Transcript WJOG4007

Randomized phase III study of
irinotecan (IRI) versus weekly paclitaxel (wPTX)
for advanced gastric cancer (AGC) refractory to
combination chemotherapy (CT) of
fluoropyrimidine plus platinum (FP):
WJOG4007 trial
Ueda S, Hironaka S, Yasui H, Nishina T, Tsuda M, Tsumura T,
Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T,
Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y,
Morita S, Okamoto I, Boku N, Hyodo I,
Gastrointestinal Group of West Japan Oncology Group
Background
 A combination chemotherapy (CT) of fluoropyrimidine and
platinum (FP) has been regarded as the standard first-line
treatment for AGC
 Two randomized phase III trials1,2 showed a survival benefit
of second-line CT (docetaxel or irinotecan (IRI) ) compared
with best supportive care
 However, no standard regimen has been established
 In Japan, wPTX3,4 has been used more commonly than
docetaxel and IRI5 based on its tolerability
1
Thuss-Patience PC, Eur J Cancer 2011, 2 Kang JH, J Clin Oncol 2012, 3 Arai, Proc ASCO 2003,
4 Hironaka, Gastric Cancer 2006, 5 Futatsuki Gan to Kagaku Ryoho 1994
Study Scheme
AGC refractory to prior FP confirmed by imaging
Age 20-75, PS 0-2, No history of CPT-11 or Taxane
RANDOMIZATION
Stratified by
Institution, PS 0-1/2, target lesion -/+
weekly Paclitaxel
IRI
80 mg/m2 d1, 8, 15 q4w
150 mg/m2 d1, 15 q4w
Endpoints and Statistical Considerations
Primary endpoint:
Secondary endpoints:
Overall survival (OS)
Response Rate (RR)
Progression Free Survival (PFS)
Toxicity
Proportion of third-line CT
Statistical Consideration
Assumed median OS:
wPTX
5 months : reference
IRI
7.5 months : investigational (Superiority)
2-sided alpha 5% and power 80%
No planned interim analysis
220 pts were required.
Eligibility Criteria
1) Histologically proven unresectable or recurrent gastric
adenocarcinoma
2) Refractory to prior combination CT with FP confirmed by
imaging during treatment or within 1 month after last CT
3) No prior CT with taxanes or IRI
4) Age range 20-75 years
5) PS (ECOG) of 0-2
6) Preserved organ functions
7) Measurable or evaluable lesions
8) No severe peritoneal dissemination
9) Written informed consent
CONSORT Diagram
Randomization
223 pts
Assigned wPTX
Assigned IRI
111 pts
112 pts
108 pts
(3 pts excluded)
108 pts
(3 pts excluded)
106 pts
(5 pts excluded)
Full Analysis
Set (FAS)
Safety Analysis
Set (SAS)
Per Protocol
Set (PPS)
111 pts
(1 pt excluded)
110 pts
(2 pts excluded)
110 pts
(2 pts excluded)
Patient Characteristics 1
Age
Gender
PS
wPTX
IRI
(n=108)
(n=111)
Median (range) 64.5 (37-75)
Male
84
Female
24
0-1
104
2
4
Gastrectomy +
Prior CT
S-1+CDDP
Cape+CDDP
S-1+Oxa
37
71
92
13
3
P
65 (38-75)
87
24
107
4
0.72
1.00
39
72
102
8
1
0.58
1.00
0.30
Fisher’s exact test
FAS
Patient Characteristics 2
wPTX
IRI
(n=108)
(n=111)
P
Target lesion
+
-
91
17
88
23
1.00
Histology*
Intestinal
Diffuse
54
54
54
57
0.97
Peritoneal mets
+
-
28
80
28
83
1.00
No. of metastatic
sites
<1
2<
57
51
64
47
0.59
* Lauren classification
Fisher’s exact test
FAS
Overall Survival
100
Probability (%)
wPTX
IRI
n
Median
108
9.5M
111
8.4M
HR (95% CI)
P
1.13 (0.86-1.49) 0.38
Log-rank test
9.5
50
8.4
0
0
6
12
18
80
75
36
29
10
10
24
30
36
(Months)
Number at risk
wPTX
IRI
108
111
2
3
0
1
0
1
FAS
Progression Free Survival
Probability (%)
100
wPTX
IRI
50
n
Median
108
3.6M
111
2.3M
HR (95% CI)
1.14 (0.88-1.49) 0.33
3.6
2.3
P
Log-rank test
0
0
3
6
9
12
15
18
21
108
111
66
46
16
18
9
8
3
6
2
2
2
1
0
0
Number at risk
wPTX
IRI
24 (Months)
0
0
FAS
Response Rate
n
CR
PR
SD
PD
NE
CR+PR
P
wPTX
91
0
19
38
32
2
21%
0.24
IRI
88
1
11
28
45
3
14%
RECIST 1.0
Fisher’s exact test
Hematological Toxicities (%Grade 3<)
wPTX
IRI
(n=108)
(n=110)
Leukocytes
20.4
19.1
0.87
Neutrophils
28.7
39.1
0.12
Hemoglobin
21.3
30.0
0.16
Platelets
0.9
1.8
1.00
CTCAE 3.0
P
Fisher’s exact test
SAS
Non-Hematological Toxicities (%Grade 3<)
Nausea
Vomiting
Anorexia
Diarrhea
Hyponatremia
Neuropathy (Sens.)
