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. KayeRoyal Marsden HospitalLondon

GCIGOrlando

2009

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 criteriaand/or • GCIG CA125

OVARIAN CANCER – the typical patient

chemo3

0 12 24 36 48 60

chemo4

chemo5

chemo2

chemo1

chemo

SURGERY

DIAGNOSIS

carboplatin

paclitaxel

carboplatin-based

carboplatin-based options include:

1st relapse death

repeat paclitaxel (weekly),doxil, topotecan, etoposide,

potentially Phase I trialThus: for typical patient, duration of survival

after 1st relapse exceeds initial time to relapse

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

RANDOMIZED TRIAL FOR PLATINUM-SENSITIVE RELAPSED OVARIAN CANCER

Platinum sensitive relapse, >6 m interval, one prior treatment

(paclitaxel)-carboplatin x 6and concurrent placebo

(paclitaxel)-carboplatin x 6and concurrent Cediranib 20 mg daily, then “maintenance” placebo for 18 m, or until PD

RANDOMIZE

(paclitaxel)-carboplatin x 6and concurrent Cediranib 20 mg daily, then “maintenance” Cediranib for 18 m, or until PDn = 2000 pts

Primary outcome:OS (hazard ratio 0.75)

ICON-6: Can VEGFR inhibitor CEDIRANIB improve survival?

RANDOMIZE

Completed

36 w

PFS at

36 w

5 15.6%

(3.6-27.3)

HR for

PFS diff is

0.68

(95% 0.42-1.09)

0 2.0%

(0-8.4)

A MAINTENANCE ANTI-ANGIOGENIC APPROACH TO OVARIAN CANCER

Relapsed ovarian cancer, responded to 2nd/3rd/4th line chemo, which had been started <12 m from previous chemo

BIBF 1120250 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

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

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?

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

0

20

40

60

80

100

120

12/ 06/ 2008 03/ 07/ 2008 24/ 07/ 2008 07/ 08/ 2008 27/ 08/ 2008 17/ 09/ 2008 03/ 10/ 2008 14/ 10/ 2008 09/ 12/ 2008 22/ 01/ 2009 25/ 02/ 2009 24/ 03/ 2009 07/ 05/ 2009

ON Treatment VEGF

31/03/09

09/09/08

Single agent AZD 2171 CA 125 vs. CT Volume %

OFF Treatment

CA125

Marker PD

(%)

CA

12

5 a

nd t

um

ou

r vo

lum

e

0

20

40

60

80

100

120

26/ 06/ 2008 04/ 08/ 2008 15/ 09/ 2008 20/ 10/ 2008 10/ 12/ 2008 19/ 12/ 2008 23/ 12/ 2008 30/ 12/ 2008 06/ 01/ 2009 09/ 02/ 2009 09/ 03/ 2009 09/ 04/ 2009 05/ 05/ 2009

Single agent AZD 2171 - CA 125 vs. CT Volume %

02/12/08 01/04/09

ON Treatment VEGFOFF Treatment

CA125

Marker PD

(%)

CA

125

and

tum

our

volu

me

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