Introduction NDA 20449SE011

1
IntroductionNDA 20-449/SE011

• Taxotere (docetaxel) for
• Injection Concentrate

Philip Chaikin, Pharm.D., M.D.
Rhône-Poulenc Rorer Pharmaceuticals
2
NDA 20-449/SE011

• TAXOTERE (docetaxel) for Injection Concentrate
• First Approval (accelerated) May 14, 1996
• Indicated for the treatment of patients with
  locally advanced or metastatic breast cancer, who
  have progressed during anthracycline-based
  therapy or have relapsed during
  anthracycline-based adjuvant therapy.
• Second Approval (full approval plus label
  expansion) June 22, 1998
• Indicated for the treatment of patients with
  locally advanced or metastatic breast cancer
  after failure of prior chemotherapy.

3
sNDA Taxotere - SE011

• Fast Track Rolling Submission granted February
  19, 1999.
• Priority review due to unmet medical need in
  previously treated patients with advanced NSCLC.

4
Survival in BSC Patients
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
0.0
Median Survival 4.6 months 1-year Survival 12
CUMULATIVE PROBABILITY
0
3
6
9
12
15
18
21
SURVIVAL TIME (MONTHS)
5
sNDA Taxotere - SE011

• Total number of patients treated with Taxotere in
  this sNDA618 Patients
• Two large Phase 3 trials
• TAX 317 - A Multicenter, Randomized Phase III
  Study of Taxotere plus Best Supportive Care
  versus Best Supportive Care alone in Patients
  with NSCLC Previously Treated with Platinum-based
  Chemotherapy
• TAX 320 - A Multicenter, Randomized Phase III
  Study of Taxotere 100 mg/m2 or 75 mg/m2 versus
  Vinorelbine/Ifosfamide in Patients with NSCLC
  Previously Treated with Platinum-based
  Chemotherapy
• Supportive Phase II data (60 - 100 mg/m2)

6
Proposed Indication

• TAXOTERE (docetaxel) for Injection Concentrate is
  indicated for the treatment of patients with
  locally advanced or metastatic Non-small Cell
  Lung Cancer after failure of prior chemotherapy.

7
AGENDA

• Overview of Chemotherapy in Mark Green, M.D.
• Advanced NSCLC and Hollings Cancer Center
• Review of RPR Phase II Data Medical
  University of South Carolina
• Study TAX 317 Frances A. Shepherd, M.D.
  Princess Margaret Hospital
  Toronto, Canada
• Study TAX 320 Frank Fossella,
  M.D. University of Texas MD
  Anderson Cancer Center
• Quality of Life Overview Richard Gralla, M.D.
• and Methodology Ochsner Cancer Institute
• New Orleans, LA
• Investigators Summary Mark Green, M.D.
• Taxotere Benefit/Risk Hollings Cancer
  Center
• for NSCLC Medical University of South
  Carolina

8
Non-Small Cell Lung Cancer Disease Overview With
an Emphasis on the Current Status of Chemotherapy
in Previously Treated Patients

• Mark Green, M.D.
• Hollings Cancer Center
• Medical University of South Carolina

9
The Status of Chemotherapy for NSCLC

• Platinum-based combinations are the standard for
  first line chemotherapy.
• Response rates for stage III/IV patients range
  from 20 to gt 50. Symptom improvement is
  frequent.
• Phase III trials and meta-analysis confirm a
  survival benefit for chemotherapy vs. BSC
• Median survival 7 months vs. 4 months
• 1 year survival 25 vs. 15

NSCLC Collaborative Group Chemotherapy in
NSCLC A Meta-Analysis. British Medical Journal,
1995
10
The Status of Chemotherapy for NSCLC

• Most first line responses are partial. Nearly
  all responding patients eventually progress.
• With BSC, median survival for second line therapy
  candidates is between 4.5 and 5.0 months.
• In the U.S., patients want additional treatment.
  Chemotherapy is frequently offered to previously
  treated patients despite the absence of FDA
  approved agents for this indication.

11
The Status of Chemotherapy for NSCLC

• there is no current evidence that either
  confirms or refutes that second-line chemotherapy
  improves survival in patients with advanced
  NSCLC.
• there are recent Phase II data to suggest some
  of the newer agents under investigation may
  provide a survival benefit in NSCLC patients who
  progress after receiving cisplatin-based
  chemotherapy.
• Treatment Guidelines For Unresectable NSCLC.
  JCO 152996-3019, August 1997 In discussing
  Fossella et al Phase II study of docetaxel for
  advanced or metastatic platinum refractory
  non-small cell lung cancer. JCO 13645-651, 1995.

