Post on 23-Feb-2016
description
Activity endpoints in soft tissue sarcoma phase II trials
Quality and correlations with overall survival
Nicolas PENEL Andrew KRAMAR
Centre Oscar Lambret, Lille, France
Primary endpoints
Critical choiceFew promising drugsPromising 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 - GeneralCriteria 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
Q 1: What is the quality of reported primary endpoints ?
Nature of primary endpointPrimary endpoint StudiesAbsence 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 StudiesDesign 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 StudiesPromising 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%)
Q 2: What are the correlation between activity endpoints and overall survival ?
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Med
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rall
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0 .1 .2 .3 .4 .5 .6Best Objective Response Rate
Trial Point L-Fit
Poor correlation between mOS and BORR: p=0.058
Good correlation between 6-month PFR and OS (p=0.005)
Endpoints strata R pBest objective response 48 0.276 0.058Best tumour control rate 48 0.276 0.2573-month progression-free rate
39 0.466 0.002
6-month progression-free rate
41 0.430 0.005
Median progression-free survival
45 0.402 0.006
Q 3: Distributions of endpoints in cases of active or inactive drugs?
Categories Inactive drug Active drug p EORTC STBSG Definition
3-month PFR <39% Or 6-month PFR <14%
3-month PFR ≥39% & 6-month PFR ≥14%
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Strata 33 26 3-month PFR (%) Median (range)
26.0 (0.0-42.0) 48.0 (40.0-75.0) (0.0001)
6-month PFR (%) Median (range)
9.0 (0.0-39.0) 30.0 (15.0-55.0) (0.0001)
BORR (%) Median (range)
0.0 (0.0-19.0) 10.0 (0.0-53.0) 0.0001
BTCR (%) Median (range)
29.0 (6.0-50.0 43.0 (14.0-77.0) 0.00001
Median PFS (months) Median (range)
1.9 (0.2-3.03) 3.35 (1.8-12.0) 0.0001
Median OS (months) Median (range)
10.3 (4.9-22.8) 11.8 (4.9-22.4) 0.463
Q1: Key-findingsNumerous (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 rate6-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
ConclusionBetter definition the primary endpointRole of the central radiological reviewStatistical 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 OSWe have to refine the thresholds of PFR3 and PFR6
defining active drugs
Thank your for your attention