Transcript Activity endpoints in soft tissue sarcoma phase II trials Quality and

Nicolas PENEL
Andrew KRAMAR
Centre Oscar Lambret, Lille, France
Primary endpoints
 Critical choice
 Few promising drugs
 Promising drugs failed to improve overall survival
 Q1: What is the quality of reported primary endpoints ?
 Q2: What are the correlation between activity endpoints and
overall survival ?
 Q3: What are the distribution of activity endpoints in positive and
negative trials ?
Method - General
 Criteria of selection of trials:
 Phase II trials
 Chemotherapy (single agents or combination) or moleculary
targeted agents
 After failure/intolerance to doxorubicin
 Full reports issued between January 1999 and August 2011
 English-written reports
 Systematic analysis of
 53 trials
 77 strata
Nature of primary endpoint
Primary endpoint
Studies
Absence of defined primary endpoint
12/53 (22%)
Defined
primary
endpoint
Best objective response
21/53 (39%)
Progression-free rate at 6 months
7/53 (13%)
Progression-free rate at 3 months
4/53 (6%)
Progression-free rate at 4 months
2/53 (4%)
Time to progression
2/53 (2%)
Progression-free survival
1/53 (2%)
Rate of “remission”
1/53 (2%)
Precise definition of primary
endpoint
Primary endpoint
Studies
Absence of defined primary endpoint
12/53 (22%)
Defined
primary
endpoint
Not precisely defined
5/53 (10%)
Precisely defined
36/53 (68%)
Design/Methodology
Key-issues
Categories
Studies
Design
Stratification
6/53 (11%)
Randomization
3/53 (5%)
Central radiological
review
Yes
2/53 (3%)
No
51/53 (97%)
Stastical hypothesis
Yes
41/53 (77%)
No
12/53 (33%)
interpretation of the results
Results
Studies
Promising drug
7/77 (10%)
Inactive drug
38/77 (50%)
Ininterpretable results because of
absence of statistical hypothesis
12/77 (15%)
Ininterpretable results because of
absence of reported data
20/77 (25%)
24
22
20
18
16
14
12
10
8
6
4
2
0
0
.1
.2
.3
.4
Best Objective Response Rate
Trial Point
.5
L-Fit
Poor correlation between mOS and BORR: p=0.058
.6
Good correlation between 6-month PFR and OS (p=0.005)
Endpoints
strata
R
p
Best objective response
Best tumour control rate
3-month progression-free rate
6-month progression-free rate
48
48
39
41
0.276
0.276
0.466
0.430
0.058
0.257
0.002
0.005
Median progression-free
survival
45
0.402
0.006
Categories
Inactive drug
Active drug
EORTC STBSG
Definition
3-month PFR <39%
Or 6-month PFR
<14%
33
3-month PFR ≥39%
& 6-month PFR ≥14%
26.0 (0.0-42.0)
48.0 (40.0-75.0)
(0.0001)
9.0 (0.0-39.0)
30.0 (15.0-55.0)
(0.0001)
0.0 (0.0-19.0)
10.0 (0.0-53.0)
0.0001
29.0 (6.0-50.0
43.0 (14.0-77.0)
0.00001
1.9 (0.2-3.03)
3.35 (1.8-12.0)
0.0001
11.8 (4.9-22.4)
0.463
Strata
3-month PFR (%)
Median (range)
6-month PFR (%)
Median (range)
BORR (%)
Median (range)
BTCR (%)
Median (range)
Median PFS (months)
Median (range)
Median OS (months) 10.3 (4.9-22.8)
Median (range)
p
26
Q1: Key-findings
Numerous (7 ≠) and not suitable primary endpoints (BORR)
Poorly defined endpoint (32% of the studies)
Absence of central radiological review (98% of the studies)
Absence of statistical hypothesis (33%)
Ininterpretable results (40%)
Q2: Endpoints possibly correlated with
OS
3-month progression free rate
6-month progression free rate
Median progression-free survival
Q3: Current definition of active drugs
Using current definitions of active/inactive drugs:
All primary endpoints are statistically higher with « active
drugs »
But
OS was not statistically different in active compared to
inactive drugs
Conclusion
 Better definition the primary endpoint
 Role of the central radiological review
 Statistical hypothesis based on primary endpoint
 Endpoints correlated with OS (PFR3 , PFR6 and PFS)
 But
 Current definitions of active drug failed to identify drugs able to
improve the OS
 We have to refine the thresholds of PFR3 and PFR6 defining
active drugs
Thank your for your attention