Docetaxel (D), cisplatin (C), 5-fluorouracil (F) compared to cisplatin (C), 5-fluorouracil (F) for chemotherapy-na

1
Docetaxel (D), cisplatin (C), 5-fluorouracil (F)
compared to cisplatin (C), 5-fluorouracil (F) for
chemotherapy-naïve patients with metastatic or
locally recurrent, unresectable gastric
carcinoma Interim results of a randomized Phase
III trial (V 325)

• Eric Van Cutsem, Jaffer Ajani, V Moiseyenko, S
  Tjulandin, M Fodor, C Boni, E Zuber,
  S Assadourian on behalf of international
  V325 study group
• University Hospital Leuven, Belgium

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Gastric Cancer

• Second most frequent
• cancer worldwide
• cause of cancer death
• Frequently diagnosed in advanced stages
• Standard chemotherapy in advanced gastric
  cancer 5-FU/cisplatin based

3
Study Design (1)

• V 325 Comprised Two Stages
• First Stage
• Randomized phase II trial docetaxel, cisplatin
  5-FU (DCF) vs docetaxel cisplatin (DC) (n155)
• IDMC selected a test arm based on
• Overall response rate
• Toxicity
• DCF selected
• ORR DCF 43 DC 26
• Acceptable toxicity

4
Study Design (2)

• Second Stage
• Randomized phase III trial comparingDCF vs CF as
  active control
• Interim analysis triggered at the occurrenceof
  162 TTP events
• Current Study Status
• Targeted accrual has been met (n463)
• Final analysis will be conducted Q4 2003

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Study Design V 325 Phase III
Stratification Factors
Docetaxel 75 mg/m2 IV over 1 hr
Cisplatin 75 mg/m2 IV over 1-3 hrsboth on Day 1
only
Liver Involvement
5-FU 750 mg/m2/day by CIV over5 days Days 1-5
Prior Gastrectomy

Cycles repeated every 3 weeks
Measurable vsEvaluable Disease
Cisplatin 100 mg/m2/IV over 1-3 hrs
Weight loss (gt5 or lt 5) in prior 3
Months
5-FU 1000 mg/m2/day by CIV over5 days Days 1-5
Cycles repeated every 4 weeks
Centers
Adequate hydration and anti-emetics
requiredResponse assessment every 8 weeks
independent of treatment schedule
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Eligibility CriteriaV 325 Phase III

• Metastatic or locally recurrent gastric
  adenocarcinoma, including EG
• Age gt 18 years KPS gt 70
• No prior chemotherapy
• Adequate hematology and biochemistry
• No brain or leptomeningeal metastases
• No peripheral neuropathy gt grade 2 NCIC
• No previous or concurrent malignancies
• Written informed consent

prior adjuvant chemotherapy if gt 12 months have
elapsed before recurrence
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EndpointsV 325 Phase III

• Primary Endpoint
• Time to progression
• Main Secondary Endpoint
• Overall survival
• Other Secondary Endpoints
• Response rate
• Time to treatment failure
• Safety
• Quality of life

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Statistical Considerations V 325 Phase III

• 230 patients per arm
• Study powered to show on full analysis population
  (per ICH 9)
• An increase in median TTP from 4 to 6
  months,with 95 power (325 events required)
• An increase in median overall survival from 8 to
  12 months, with a 95 power (325 deaths
  required)
• The study provides 90 power to win on both TTP
  and OS (assuming independence of TTP and OS)

unadjusted logrank test with two-sided, 5
significance level
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Planned Interim Analysis V 325 Phase III
Interim Analysis

• When 162nd TTP event occurred
• 50 of 325 events neededfor final analysis
• Pre-specified boundary for superiority
• TTP p0.0036
• Overall survival p0.0053

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Patient Characteristics (1)V 325 Phase III
Interim Analysis
Demographics and Baseline Characteristics
DCF n111
CF n112
Male
69
71
Age (years) Median (Range)
52 (26-79)
54 (25-74)
gt 65 Years
24
23
55
55
gt 5 Wt Loss Prior 3 Months
63 35
63 37
KPS 90-100 KPS 80

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Patient Characteristics (2)V 325 Phase III
Interim Analysis
Tumor Characteristics
DCF n111
CF n112
Antrum, Body
72
63
GE Junction, Fundus
28
37
Metastatic cancer
98
97
Liver involved
43
41

