Assessing Response and Progression in Ovarian Cancer Clinical trials RECIST 1.1 and CA125 Criteria

1. Assessing Response and Progression in Ovarian Cancer Clinical trialsRECIST 1.1 and CA125 Criteria E.A. Eisenhauer GCIG Ovarian cancer clinical trials planning meeting May 29, 2009

2. Outline • Response /progression Criteria: • RECIST 1.0/1.1 • CA125 criteria • Major uses in ovarian cancer trials • Issues / questions

3. RECIST • Response evaluation criteria in solid tumours • Anatomically based • Major uses in solid tumour trials: • Phase II – objective response, stable disease rates • Phase III – PFS • Several issues with initial RECIST, for e.g. • Assessment of PD in non-measurable disease • Lymph node assessment • Number of lesions • RECIST 1.1 (EJC, Jan 2009) addresses all and more. Changes based on evidence from trial data and simulation work.

4. What HAS changed in RECIST 1.1

5. GCIG CA125 criteria • Developed by GCIG to complement RECIST criteria • Response criteria1 • For use in phase II studies in relapsed disease • Evaluable pts must have baseline CA125 > 2 x ULN • CA125 response: 50% decrease confirmed > 28 days • Date response = date of first 50% fall • Progression Criteria2 • For use in front-line setting to complement objective PD • CA125 PD: Double of UNL (or nadir if > UNL) confirmed > 7 days • Date CA125 PD = date of first doubling • Date overall PD = earliest date of CA125 or objective PD • Exception: recent surgery or intraperitoneal procedure • Rustin GJ, et al: J Natl Cancer Inst. 2004 96:487-8 • Vergote I, et al. J Natl Cancer Inst. 2000, 92:1534-5

6. Primary Endpoints: Front-line studies • Baden Baden meeting 2004: “Advanced OVCA first-line – Both PFS and OS are important endpoints to understand the full impact of any new treatment. Thus either may be designated as the primary endpoint. Regardless of which is selected, the study should be powered so both PFS and OS can be appropriately evaluated” • Good evidence that PFS is surrogate for OS, and acceptable endpoint for front-line studies

7. HR of PFS vs OS: Front-Line Trials CAP vs CA (GOG 47) T vs P (GOG132b)

8. Issues with combined use of CA125 and Objective PD in front-line studies • Data collection more complex • Timing of CA125 measurement very important to avoid bias • If PD by one method, do we still need to collect PD by other? • How many PD events are found solely by CA125? • Do we count CA125 PD if patients still on front-line therapy? (some Groups do, some do not)

9. OV.16 Progression Events

10. OV.16: PFS (GCIG definition: Objective and CA125 -- whichever is first) Arm 1 median 14.6 mo Arm 2 median 16.2 mo Hazard ratio: 1.10 p = 0.25 Adjusted p = 0.23

11. OV.16 PFS: Objective PD only Arm 1 median 17.5 mo Arm 2 median 17.9 mo Hazard ratio: 1.03 p = 0.69

12. CA125 PD definition • Does including CA125 as part of PD definition add value or just complexity? • Majority of pts with elevated CA125 have imaging and are found to have objective PD i.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplified Need data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint

13. Primary Endpoints: Recurrent Disease Studies Baden Baden meeting 2004: • Phase II “screening” trials: • Response using RECIST criteria or GCIG CA125 response definition -- to be specified in protocol • Phase III second-line • Symptom control/Quality of life (for early relapse) and overall survival (for late relapse) are preferred primary endpoints, although PFS should still be used in assessing new treatments.

14. Issues recurrent disease studies (1) • Phase II screening trials: • CA125 RR is usually higher than objective RR: does this mean anything? • Are drugs with CA125 responses but no objective responses “active”? Have any been identified and tested in phase III? • Is CA125 RR value added in drug development? (there is no doubt CA125 is useful in clinical management but that is another question) • Are other functional/molecular imaging endpoints of value? • Is non-progression rate (CR + PR + SD) more meaningful than response rate? • Need DATA to answer all these questions!

15. Issues recurrent disease studies (2) • Phase III trials: • Although Baden Baden endpoint recommendations are symptom benefit or OS, PFS is often used in these trials as primary endpoint. • Does PFS prolongation of 1-2 mo have any “meaning” for patients in situation of recurrent disease if NOT accompanied by either OS or symptom improvement? • Is PFS a surrogate for OS in recurrent disease?

16. HR of PFS vs OS: Second line combination trials

17. Issues recurrent disease studies (2) • Phase III trials: • Although Baden Baden endpoint recommendations are symptom benefit or OS, PFS is often used in these trials as primary endpoint. • Does PFS prolongation of 1-2 mo have any “meaning” for patients in situation of recurrent disease if NOT accompanied by either OS or symptom improvement? • Is PFS a surrogate for OS in recurrent disease? • Is PFS a surrogate for symptom improvement? • If so: isn’t it easier and more meaningful to measure symptom benefit? • If so, shouldn’t trials with PFS improvement show symptom benefit? Do they?? • Need DATA to answer all these questions!

18. Extra slides

19. Relationship between PFS and OS:Recent front-line RCTs in OVCA

20. HR of PFS vs OS in second line trials