Transcript Slide 1

WHAT WILL THE KEY ISSUES IN ENDPOINT 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
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?
•
and/or
•
RECIST 1.1 criteria
GCIG CA125
OVARIAN CANCER – the typical patient
1st relapse
DIAGNOSIS
0
SURGERY
12
death
24
chemo
1
36
chemo
2
48
chemo
3
60
chemo chemo
5
4
chemo
carboplatin
 paclitaxel
carboplatin
-based
carboplatin
-based
Thus: for typical patient, duration of survival
after 1st relapse exceeds initial time to
relapse
options include:
repeat paclitaxel (weekly),
doxil, topotecan, etoposide,
potentially Phase I trial
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?
• Example: ICON-6
(b) RECURRENT DISEASE (IN REMISSION)
• drug Y vs. placebo
Question: does drug Y
- delay recurrence, i.e. increase progressionfree survival as maintenance therapy?
• Example: BIBF 1120 study
RANDOMIZED TRIAL FOR PLATINUMSENSITIVE RELAPSED OVARIAN CANCER
ICON-6: Can VEGFR inhibitor CEDIRANIB improve
survival?
Platinum sensitive
relapse, >6 m
interval, one prior
treatment
n = 2000 pts
Primary outcome:
OS (hazard ratio 0.75)
R
A
N
D
O
M
I
Z
E
(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
(paclitaxel)-carboplatin x 6
and concurrent Cediranib 20 mg daily,
then “maintenance” Cediranib for 18 m,
or until PD
A MAINTENANCE ANTI-ANGIOGENIC
APPROACH TO OVARIAN CANCER
Randomized Phase II trial of Vargatef, BIBF 1120 (VEGFR, PDGFR, FGFR
inhibitor
Relapsed
ovarian cancer,
responded to
2nd/3rd/4th line
chemo, which
had been
started <12 m
from previous
chemo
R
A
N
D
O
M
I
Z
E
BIBF 1120
n = 43
250 mg bd
for up to 36 w
placebo
n = 40
Completed
36 w
PFS at
36 w
5
15.6%
(3.6-27.3)
0
2.0%
(0-8.4)
HR for
PFS diff is
0.68
(95% 0.421.09)
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 platinumsensitive relapse (ICON-6)
• experience in patients, relapsing on single agent
treatment, continues to accumulate, particularly in
respect of rate of change (rising ) CA125
Single agent AZD 2171 CA 125 vs. CT Volume %
09/09/08
31/03/09
120
OFF Treatment
ON Treatment VEGF
(%) CA125 and tumour volume
100
80
60
Marker PD
40
CA125
20
0
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
Single agent AZD 2171 - CA 125 vs. CT Volume %
02/12/08
01/04/09
ON Treatment VEGF
OFF Treatment
120
(%) CA125 and tumour volume
100
Marker PD
80
CA125
60
40
20
0
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
CONCLUSIONS
• progression-free survival will become
increasingly important endpoint as treatment
options in recurrent disease increase
but ….. in the modern era of novel targeted
therapies in ovarian cancer
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