Measurable disease
83
88
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Drug DeliveryV 325 Phase III Interim Analysis
DCF n111
CF n112
Median Number of Cycles 6 4 Median
Duration of Tx (weeks) 19 16 Median
Administered Dose Intensity Cisplatin
(mg/m²/week) 23 24 5-FU
(mg/m²/week) 1110 1194 Docetaxel (mg/m²/week)
23 -- Cycles with Dose Reduction
12 12
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Reasons for Off Treatment V 325 Phase III
Interim Analysis
DCF n111
CF n112
() () Still on Treatment 3 (3) 2
(2) Discontinuation from Treatment 108 (97) 110
(98) Progressive Disease 30 (27) 53
(47) Adverse Event 25 (23) 23 (21)
Related 22 (20) 23 (21) Not
Related 3 (3) 0 (0) Consent Withdrawn
30 (27) 18 (16) Death 14 (13) 11
(10)
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Response Rate V 325 Phase III Interim Analysis
DCFn111
CFn112

CR
2.7
2.7
PR
36.0
20.5
Overall RR (CRPR)
38.7
23.2
95 CI
29.6 - 48.5
15.8 - 32.1
P-value Chi Square
p0.012
NC/SD
30.6
34.8
PD
17.1
27.7
14.3
Not Evaluable
13.5
Responses confirmed by External Response Review
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Time to Progression V 325 Phase III Interim
Analysis
DCF n111
CF n112
Events
77
85
Progressive Disease
67
80
Deaths
10
5
TTP Median (Months) 95 CI
5.2 4.3 - 6.8
3.7 3.1- 4.8
P value Log-rank Test
p 0.0008
Hazard Ratio 95 CI
1.704 1.244, 2.335

p lt pre-specified boundary for superiority
p0.0036
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Probability Progression Free SurvivalV 325 Phase
III Interim analysis

• DCF CF (n111) (n112)
• 6 mo 45.9 26.1
• 9 mo 30.7 11.2

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Time to Progression V 325 Phase III Interim
Analysis
DCF CF (n111) (n112) Events 77 (69) 85
(76) Censored 34 (31) 27 (24)
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
Log-rank Test p-value0.0008 Risk ratio
1.704 95 CI 1.244,2.335
0.6
0.6
Probability
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0.0
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Duration (Months)
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Overall Survival V 325 Phase III Interim
Analysis
CFn112 ()
DCFn111 ()
Events
83 (75)
98 (88)
Survival Median (Months) 95 CI
10.2 8.5-12.3
8.5 6.6-9.5
P-value Log-rank Test
p0.0064
Hazard Ratio (Test/Control) 95 CI
1.5051.119- 2.025
p gt pre-specified boundary for superiority
p0.0053
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Overall SurvivalV 325 Phase III Interim Analysis
DCF CF (n111) (n112) Events 83 (75) 98
(88) Censored 28 (25) 14 (13)
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
Log-rank Test p-value0.0064 Hazard ratio
1.505 95 CI 1.119-2.025
0.6
0.6
0.5
0.5
Probability
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0.0
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
29
28
27
26
25
24
23
22
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Duration (Months)
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Hematologic Toxicity V 325 Phase III Interim
Analysis
DCF () CF() Patients evaluable (no
G-CSF) 111 112 Cycles evaluable (no G-CSF) 528
400 Cycles with G-CSF 66 20 Patients with
grade 3/4 neutropenia 93 (84) 66 (60) Patients
with febrile neutropenia 18 (16) 7
(6) Patients with neutropenic infection 15
(14) 8 (7)
Grade ? 2 Fever concomitant with Grade 4
neutropenia (without infection) Grade ? 2
related Infection concomitant with Grade 3/4
neutropenia
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Non-hematologic ToxicityV 325 Phase III Interim
Analysis
NCIC Grade 3/4 Related Adverse Events

• DCF CF n111 n112
• Neurosensory 8 5
• Infection 12 6
• Anorexia 13 13
• Nausea 14 20
• Vomiting 15 21
• Lethargy 20 19
• Diarrhea 20 8
• Stomatitis 23 30
• At least 1 related G3/4 AE 68 65

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Death on Study V 325 Phase III Interim Analysis
Any cause mortality within 30 days of first
infusion

• V 325
• DCF 2.3
• CF 3.1
• EORTC 40902 (Vanhoeffer et al)
• CF 6.2

JCO
200018(14)2648-57
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Death on StudyV 325 Phase III Interim Analysis
Any cause mortality within 30 days of last
infusion

• DCF 13/111 (11.7)
• CF 9/112 (8.0)
• Any cause mortality malignant disease,toxicity
  and other (pulmonary embolism, abdominal event,
  pneumonia, tumor lysis)
• Jacog (Ohtsu et al) CF 7/105 (6.7) (using
  lower doses)

JCO 200321(1)54-9
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Conclusions (1)V 325 Phase III Interim Analysis

• Myelotoxicity was predictable and manageable for
  DCF
• GI is the lead non-hematologicalgrade 3/4
  toxicity
• CF stomatitis (30) vomiting (21)
• DCF stomatitis (23) diarrhea (20)

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Conclusions V 325 Phase III Interim Analysis