12
Older Agents As Monotherapy for Previously
Treated Patients With Advanced NSCLC
Median Survival
Overall RR
N
Agent
NR
12-17
53
Vindesine
NR
2
53
Epirubicin
NR
4
24
Etoposide
NR
7
95
Cisplatin
6 mo.
4-20
87
Ifosfamide
13
Newer Agents As Monotherapy for Previously
Treated Patients With Advanced NSCLC
14
Single Agent Taxotere in Previously Treated
Patients With NSCLC Phase II Trial Data
Overall RR
Number Enrolled
Number of Trials
Dose Level
15
Single Agent Taxotere in Previously Treated
Patients With NSCLC Phase II Trial Data
16
Taxotere as Monotherapy for Previously Treated
NSCLC Patients

• Unmet need for proven effective chemotherapy in
  previously treated patients.
• Poor outlook for BSC in previously treated
  patients.
• Consistent encouraging activity of Taxotere in
  previously treated patients.
• Two Phase III trials undertaken
• TAX 317 Taxotere plus BSC vs. BSC alone
• TAX 320 T100 or T75 vs. vinorelbine or
  ifosfamide

17
Taxotere Phase III Studies As Monotherapy for
Previously Treated NSCLC Patients

• The results of these two studies (TAX 317 and TAX
  320), which will be presented by Drs. Shepherd
  and Fossella, demonstrate that Taxotere, in
  particular Taxotere 75 mg/m2, improves survival.
• The improvement in clinical benefit parameters
  and QoL will be presented by Dr. Gralla.

18
TAX 317A Prospective Randomized Trial of
Taxotere plus BSC versus BSC in NSCLC Patients
Previously Treated with Platinum-Based
Chemotherapy

• Frances Shepherd, M.D.
• Princess Margaret Hospital
• University of Toronto, Canada

19
Objectives TAX 317

• PRIMARY
• Survival
• SECONDARY
• Response
• Time To Progression
• Safety (Toxicity)
• Quality of Life
• Clinical Benefit

20
Study Design - TAX 317
NSCLC Stratified by ECOG PS (0,1 vs. 2)
and Best response to prior platinum (PD vs.
non-PD)
317 A Taxotere 100 mg/m2, one-hour IV infusion on
Day 1, every 21 days Premedication Dexamethasone
8 mg x 10 doses, beginning 12 hours before
Taxotere
RANDOMIZE
By Protocol Amendment 6
317 B
Taxotere 75 mg/m2, one-hour IV infusion on Day 1,
every 21 days Premedication Dexamethasone 8 mg x
5 doses, beginning 12 hours before Taxotere
Best Supportive Care without chemotherapy
21
Primary Comparison - TAX 317
Taxotere 75 mg/m2 BSC versus Best Supportive
Care
22
Eligibility Criteria TAX 317

• Documented NSCLC
• 1 or more platinum-based regimens
• ECOG PS 0-2
• Adequate hematology and biochemistry
• 21 days from last chemotherapy
• Asymptomatic, treated brain metastases
• No peripheral neuropathy gt grade 2
• No prior Taxol

23
Patient Characteristics - TAX 317
317 A
317 B
T100
BSC100
BSC75
T75
(n49)
(n49)
(n51)
(n55)
Stratification Factors
22
29
26
20
PS 2
18 82
22 78
18 82
18 82
Best Response to Last Platinum-based Regimen
PD Non-PD
24
Patient Characteristics - TAX 317
317 A
317 B
BSC75
T75
T100
BSC100
(N49)
(N55)
(N49)
(N51)

Median Age (yrs)
61
63
61
56
76
71
64
59
Male ()
Stage IV ()
82
82
73
80
32
25
20
22
gt 2 prior regimens ()
25
Response TAX 317
All TAX (n104)
T100 (n49)
T75 (n55)
6
6
6
Response Rate
43
38
47
Stable Disease
49
44
53
PR SD
6 mo.
6 mo.
6 mo.
Resp. Duration (median)
26
Time to Disease Progression - TAX 317
317A
317B
BSC75 (n49)
T75 (n55)
BSC100 (n51)
T100 (n49)
7.0
12.3
5.9
9.1
Median (weeks)
p0.004
p0.037
Log-rank Test
27
Time To Progression - TAX 317B Taxotere 75 mg/m2
vs. BSC (ITT)
28
Survival TAX 317
Median (mo.)
1 Year ()
Log-rank Test
29
Survival Update - TAX 317B Taxotere 75 mg/m2 vs.
BSC

