Esophagogastric Cancer
Barbara Burtness, MD
Fox Chase Cancer Center
June 3, 2013
Lapatinib in combination with capecitabine plus
oxaliplatin in HER2-positive advanced or
metastatic gastric, esophageal, or
gastroesophageal adenocarcinoma:
The TRIO-013/LOGiC Trial
JR Hecht, Y Bang, S Qin, H Chung, J Xu, J Park, K Jeziorski,
Y Shparyk, PM Hoff, AF Sobrero, P Salman, J Li, S Protsenko,
ME Buyse, K Afenjar, T Kaneko, A Kemner, S Santillana,
MF Press, DJ Slamon
Translational
Research In Oncology
HER2 in Gastric Cancer
• Amplified in 7-34%1
• Amplification may
predict resistance
to conventional
modalities2
OS INT0116 According to Treatment Arm
1.
1. Gravalos and Jimeno. Ann Oncol 2008; 19:1583
2. Gordon M A et al. Ann Oncol 2013;annonc.mdt106
HER2 Directed Therapy in Gastric Cancer
ToGA Trial demonstrated
survival advantage for
addition of trastuzumab in
HER2 + gastric cancer1
1. Bang et al. Lancet 2010; 376:687
Comparing Lapatinib and Trastuzumab
• Antibody may also exert anticancer activity via
recruitment of immune effectors
• Interpatient variation in lapatinib drug
metabolism and bioavailability is significant
– Pharmacogenomic predictors, role of smoking
undefined
• Markers of resistance
– MET associated with lapatinib resistance in HER2
activated gastric cancer cell lines1
– Secondary HER2 mutations described in acquired
lapatinib resistance in BrCa2
• Downstream signaling intermediaries
– Kras mutation 6%, PTEN loss 15%3
1. Chen CT et al. Mol Cancer Ther. 2012 Mar;11(3):660-9.
2. Kancha RK, et al. PLoS One. 2011;6(10):e26760.
3. Okines et al. Eur J Can 2013; S0959:115
Lapatinib in Gastric Cancer
• Lapatinib administered to 47 chemonaive
metastatic gastric cancer patients at 1500 mg
orally daily1
– PR =9%
– Median TTF 1.9 months
– OS 4.8 months
• Gene expression of HER2, IL-8 and genomic
polymorphisms IL-8, and vascular endothelial
growth factor correlated with OS
1. Iqbal S, et al. Ann Oncol. 2011;22:2610.
OS by gene expression
Marker
RECIST
Response
OS median p
months
EGFR >
median
11%
3.3
EGFR
<median
0%
5.7
HER2>
median
13%
6.8
HER2
<median
0%
3.0
IL-8>
median
0%
3.0
IL8<
median
17%
5.6
0.24
0.0031
0.016
Iqbal S, et al. Ann Oncol. 2011;22:2610-5
TRIO-013/LOGiC Study Design
Day 1: Oxaliplatin 130 mg/m2
Day 1−14: Capecitabine 850 mg/m2, bid
1. Confirmed
histology
Day 1−21: Lapatinib 1250 mg, qd
(one cycle = 21 days)
2. Local/central
HER-2+
3. Confirmed
eligibility
R
Day 1: Oxaliplatin 130 mg/m2
Day 1−14: Capecitabine 850 mg/m2, bid
Stratification factors
•Prior (neo)Adjuvant
therapy
Day 1−21: Placebo, qd
(one cycle = 21 days)
•Region (Asia,
North America,
Rest of the World)
Tumor tissue sent
to central lab
Primary Efficacy Population (PEP)
(HER-2 status confirmed by FISH)
Cumulative survival
probability
Primary Endpoint: Overall Survival
(PEP)
1.0
PEP
0.8
Median (95% CI)
(mo)
0.6
HR (95% CI)
CapeOx+L
N=249
CapeOx+P
N=238
12.2 (10.6, 14.2)
10.5 (9.0, 11.3)
0.91 (0.73, 1.12)
0.4
0.2
CapeOx+L
CapeOx+P
0.0
Subjects at risk
CapeOx+L
CapeOx+P