Febrile Neutropenia
Treatment Related Death
CTCAE 3.0
wPTX
IRI
(n=108)
(n=110)
1.9
2.8
7.4
0.9
3.7
7.4
2.8
2.8
4.5
0.9
17.3
4.5
15.5
0
9.1
3.6
P
0.45
0.37
0.04
0.21
0.005
0.003
0.08
1.00
Fisher’s exact test
SAS
Reasons for Treatment Discontinuation
Disease Progression
wPTX
IRI
Total
(n=106)
(n=110)
(n=216)
93 ( 88%)
96 ( 87%)
189
Adverse Event
6 ( 6%)
10 ( 9%)
16
Withdraw
5 ( 5%)
2 ( 2%)
7
Death
1 ( 1%)
1 ( 1%)
2
Other
1 ( 1%)
1 ( 1%)
2
PPS
Post-Study Chemotherapy (3rd line)
wPTX
IRI
(n=108)
(n=111)
Received 3rd line CT
97 (90%)
80 (72%)
CPT-11 containing
81 (75%)
5 ( 5%)
Taxane containing
8 ( 7%)
67 (60%)
Others
8 ( 7%)
8 ( 7%)
P
0.001
Fisher’s exact test
FAS
Summary
 Median OS was 9.5 months for wPTX and 8.4 months
for IRI (HR 1.13, P=0.38)
 Median PFS was 3.6 months for wPTX and 2.3 months
for IRI (HR 1.14, P=0.33)
 RR was 21% for wPTX and 14% for IRI (P=0.24)
 Toxicities were tolerable in both arms
 90% of pts with wPTX and 72% with IRI received poststudy CT (P=0.001)
Conclusion
 WJOG4007 trial failed to demonstrate the superiority
of IRI to wPTX in OS
 wPTX can be adopted as a control arm of future
phase III trials of second-line CT for AGC
Acknowledgement
We would like to express special thanks to all participating patients,
Data and Safety Monitoring Committee, Audit Committee of WJOG, and
WJOG Data Center (Ms Hirai Y, Mrs. Nonogaki K, Ms. Ozumi N and Dr. Nakamura S)
37 Participating Institutions
•Aichi Cancer Center
•Chiba Cancer Center
•Ibaraki Prefectural Central Hosp.
•Fujita Health University Hosp.
•Hiroshima Prefectural Hosp.
•Hyogo Cancer Center
•Jichi Medical University
•Kenseikai Dongo Hosp.
•Kinki University
•KKR Sapporo Medical Center Tonan hospital
•Kobe University Hosp.
•Kochi Health Sciences Center
•Kouseiren Takaoka Hosp.
•Kushiro City General Hosp.
•Kyushu Cancer Center
•Kyushu University Hosp.
•Narita Red Cross Hosp.
•Niigata Cancer Center
•Osaka City General Hosp.
•Osaka Medical Center for Cancer and Cardiovascular Disease
• Oita University Hosp.
• Osaka Medical college
• Osaka National Hosp.
• Osaka Red Cross Hosp.
• Ryugasaki Saiseikai Hosp.
• Saitama Cancer Center
• Shikoku Cancer Center
• Shizuoka Cancer Center
• Shizuoka General Hosp.
• St. Marianna University School of Medicine Hosp.
• Teikyo University Hosp.
• Tochigi Cancer Center
• Tohoku University Hosp.
• Tokai University Hosp.
• Tsukuba University Hosp.
• Tsuyama Chuo Hosp.
• Yamagata Prefectural Central Hosp.
• Yokohama City Hosp.