1. WHAT WILL THE KEY ISSUES IN END- POINT ASSESSMENT BE, IN FUTURE OVARIAN CANCER TRIALS INVOLVING NOVEL TARGETED AGENTS? first line treatment maintenance/consolidation treatment of recurrent disease Prof. S.B. Kaye Royal Marsden Hospital London GCIG Orlando 2009

2. FUTURE END-POINT ASSESSMENT IN OVARIAN CANCER TRIALS in randomised trials with novel targeted agents (first line/recurrent disease/maintenance) SHOULD PROGRESSION-FREE SURVIVAL BE THE PRIMARY END-POINT IN ALL CASES? If so, how will assessment of progression differ with addition of novel targeted therapy? RECIST 1.1 criteria and/or GCIG CA125

3. OVARIAN CANCER – the typical patient chemo 3 01224364860 chemo 4 chemo 5 chemo 2 chemo 1 c hemo SURGERY DIAGNOSIS carboplatin  paclitaxel carboplatin -based carboplatin -based options include: 1 st relapsedeath repeat paclitaxel (weekly), doxil, topotecan, etoposide, potentially Phase I trial Thus: for typical patient, duration of survival after 1 st relapse exceeds initial time to relapse

4. FUTURE RANDOMISED TRIALS IN OVARIAN CANCER WITH NOVEL TARGETED AGENTS: 2 EXAMPLES (a) FIRST-LINE or PLATINUM-SENSITIVE RELAPSED DISEASE: carboplatin-based chemo ± drug X Question: does drug X - increase response rate - increase progression free survival? (b) RECURRENT DISEASE (IN REMISSION) drug Y vs. placebo Question: does drug Y - delay recurrence, i.e. increase progression- free survival as maintenance therapy? Example: ICON-6 Example: BIBF 1120 study

5. RANDOMIZED TRIAL FOR PLATINUM- SENSITIVE RELAPSED OVARIAN CANCER Platinum sensitive relapse, >6 m interval, one prior treatment (paclitaxel)-carboplatin x 6 and concurrent placebo (paclitaxel)-carboplatin x 6 and concurrent Cediranib 20 mg daily, then “maintenance” placebo for 18 m, or until PD RANDOMIZERANDOMIZE (paclitaxel)-carboplatin x 6 and concurrent Cediranib 20 mg daily, then “maintenance” Cediranib for 18 m, or until PD n = 2000 pts Primary outcome: OS (hazard ratio 0.75) ICON-6: Can VEGFR inhibitor CEDIRANIB improve survival?

6. RANDOMIZERANDOMIZE Completed 36 w PFS at 36 w 515.6% (3.6-27.3) HR for PFS diff is 0.68 (95% 0.42- 1.09) 02.0% (0-8.4) A MAINTENANCE ANTI-ANGIOGENIC APPROACH TO OVARIAN CANCER Relapsed ovarian cancer, responded to 2 nd /3 rd /4 th line chemo, which had been started <12 m from previous chemo BIBF 1120 250 mg bd for up to 36 w placebo Randomized Phase II trial of Vargatef, BIBF 1120 (VEGFR, PDGFR, FGFR inhibitor n = 43 n = 40 G 3/4 adverse events: 61% vs 28% with frequent elevated transaminases on BIBF 1120 (43%) but only 2 pts discontinued Conclusion:BIBF 1120 could delay disease progression in previously responding ovarian cancer patients ASCO 2009

7. HOW WILL ADDITION OF NOVEL TARGETED AGENTS IMPACT ON FUTURE OVARIAN CANCER TRIALS ASSESSMENTS? for response assessment (RECIST 1.1*, GCIG CA125 criteria) -addition of novel targeted agent should not change these criteria BUT for progression-free survival (RECIST 1.1*, GCIG CA125 criteria) -evaluation may well change as a result of addition of novel targeted agent Why? *Eisenhauer et al, 2009

8. ASSESSMENT OF DISEASE PROGRESSION IN PATIENTS RECEIVING NOVEL TARGETED AGENTS novel agents targeting VEGFR/PDGFR/SRC, etc -impact on angiogenesis may profoundly affect growth rate of recurrent disease even when resistance is developing - are there examples?

9. ASSESSMENT OF DISEASE PROGRESSION ON NOVEL TARGETED AGENTS AZD 2171 (Recentin, Cediranib) potent VEGFR/PDGFR inhibitor single agent efficacy in ovarian cancer demonstrated in 2 Phase II trials now incorporated in randomized trial in platinum- sensitive relapse (ICON-6) experience in patients, relapsing on single agent treatment, continues to accumulate, particularly in respect of rate of change (rising ) CA125

10. ON Treatment VEGF 31/03/0909/09/08 Single agent AZD 2171 CA 125 vs. CT Volume % OFF Treatment CA125 Marker PD (%) CA125 and tumour volume

11. Single agent AZD 2171 - CA 125 vs. CT Volume % 02/12/0801/04/09 ON Treatment VEGF OFF Treatment CA125 Marker PD (%) CA125 and tumour volume

12. CONCLUSIONS but ….. in the modern era of novel targeted therapies in ovarian cancer progression-free survival will become increasingly important endpoint as treatment options in recurrent disease increase do not assume that the same rules apply in assessment of disease progression, and more emphasis may need to be placed on RECIST, rather than CA125 changes