Nicolas PENEL Andrew KRAMAR Centre Oscar Lambret , Lille, France
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Transcript of Nicolas PENEL Andrew KRAMAR Centre Oscar Lambret , Lille, France
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Activity endpoints in soft tissue sarcoma phase II trials
Quality and correlations with overall survival
Nicolas PENEL Andrew KRAMAR
Centre Oscar Lambret, Lille, France
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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 ?
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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
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Q 1: What is the quality of reported primary endpoints ?
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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%)
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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%)
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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%)
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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%)
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Q 2: What are the correlation between activity endpoints and overall survival ?
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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
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Good correlation between 6-month PFR and OS (p=0.005)
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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
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Q 3: Distributions of endpoints in cases of active or inactive drugs?
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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
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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%)
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Q2: Endpoints possibly correlated with OS
3-month progression free rate6-month progression free rate Median progression-free survival
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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
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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
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Thank your for your attention