD rate above which agent above which agent will be rejectedwill be rejected

PD rate of interest will depend on tumor PD rate of interest will depend on tumor typetype

TumorTumor RRRR PD ratePD ratebreastbreast >30%>30% <20%<20%

NSCLCNSCLC >20%>20% <30%<30%

GliomaGlioma >10%>10% <40% <40%

STSSTS >10%>10% <50% (??)<50% (??)

0

10

20

30

40

50

60

70

80

90

100

Progressionarrest (%)

%%

Progression Arrest* RatesProgression Arrest* Rates

* Van Oosterom, In: Clinical Management of soft tissue * Van Oosterom, In: Clinical Management of soft tissue sarcomas. Martinus Nijhoff Publishers, 131-138, 1986sarcomas. Martinus Nijhoff Publishers, 131-138, 1986

0102030405060708090

100

DX

TR

OF

OS

ET

-74

3

IFO

S

ES

O

TP

T

TX

T

GE

M

DT

IC

IMA

TIN

IB

IFN

-G

Mean%%

Progression Arrest RatesProgression Arrest Rates

Response versus Symptom benefit rate*Response versus Symptom benefit rate*

0

20

40

60

Symptom benefit rate (%)0

20

40

60

250 mg 500 mg 250 mg 500 mg

Response Rate (%)

0

20

40

60

80

Response rate Symptom improvement rate

Response rate Symptom improvement rate

Gefitinib in NSCLCGefitinib in NSCLC

Imatinib in GISTImatinib in GIST

ConclusionsConclusions

Aim of screening studiesAim of screening studies

To estimate a.s.a.p.if a drug may be To estimate a.s.a.p.if a drug may be useful for patientsuseful for patients

Endpoint for screening studiesEndpoint for screening studies

Progression free ratesProgression free rates

Progression arrest ratesProgression arrest rates

TTP ratioTTP ratio

Symptom improvement?Symptom improvement?

All of these require proper validationAll of these require proper validation