Use Irinotecan or a Taxane for
nd
2 Line GE Cancer Therapy:
Don’t Use What Dr. Fuchs
Tells You to Use
Jordan D. Berlin, M.D.
Ingram Professor of Cancer Research
Co-director, GI Oncology
Director, Phase I Research
Vanderbilt-Ingram Cancer Center
Disclosures
• Advisory Boards here and
there in last year
–
–
–
–
–
–
–
–
–
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Genentech/Roche
Karyopharm
Amgen
Astra Zeneca
BMS
Lilly/Imclone
Symphogen
Celgene
Vertex
Ipsen
• Current Research
Support
– Amgen, Lilly/Imclone,
Pfizer, Novartis, Abbvie,
Immunomedics, Otsuka,
Merrimack, Oncomed,
Genentech/Roche,
Taiho
So what is the data for second-line
chemotherapy?
AIO:
Small trial
of
irinotecan
vs BSC
Fig. 2 Overall survival (intention to treat population) Median survival
Irinotecan: 4.0 months, BSC: 2.4 months; one sided logrank test: p =
0.012; HR: 0.48 (95% CI: 0.25–0.92).
Peter C. Thuss-Patience , Albrecht Kretzschmar , Dmitry Bichev , Tillman Deist , Axel Hinke , Kirstin Breithaupt ,...
European Journal of Cancer, Volume 47, Issue 15, 2011, 2306 - 2314
Salvage Chemotherapy for Pretreated
Gastric Cancer: A Randomized Phase
III Trial Comparing Chemotherapy Plus
Best Supportive Care With Best
Supportive Care Alone
Jung Hun Kang, Soon Il Lee, Do Hyoung Lim, KeonWoo Park, Sung Yong Oh, Hyuk-Chan Kwon, In Gyu
Hwang, Sang-Cheol Lee, Eunmi Nam, Dong Bok Shin,
Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong
Lim, Won Ki Kang and Se Hoon Park⇑
JCO Aug 20, 2012:3035
Next 2nd line Chemotherapy (SLC) RCT
Screening & consent for RCT
Refused RCT, but
prefer SLC
Willing to participate RCT
Refused RCT, but
prefer BSC
2:1 randomization
SLC
Docetaxel
or irinotecan
BSC
SLC
BSC
N = 202
RCT
RCT + PPT
RCT: randomized controlled trial
PPT: patient-preference trial
ClinicalTrials.gov,
NCT00821990
From Park ASCO 2011
Kaplan-Meier estimates for overall survival in
randomly assigned patients.
OS 5.3 vs 3.8 months,
HR 0.66, p = 0.007
Kang J H et al. JCO 2012;30:1513-1518
©2012 by American Society of Clinical Oncology
COUGAR-02: Randomised phase III study of
docetaxel versus active symptom control in patients
with relapsed esophago-gastric adenocarcinoma
N Cook, A Marshall, JM Blazeby, JA Bridgewater, J
Wadsley, FY Coxon, W Mansoor, S Madhusudan, S Falk,
GW Middleton, D Swinson, I Chau, J Thompson, D
Cunningham, P Kareclas, JA Dunn, HER Ford
On behalf of COUGAR 02 investigators and NCRI Upper GI Clinical
Studies Group
Trial funded by Cancer Research UK grant CRUK/07/013
EudraCT Number: 2006-005046-37
ISRCTN 13366390
Trial Design
Arm A (n=84):
Docetaxel 75mg/m2 IV every 3
weeks for up to 6 cycles
+ ASC
Adenocarcinoma
of esophagus,
esophagus-gastric
junction or
stomach refractory
to platinum and
fluoropyrimide
Assess every 3
weeks for 18
weeks, then
every 6 weeks
RANDOMISE
1:1
n=168
Arm B (n=84):
Active symptom control
May include: Radiotherapy,
analgesia, anti-emetics,
steroids
Stratified by:
1.Disease status (Locally advanced vs metastatic);
2. Site of disease (Esophagus vs GEJ vs Stomach);
3. Time to progression after previous chemotherapy ( 0 vs 0-3 vs 3-6 months);
4. ECOG PS ( 0/1 vs 2)
Overall survival
100
Median survival: 5.2 months (95% CI 4.1-5.9) for Docetaxel
3.6 months (95% CI 3.3-4.4) for ASC
Hazard ratio 0.67 (95% CI 0.49-0.92), p=0.01
Percentage surviving
75
Docetaxel
ASC
50
25
0
0
2
4
6
8
10
12
14
16
10
6
8
2
5
1
18
Months from randomisation
No. at Risk:
Docetaxel
ASC
84
84
69
70
53
38
33
19
25
13
17
9
4
1
This is a difficult population to treat
Docetaxel
BSC
23%
36%
Death
15%
38%
PD
40%
2%
Tox
31%
N/A
Treatment
N/A
14%
Completed
18 weeks
Reason off
• These patients are
sick
• Most do not complete
treatment plan
• We still need to learn
how best to select
patients who will
benefit
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
WJOG4007 Trial – Second line
chemotherapy for metastatic gastric
cancer
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
Ueda ASCO 2012
Progression Free Survival
100
Probability (%)
n
50
Median HR (95% CI)
wPTX
108
3.6M
IRI
111
2.3M 1.14 (0.88-1.49) 0.33
3.6
2.3
P
Log-rank test
0
0
Number at risk
wPTX
IRI
108
111
3
66
46
6
16
18
9
12
15
18
21
9
8
3
6
2
2
2
1
0
0
24 (Months)
0
0
FAS
Overall Survival
100
Probability (%)
n
Median HR (95% CI)
P
wPTX
108
9.5M
IRI
111
8.4M 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
Number at risk
wPTX
IRI
108
111
2
3
0
1
36
(Months)
0
1 Udea ASCO 2012
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
FROM KANG STUDY SHOWN EARLIER
Kaplan-Meier estimates for overall survival in patients treated with
best supportive care (BSC), docetaxel, or irinotecan.