T
75
Median 7.5 vs. 4.6 mos. Log-rank p
0.010 1-year 37 vs. 12 Chi-square p 0.003

1.0

BSC75


0.9



0.8


0.7


0.6


Cumulative Probability
0.5


0.4


0.3


0.2


0.1


0.0

0

3

6


9

12

15
18

21

Survival Time (months)
30
Overall Survival Update - TAX 317 Taxotere 75
mg/m2100 mg/m2 vs. BSC
1.0
T100 T75
0.9
BSC
0.8
Log-rank Test p 0.047
0.7
0.6
Cumulative Probability
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
Survival Time (Months)
31
Hematologic Toxicity TAX 317
T100 n49 17 88 2 22 10
T75 n55 6 67 0 2 1.8
Anemia Neutropenia Thrombocytopenia Febrile
Neutropenia Toxic Death
Grade 3/4
32
Drug Delivery TAX 317
T75 (n55) 264 299 4 (1-17)
T100 (n49) 187 211
2 (1-22)
Total no. of cycles Median cumulative
dose (mg/m2) Median no. of cycles (range)
33
Treatment Emergent Adverse Events TAX 317 - of
Patients
T100
BSC100
T75
BSC75
Asthenia 22 18 18
39 Infection 14 4 6 6
Diarrhea 4 0 2 0
Nausea 2 6 4 4
Vomiting 0 0 4 2
Motor 4 0 2 6 Sensory
2 0 2 6 Allergy 4
0 7 0 Skin 6 0 0
2 Fluid Ret. 4 2 4 4
Grade 3/4 or Severe, regardless of relationship
to treatment
34
Quality of Life TAX 317

• Both the LCSS and EORTC instruments were used.
• Advantages in several Quality of Life and
  Clinical Benefit parameters were shown.

35
Tumor-Related Therapy TAX 317B
36
Conclusions - TAX 317

• Taxotere improves overall survival, 1-year
  survival, and time to disease progression in
  NSCLC patients after platinum-based chemotherapy.
• Taxotere offers clinically meaningful benefit in
  previously treated NSCLC.
• Quality of Life analysis also favors Taxotere
  over BSC.
• Taxotere 75 mg/m2 is a safe and effective dose
  for previously treated NSCLC.

37
TAX 320A Randomized Phase III Trial of Taxotere
100 mg/m2 or 75 mg/m2 vs Vinorelbine/Ifosfamide
in Patients with Non-Small Cell Lung Cancer
Previously Treated with Platinum-Based
Chemotherapy

• Frank Fossella, M.D.
• The University of Texas
• M. D. Anderson Cancer Center
• Houston, Texas

38
Study Objectives TAX 320

• PRIMARY
• Survival
• SECONDARY
• Overall Response Rate
• Time to Progression
• Duration of Response
• Safety
• Quality of Life
• Clinical Benefit

39
RANDOMIZE
Study Design TAX 320

• NSCLC
• Stratified by
• Best response to last platinum
• (PD vs. non-PD)
• and
• ECOG PS
• (0,1 vs. 2)

• Taxotere 100 mg/m² IV Q 3 wks
• Premedication Dexamethasone 8 mg x 5 doses,
  beginning 12 hours before Taxotere
• Taxotere 75 mg/m² IV Q 3 wks
• Premedication Dexamethasone 8 mg x 5 doses,
  beginning 12 hours before Taxotere
• Vinorelbine 30 mg/m² IV
• Days 1, 8, 15 Q 3 wks
• - or -
• Ifosfamide 2 gm/m² IV ( Mesna)
• Days 1, 2, 3 Q 3 wks

Response assessment every 2 cycles
40
Eligibility Criteria TAX 320

• Locally advanced or metastatic NSCLC.
• At least one prior platinum-based regimen.
• No restriction on number of prior regimens
  (including Taxol), or on prior radiotherapy.
• ECOG PS 0-2.
• Adequate hematology and biochemistry.
• Asymptomatic treated brain metastases.
• No peripheral neuropathy gt grade 2.