• DCF resulted in a statistically significantly
  superior
• TTP 5.2 vs 3.7 mo p 0.0008
• ORR 38.7 vs 23.2 p 0.012
• Median survival was 10.2 mo with DCF and 8.5 mo
  with CF (p 0.0064)
• DCF a standard option for patientswith advanced
  gastric cancer asfrontline therapy

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Final Analysis of V325

• ASCO 2005

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Phase III Study Design
Docetaxel 75 mg/m2 IV over 1 hr, D1 Cisplatin 75
mg/m2 IV over 1- 3 hrs, D1 5-FU 750 mg/m2/day by
CIV over 5 days Q3W 227 patients

• Measurable or evaluable metastatic or measurable
  locally recurrent gastric adenocarcinoma
• Age ? 18 years old
• KPS gt 70
• Adequate hematological and biochemical
  parameters
• Signed written informed consent

R A N D O M I Z E
Treatment until PD, consent withdrawn or
unacceptable toxicity
Cisplatin 100 mg/m2 IV over 1-3 hrs, D1 5-FU
1000 mg/m2/day by CIV over 5 days Q4W
230 patients

• Stratification factors
• Liver involvement (y/n)
• Prior gastrectomy (y/n)
• Measurable vs evaluable disease
• Weight loss (gt5 vs ?5) in prior 3 months
• Center
• Tumor assessments planned every 8 weeks in both
  arms

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TTP Final Analysis (FAP)
p0.0004 HR 1.473 (95 CI 1.189 - 1.825) Risk
reduction 32.1
100
90
80
Cut-off May 2003
70
TCF CF Median
(months) 5.6 3.7 (95CI)
(4.86-5.91) (3.45-4.47) Any TTP event
167 (75.6) 174
(77.7)
60
Probability ()
50
40
30
20
TCF
10
CF
0
0 3 6 9 12
15 18 21 24

months

• Patients at risk
• TCF 221 148 71 40
  17 10 7 6
  
• CF 224 119 42 18
  10 5

28
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Overall Survival - Final Analysis (FAP)
p0.0201 HR 1.293 (95 CI 1.041 - 1.606) Risk
reduction 22.7
100
90
80
TCF CF Median (months)
9.2 8.6 (95CI)
(8.38-10.58) (7.16-9.46) Death
162 (73.3) 172 (76.8)
70
60
Survival Probability ()
50
One year survival 40.2
31.6 Two year survival 18.4
8.8
40
30
20
TCF
10
CF
0
0 3 6 9 12 15 18
21 24 27 30 33 36

months

• Patients at risk
• TCF 221 199 149 93 68 45 36
  28 22 17 12 7 5
  
• CF 224 195 136 87 54 35 17
  11 8

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Grade 3-4 Hematological Abnormalities (SP)
Number () of patients
TCF
CF
Regardless of secondary prophylactic treatment
N221
N224
Hematological abnormalities (Grade
3-4) Neutropenia Anemia Thrombocytopenia Febrile
neutropenia or neutropenic infection
181 (82.3) 40 (18.2) 17 (7.7) 66 (30.0)
126 (56.8) 57 (25.6) 30 (13.5) 30 (13.5)
Without or with secondary prophylactic G-CSF
Without
Without
With
With
219
41
222
20
Number of evaluable patients
62 (28.3)
5 (12.2)
29 (13.1)
3 (15.0)
Febrile neutropenia or neutropenic infection
is calculated in evaluable patients
Regardless of relationship
Febrile neutropenia grade ? 2 fever concomitant
with grade 4 neutropenia Neutropenic infection
grade ? 2 infection concomitant with grade 3-4
neutropenia
30
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QoL and Clinical Benefit (FAP)
Hazard Ratio (gt1 favors TCF)
0.4
0.8
1.2
1.6
2.0
2.4
EORTC QLQ-C30 (time to 5 definitive worsening)
Global Health Status (n384)
Physical Functioning (n389)
Social Functioning (n387)
Nausea and Vomiting (n390)
Pain (n391)
Appetite Loss (n388)
EQ-5D
Thermometer (n223)
Clinical Benefit
Time to definitive worsening KPS (n444)
Time to definitive 5 weight loss (n444)
Time to definitive worsening appetite (n425)
Pain-Free Survival (n200)
Time to 1st cancer pain req. opioid (n355)
31
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Key Messages

1. Taxotere in combination with CF is a new
   reference treatment in advanced gastric cancer
2. In this large pivotal phase III trial, Taxotere
   demonstrated significantly superior efficacy in
   EVERY parameter RR, PFS and SURVIVAL!!!
3. QoL maintained for a longer period despite the
   toxicities observed
4. This positive trial adds to the overall Taxotere
   survival message, as demonstrated in other tumour
   typesand further differentiates Taxotere from
   paclitaxel

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