nda 20-449 se-011 docetaxel fda review. fda review team biostatistics –clara chu, phd. –gang...

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