41
Patient Characteristics TAX 320
Stratification Factors
15
18
17
PS 2
32 68
24 76
33 67
Best Response to Last Platinum-based Regimen
PD Non-PD
42
Patient Characteristics - TAX 320

Median Age (yrs)
60
60
59
Male ()
66
66
65
Stage IV ()
86
90
91
gt 2 Prior Regimens ()
35
26
29
Prior Taxol ()
31
42
41
43
Drug Delivery - TAX 320
V/I (n87/32)
T75 (n121)
T100 (n121)
Total number of cycles
452 518 305 / 96
Median number of cycles 3
3 3 / 2
(range) (1-13) (1-28) (1-13 / 1-7)
Cycles with G-CSF () 28.1
6.7 1.0 / 9.4
44
Response Rate TAX 320
V/I (n122)
T75 (n124)
T100 (n124)

• Partial Response 11 7 1
• T vs V/I p0.001
  p0.036
• T (10075) vs. V/I
  p0.002
• Stable Disease 33
  36 31
• PR SD 44 43 32
• Median Response
• Duration (months) 7.4 9.0
  5.9

Fishers Exact Test
45
Time To Progression - TAX 320
46
Survival TAX 320
47
Survival TAX 320
V/I (n123)
T75 (n125)
T100 (n125)

• Median (months) 5.5 mos 5.7 mos 5.6 mos
• T vs V/I p0.93 p0.14
• Log-rank Test
• 1-year survival () 21 32 19
• T vs V/I pns p0.025
• Chi-square Test

48
Overall Survival Update - TAX 320
49
Hematologic Toxicity - TAX 320

Anemia () Neutropenia () Thrombocytopenia
() Febrile Neutropenia () Infection NCI
()
16
11
15
89
66
59
3
4
2
12
8
1/0
15
12
9
Grade 3/4 or Severe
50
Treatment Emergent Adverse Events TAX 320
T100 () (n 121)
T75 () (n 121)
V/I () (n 119)
Pulmonary
29
21
18
24
18
23
Asthenia
11
6
8
Nausea
8
2
6
Vomiting
7
2
5
Neurosensory
Neuromotor
6
3
4
Fluid Retention
4
3
4
3
2
2
Anorexia
Grade 3/4 or Severe, regardless of relationship
to treatment
51
Death and Discontinuation Due to Adverse Events
- TAX 320
V/I (n123)
T75 (n125)
T100 (n125)
Adverse Event ()
14
9
9
Death due to Toxicity ()
5
3.3
3.4
Regardless of relationship to treatment
52
Quality of Life TAX 320

• The LCSS instrument was used.
• Advantages in several Quality of Life and
  Clinical Benefit parameters were shown.

53
Conclusions TAX 320

• This randomized Phase III trial of previously
  treated advanced NSCLC patients showed
  significant differences favoring Taxotere in
  1-year survival, response rate, and
  time-to-progression versus the comparator V/I.
• The data from this trial with Taxotere 75 mg/m2
  confirm the clinical benefit observed in TAX 317.

54
Clinical Benefit and Quality of Life Assessment

• Richard J. Gralla, M.D.
• Ochsner Cancer Institute
• New Orleans, LA

55
TAXOTERE IN LUNG CANCERValue of Quality of Life
andClinical Benefit Evaluation

• Palliation, or cancer-related symptom relief, is
  an important goal of treatment.
• Even modest survival or response advantages are
  associated with larger palliative benefits.
• Important to ascertain that response and survival
  advantages with chemotherapy are not
  counter-balanced by a negative impact on quality
  of life.

56
TAXOTERE IN LUNG CANCERClinical Benefit and
Quality of Life

• Clinical Benefit
• Subjective or Palliative Control of Common
  Problems
• Previously Defined to Evaluate
• Pain Control
• Weight Loss
• Performance Status
• Quality of Life
• Multidimensional
• Includes many areas not likely to be affected by
  chemotherapy

57
TAXOTERE IN LUNG CANCERQuality of Life
Methodology

• Instruments
• EORTC QLQ - C30 / LC - 13
• LCSS
• Frequency of Measurement
• Every 3 Weeks
• Analysis
• ANCOVA
• Longitudinal
• Pattern Mixture

