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

2. Time Disease Surrogate Endpoint Surrogate Endpoint True Clinical Outcome True Clinical Outcome Time

3. Disease Surrogate Endpoint Surrogate Endpoint True Clinical Outcome True Clinical Outcome Intervention

4. 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

5. Disease Surrogate Endpoint Surrogate Endpoint True Clinical Outcome True Clinical Outcome Intervention

6. 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

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

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

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

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

11. 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

12. Hypothetical tumor evolution during treatment

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

14. (months) 03691215 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 221234471651 13614655181411 Inactive agents Active agents Progression free rate (2 nd line treatment) Van Glabbeke et al, EJC 38:543-549,2002

15. 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 38:543-549,2002

16. Hypothetical tumor evolution during treatment TTP1 TTP2 If TTP2/TTP1 > 1.33: potentially active agent* * Mick et al, Contr.Clin.Trials 21:343-359. 2000

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

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

19. 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% (??)

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

21. % Progression Arrest Rates

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

23. 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