Kang J H et al. JCO 2012;30:1513-1518
©2012 by American Society of Clinical Oncology
Chemotherapy Conclusions
• Basically, it works
– It is not super, but HR of 0.67 or better fairly
consistently
– Either irinotecan or taxane—both are reasonable
– Don’t give both at the same time. That’s just mean
• Probably works best in highly selected patients as
in the WJOG study
– PS 0-1
– Doubtful it benefits PS = 2
– But it would be nice to have more selection factors
Phase 3 Trial of Everolimus in
Previously Treated Patients With
Advanced Gastric Cancer:
GRANITE-1
Eric Van Cutsem*,
K. H. Yeh, Y. J. Bang, L. Shen, J. A. Ajani, Y. X.
Bai, H. C. Chung, H. M. Pan, K. Chin, K. Muro, Y.
H. Kim, H. Smith, C. Constantini, S. Rizvi, T.
Sahmoud, A. Ohtsu
On behalf of the GRANITE-1 Investigators
* University Hospital Leuven/Belgium
Presented at the 2012 Gastrointestinal
Cancers Symposium.
20
Overall Survival (FAS)
Probability of overall survival (%)
100
Censoring Times
Everolimus + BSC (n/N = 352/439)
Placebo + BSC (n/N = 180/217)
80
Everolimus + BSC: 5.39 months
Placebo + BSC: 4.34 months
60
Hazard ratio: 0.90 (95% CI, 0.75-1.08)
Log-rank P value = 0.1244
40
20
0
0
2
4
6
8
10
12
14
16
18
20
22
24
16
13
12
18
6
8
20
3
4
22
1
1
24
0
0
Time (months)
No. of patients still at risk
Time (months) 0
Everolimus
439
217
Placebo
2
355
172
4
253
117
6
195
82
8
139
60
10
87
35
12
52
28
14
30
16
21
Figure 2 Kaplan-Meier estimates of overall survival (A) and progression-free survival (B)
REGARD TRIAL
OS HR = 0.776
The Lancet, Volume 383, Issue 9911, 2014, 31 - 39
Charles S Fuchs , Jiri Tomasek , Cho Jae Yong , Filip Dumitru , Rodolfo Passalacqua , Chanchal Goswami , Howard S...
http://dx.doi.org/10.1016/S0140-6736(13)61719-5
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma
(REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
Let’s Compare: Trials vs BSC
Chemotherapy
Targeted Therapy
AIO (irinotecan)
HR 0.48
Granite-1 (everolimus)
HR 0.90
Kang (irinotecan or
docetaxel)
HR 0.66
REGARD (ramucirumab)
HR 0.776
Cougar-02 (docetaxel)
HR 0.67
It all comes down to hazard ratio: For chemotherapy, it
is very consistent, but for targeted agents, it is
consistently not as good
So, if I were Dr. Fuchs, I would
concede defeat and
“If you can’t beat ‘em, join ‘em”
RAINBOW: A Global, Phase 3, Randomized, Double-Blind
Trial of Ramucirumab and Paclitaxel (PTX) Versus Placebo
and PTX in the Treatment of Metastatic Gastric or
Gastroesophageal Junction (GEJ) Adenocarcinoma
Following Disease Progression on First-Line Platinum- and
Fluoropyrimidine-Containing Combination Therapy
H. Wilke*
Eric Van Cutsem, Sang Cheul Oh, György Bodoky,
Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto,
Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe
Rougier, Michael Emig, Roberto Carlesi,
Kumari Chandrawansa, Kei Muro
*On
behalf of the RAINBOW Investigators
26
RAINBOW: Randomized Phase III Trial
2nd Line Paclitaxel +/- Ramucirumab
Paclitaxel 80 mg/m2 d1,
8, 15 +
Ramucirumab IV
q 2 weeks
Second line
metastatic gastric and
GEJ adenocarcinoma
R
1:1
Paclitaxel 80 mg/m2
d1, 8, 15 +
Placebo
q 2 weeks
Primary EP: OS
N = 665
RAINBOW: Overall Survival
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
RAM + PTX
PBO + PTX
Patients / Events
330 / 256
335 / 260
Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)
6-month OS
72%
57%
12-month OS
40%
30%
Δ mOS = 2.3 months
Censored
No. at risk
RAM + PTX
PBO + PTX
330
335
308
294
267
241
228
180
185
143
148
109
116
81
78
64
60
47
41
30
24
22
13
13
6
5
1
2
0
0
Overall conclusion
• Thanks to the organizers for giving me the
obviously better choice
– I can stick with hazard ratio and not even point out the
price differentials
• And also, thank the organizers for not giving Dr.
Fuchs the option of combining targeted and
chemo
• And also, thank Drs. Van Cutsem, Bendell, Kang,
and Cook for the slides of theirs I used.