Other endpoints in screening Other endpoints in screening studies for Soft Tissue Sarcomasstudies for Soft Tissue Sarcomas
Jaap Verweij MD.PhDJaap Verweij MD.PhDDept of Medical OncologyDept of Medical Oncology
Erasmus University Medical CenterErasmus University Medical CenterRotterdamRotterdam
The NetherlandsThe Netherlands
TimeTime
Disease
SurrogateEndpoint True
ClinicalOutcome
TimeTime
Disease
Surrogate
Endpoint
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
Disease
Surrogate
Endpoint
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
01020304050607080
1 2 3 4 5 6 7 8 9
time (months)
tum
orsi
ze
SDPR
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
orsi
zeHypothetical tumor Hypothetical tumor
evolution during evolution during treatmenttreatment
TTP1TTP1TTP2TTP2
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 diseaseASCO 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 rateSet maximum PD rate Set maximum PD rate above which agent will above which agent will
be rejectedbe rejectedPD rate of interest will depend on tumor typePD rate of interest will depend on tumor type
TumorTumor RRRR PD ratePD ratebreastbreast >30%>30% <20%<20%NSCLCNSCLC >20%>20% <30%<30%GliomaGlioma >10%>10% <40% <40% STSSTS >10%>10% <50% (??)<50% (??)
0102030405060708090
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
TRO
FOS
ET-7
43
IFO
S
ESO
TPT
TXT
GEM
DTI
C
IMAT
INIB
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
ConclusionsConclusionsAim 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