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NDA 20-449 SE-011Docetaxel
FDA Review
FDA Review Team
• Biostatistics– Clara Chu, PhD.
– Gang Chen, PhD.
• Biopharmaceutics– Safaa Ibrahim PhD
– Atiq Rahman, PhD.
• Project Manager– Ann Staten, RD
• Medical– Julie Beitz, MD
Proposed Indication
“for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior
chemotherapy”
The Randomized, Controlled Trials
• TAX 317– Docetaxel 100 mg
(N= 49)
– Best Supportive Care (N=51)
– Docetaxel 75 mg(N=55)
– Best Supportive Care (N=49)
• TAX 320– Docetaxel 100 mg
(N=125)
– Docetaxel 75 mg(N=125)
– Vinorelbine OR Ifosfamide(N=123)
Trials’ Shared Features
• Eligibility/Exclusion Criteria– prior platinum-based chemotherapy required in
both studies– prior taxane exposure excluded in TAX 317
only
• Primary Endpoint = Survival
• Secondary Endpoints
Major Efficacy Issues
• Pre-specified vs. Other Analyses
• Consistency across studies
Survival - Prespecified Analyses
TAX 317 TAX 320Tax
(100+75)N=103
BSC
N=99
Tax(75mg)N=125
V/I
N=123
MedianSurvival
7.2 mo 4.7 mo 5.7 mo 5.6 mo
95% CI (5.5, 9.2)p=0.14
(3.7, 6.0) (5.1, 7.9)p=0.14
(4.3, 7.9)
Sept. 99Update
7.0 mo 4.6 mo 5.7 mo 5.6 mo
95% CI (5.5, 9.0)P=0.047
(3.7, 6.0) (5.1, 7.1)P=0.13
(4.4, 7.9)
Survival - Retrospective Analyses
TAX 317 TAX 320Tax
75mgN=55
BSC(75mg)
N=49
Tax75mgN=125
V/I
N=123
MedianSurvival
9.0 mo 4.6 mo 5.7 mo 5.6 mo
95% CI (5.5,13.1)p=0.016*
(3.7, 6.1) (5.1, 7.9)p=0.14
(4.3, 7.9)
Sept 99Update
7.5 mo 4.6 mo 5.7 mo 5.6 mo
95% CI (5.5,12.8)P=0.010*
(3.7, 6.1) (5.1, 7.1)P=0.13
(4.4, 7.9)
* Unadjusted
K-M Survival Curves - 75 mg vs. Control
TAX 317 TAX 320
Product-Limit Survival Estimates
Time Variable: Survival Time (Days)
Censoring Variable: Survival Censoring Y/N
Survival Plot
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 200 300 400 500 600
Survival Time (Days)
1.2
55.2
Tests Between Groups
Test
Log-Rank
Wilcoxon
Chi-Square
5.7584
4.9894
DF
1
1
Prob>ChiSq
0.0164
0.0255
1.2
55.2
Combined
Product-Limit Survival Estimates
Time Variable: Survival Time (Days)
Censoring Variable: Survival Censoring Y/N
Survival Plot
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 300 500 700
Survival Time (Days)
1.2
813
Tests Between Groups
Test
Log-Rank
Wilcoxon
Chi-Square
2.1719
0.3318
DF
1
1
Prob>ChiSq
0.1406
0.5646
1.2
813
Combined
SurvIvIng
SurvIvIng
Tax
BSC
Tax
Control
Rate of Survival at One Year - Retrospective Analyses
TAX 317 TAX 320Tax
75mgN=55
BSC(75mg)
N=49
Tax75mgN=125
V/I
N=123
1-yearSurvival
40%* 16% 32%* 19%
95% CI (26, 54) (3, 30) (23,40) (12, 26)
Sept 99Update
37%* 12% 30% 20%
95% CI (24, 50) (2, 23) (22, 39) (13, 27)
* Unadjusted p<0.05
Historical Perspective
Lack of phase 3 data in the second line setting First line rates of survival at one year are
reported in the range of 18 - 43% for combination regimens (in randomized controlled trials)Gemcitabine + Cisplatin = 39%Pactilaxel + Cisplatin = 36%Vinorelbine + Cisplatin = 35%
Survival: Summary of Review Issues
• A significant difference between arms was demonstrated in a pre-specified survival analysis in only one study (TAX317, pooled), in an updated analysis
• The analysis of overall survival at the 75 mg dose level favored docetaxel in a retrospective analysis of a single study (TAX317)
• Exploratory analyses of rates of one year survival favor docetaxel in both studies
• Rates of one year survival are comparable to those reported in the first line setting
Clinical Benefit Parameters
TAX 317 TAX 320
PerformanceStatus
MorphinicAnalgesic
Use
Weight Loss LCSS QoL
Safety
TAX 317 TAX 320 BreastCancer
100 mg 75 mg 100 mg 75 mg 100 mg
FebrileNeutropenia
22.4% 1.8% 11.6% 8.3% 11.8%
Grade 3/4Infection
14.3% 5.5% 15.7% 12.4% 7.1%
TRM 14.3% 1.8 % 5.0% 3.3% 1.5%
Summary
• Safety • QoL • Survival