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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