Other endpoints in screening studies for Soft Tissue Sarcomas Jaap Verweij MD.PhD Dept of Medical Oncology Erasmus University Medical Center Rotterdam The Netherlands

Time Disease Surrogate Endpoint Surrogate Endpoint True Clinical Outcome True Clinical Outcome Time

Disease Surrogate Endpoint Surrogate Endpoint True Clinical Outcome True Clinical Outcome Intervention

Question: If you know of all these ……… (Your Markers!) Would you be able to cure metastatic soft tissue sarcoma (your ultimate aim)? This is just a random selection of photographs. I apologize to anyone who is not listed

Disease Surrogate Endpoint Surrogate Endpoint True Clinical Outcome True Clinical Outcome Intervention

We Should Desist Using RECIST at Least in GIST Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center p = 0.02

It is easier to splice an atom than a prejudice A.Einstein

How can we find the proof of concept: early early when tumors do not shrink with treatment when tumors do not shrink with treatment?

Screening for new drugs in STS Are we looking at the right spot? Are we looking at the right spot?

Which endpoint to use in screening for new agents? l Response rate l Progression Free Rate l Progression Arrest Rate l TTP ratio

Response Rate l Advantage: l Response relatively easily measurable l Disadvantage: l Does not take duration into account (DTIC 17%, duration 10 weeks) l Several cytotoxics discarded for response rate, but high SD rate l May not be appropriate for new cytostatic agents

Hypothetical tumor evolution during treatment

Is stable disease a relevant achievement? i.e: CR+PR+SD vs PD

(months) ONNumber of patients at risk : Inactive agents Active agents Progression free rate (2 nd line treatment) Van Glabbeke et al, EJC 38: ,2002

Progression free rates (2 nd line) 2 % 10 % 3 % 28 % 380 All patients 3 %3 %3 %3 % 14 % 4 %4 %4 %4 % 39 % 146Active 2 % 8 % 3 % 21 % 234Inactive SEEstim.SEEstim. 6 months 3 months N Type of drug Van Glabbeke et al, EJC 38: ,2002

Hypothetical tumor evolution during treatment TTP1 TTP2 If TTP2/TTP1 > 1.33: potentially active agent* * Mick et al, Contr.Clin.Trials 21:

ET-743 as 3rd line treatment inj soft tissue sarcoma Total population Patients without tumor regression but long lasting stable disease ASCO 2003, # 3293

* It could take long to assess * And in screening studies we would like to know early The problem of duration

Using progression rate Set maximum PD rate above which agent will be rejected PD rate of interest will depend on tumor type TumorRRPD rate breast>30% 30%<20% NSCLC>20% 20%<30% Glioma>10% 10%<40% STS>10% 10%<50% (??)

% Progression Arrest* Rates * Van Oosterom, In: Clinical Management of soft tissue sarcomas. Martinus Nijhoff Publishers, , 1986

% Progression Arrest Rates

Response versus Symptom benefit rate* Gefitinib in NSCLC Imatinib in GIST

Conclusions Aim of screening studies l To estimate a.s.a.p.if a drug may be useful for patients Endpoint for screening studies l Progression free rates l Progression arrest rates l TTP ratio l Symptom improvement? All of these require proper validation