58
WEIGHT LOSS DURING TREATMENTPercent of Patients
with Weight Loss gt 10
TAX 317B
TAX 320
25
25
25
20
20
15
15
10
10
8
5
5
5
2
0
0
T75
BSC75
T75
V/I
plt0.001
pns
59
EVALUATION OF PAIN CONTROLDifference in
Treatment Group Means
TAX 317B
TAX 320
Better for
Better for
Better for
Better for
BSC75
T75
V/I
T75
PAIN SCORES (LCSS)
Patient Scale
Observer Scale
60
OPIOID ANALGESIC USE TAX 317BChange from
Baseline
60
49
50
40
35
T75
Percentage of Patients
30
BSC75
20
18
20
13
10
5
0
Ongoing at Baseline
Additional Opioid Analgesic
Newly-started Opioid Analgesic
pns
plt0.001
plt0.001
61
PERFORMANCE STATUS EVALUATION Change from
Baseline Difference in Treatment Group Means
TAX 317B
TAX 320
Better for
Better for
Better for
Better for
BSC75
T75
V/I
T75
Performance Status (ECOG)
Cycle 1
Cycle 2
Cycle 3
Mean Across Cycles 1-3
Last Assessment
62
QUALITY OF LIFE ASSESSMENT Difference in
Treatment Group Means
Lung Cancer Symptom Scale
Patient Total Score
Patient Scale Global QoL
Observer Total Score
EORTC QLQ-C30
Global QoL
The analysis for the EORTC QLQ -C30 Global QoL
is based on change from baseline to last
assessment

.
63
TAXOTERE IN LUNG CANCERQuality of Life and
Clinical Benefit Conclusions

• Significant advantages in both patient and
  observer rated clinical benefit were observed in
• Pain control
• Prevention of weight loss
• Performance status
• Taxotere treatment resulted in better palliation
  than achieved with best supportive care alone,
  including reduction in opioid and other pain
  medications.
• No detrimental effects on patient rated quality
  of life occurred with Taxotere treatment.
• Results were consistent with all three analysis
  methods.

64
Benefit / RiskInvestigators Summary

• Mark Green, M.D.
• Hollings Cancer Center
• Medical University of South Carolina

65
1997 ASCO Guidelines for NSCLC
there is no current evidence that either
confirms or refutes that second-line chemotherapy
improves survival in patients with advanced
NSCLC.
Treatment Guidelines For Unresectable NSCLC.
JCO 152996-3019, August 1997 In discussing
Fossella et al Phase II study of docetaxel for
advanced or metastatic platinum refractory
non-small cell lung cancer. JCO 13645-651, 1995.
66
State of the Art - December 1999

• TAX 317 B Significant overall survival benefit
  for TAX 75 vs BSC (p 0.010)
• Updated 1-year survival 37 vs 12 (p
  0.003)
• TTP significantly superior for TAX 75
• Clinical benefit enhancements achieved

67
State of the Art - December 1999

• TAX 320 Survival curves diverge after 8 month
  point
• Updated 1-year survival for TAX 75 (30) is
  better than that for V/I (20) (p 0.05)
• Overall response rates favor both TAX 75 (p
  0.036) and TAX 100 (p 0.001) compared to V/I
• QoL for TAX 75 at least as good as V/I

68
Safety Profile Taxotere
RPR
69
Based on these data, we believe that Taxotere 75
mg/m2 represents a significantly effective
treatment option with a favorable therapeutic
index for patients with NSCLC who have already
received chemotherapy.
70
CONCLUSIONNDA 20-449/SE011

• Taxotere (docetaxel) for
• Injection Concentrate

Philip Chaikin, Pharm.D., M.D.
Rhône-Poulenc Rorer Pharmaceuticals
71
Proposed Indication

• Taxotere (docetaxel) for Injection Concentrate is
  indicated for the treatment of patients with
  locally advanced or metastatic non-small cell
  lung cancer after failure of previous
  chemotherapy.
• Recommended dose 75 mg/m2

72
Experts Present to Answer Questions

• Thierry Le Chevalier, M.D.
• Institute Gustave Roussy
• France
• Thomas Lynch, M.D.
• Massachusetts General Hospital
• Boston, MA

• Howard Burris, M.D.
• The Sarah Cannon Cancer Center
• Centennial Medical Center
• Nashville, TN
• Gary Koch, Ph.D.
• University of North Carolina
• Chapel Hill, NC
• Mark Kris, M.D.
• Memorial Sloan Kettering
• New York, NY

73
Experts Present to Answer Questions (Cont.)

• Karin Mattson, M.D.
• Helsinki University Hospital
• Helsinki, Finland
• James Rigas, M.D.
• Dartmouth-Hitchcock Medical Center
• Lebanon, NH

• Kazimierz Roszkowski, M.D.
• National Tuberculosis and
• Lung Diseases Institute
• Warsaw, Poland
• Rafael Rossell, M.D.
• Hospital Germans Trias Pujol
• Barcelona, Spain

74
CONCLUSIONNDA 20-449/SE011

• Taxotere (docetaxel) for
• Injection Concentrate

Philip Chaikin, Pharm.D., M.D.
Rhône-Poulenc Rorer Pharmaceuticals