0
5
10
249
238
199
189
133
106
15
20
25
30
Time since randomization (months)
83
53
47
34
24
17
9
11
ITT analysis HR 0.91
35
40
45
3
7
3
2
2
Overall Survival: Subgroup Analysis
Hazard ratio (95% CI)
Primary efficacy population (N=487)
0.91 (0.73, 1.12)
Region
Asia (n=193)
North America (n=17)
Rest of World (n=277)
0.68 (0.48, 0.96)
1.61 (0.53, 4.83)
1.04 (0.79, 1.37)
Yes (n=38)
No (n=449)
1.52 (0.68, 3.41)
0.83 (0.67, 1.04)
Age (years)
<60 (n=236)
≥60 (n=251)
0.69 (0.51, 0.94)
1.08 (0.81, 1.45)
Baseline ECOG status
0−1 (n=444)
2 (n=43)
0.88 (0.70, 1.10)
0.76 (0.41, 1.44)
Esophagus (n=20)
GE Junction (n=43)
Gastric (n=424)
0.87 (0.32, 2.35)
0.90 (0.44, 1.85)
0.89 (0.71, 1.11)
Diffuse (n=19)
Intestinal (n=436)
Other (n=32)
0.64 (0.25, 1.65)
0.93 (0.75, 1.17)
0.58 (0.26, 1.29)
Yes (n=373)
No (n=114)
0.80 (0.63, 1.01)
1.06 (0.67, 1.68)
Prior adjuvant use
Primary site
Histological type
Pylorus intact
HER2 status (all FISH+)
IHC 0 (n=27)
IHC 1+ (n=54)
IHC 2+ (n=108)
IHC 3+ (n=297)
0.56 (0.24, 1.31)
1.16 (0.61, 2.20)
0.79 (0.50, 1.25)
0.90 (0.69, 1.18)
IHC 0−1+ (n=81)
IHC 2−3+ (n=405)
0.91 (0.55, 1.51)
0.86 (0.68, 1.09)
0
Favors CapeOx+L
1
2
5
4
3
Hazard Ratio (CapeOx+L / CapeOx+P)
Favors CapeOx+P
TRIO/LOGIC Vs. ToGA
TRIO/LOGIC
Chemo Duration
ToGA
% from Asia
Fluoropyrimidine 6 cycles
not fixed
40%
50%
RR
40 -> 53%
35 -> 47%
PFS
5.4 -> 6.0 mo
5.5 -> 6.7 mo
OS
10.5 -> 12.2 mo
11.1 -> 13.8 mo
HR for HER2 high .86
.65
Conclusions Lapatinib Trial
• Lapatinib and capecitabine/oxaliplatin did not lead
to a significant survival advantage over
capecitabine/oxaliplatin
• Impact on RR comparable to trastuzumab
• Source of regional differences not clear
• Role of markers of resistance
– c-MET, EGFR, IL-8
– Can acquired HER2 mutations be identified?
• Studies ongoing to assess role of pertuzumab,
TDM-1
Stomach Cancer Adjuvant
Multi-institutional Trial, SAMIT, Group
A phase III randomized clinical trial of
adjuvant paclitaxel followed by oral
fluorinated pyrimidines for locally advanced
gastric cancer –SAMIT StudyK. Yoshida, A. Tsuburaya, M. Kobayashi, S. Yoshino,
M. Takahashi, N. Takiguchi, K. Tanabe, N. Takahashi,
H. Imamura, N. Tatsumoto, A. Hara, K. Nishikawa,
R. Fukushima, A. Kurita, H. Kojima, Y. Miyashita,
K. Oba, ME Buyse, S. Morita, J. Sakamoto,
Adjuvant Therapy in Gastric Cancer
JAMA. 2010;303(17):1729-1737.
Adjuvant Systemic Therapy
• CA80101 randomized 546 patients to
Macdonald (bolus 5-FU/LV, infusional 5-FU RT,
bolus 5-FU/LV) vs. ECF-> 5FU/RT -> ECF
– ECF did not improve OS [HR 1.03, P = .80]
– Toxicity profile favored ECF over bolus 5-FU/LV1
• CLASSIC trial randomized 1035 patients with D2
lymph node dissection to observation or
adjuvant capecitabine/oxaliplatin
– 3-year DFS 74% on cape/ox vs. 60% for observation
1. Fuchs CS et al. Proc ASCO 2011
[HR 0.56, P<.001]
2. Bang et al. Proc ASCO 2011
Study scheme
Randomized phase III, two-by-two factorial design
UFT
Arm A
S-1
Arm B: Control
Monotherapy
oral FUs
48wks
Arm C
48wks
Arm D
Sequential
PTXoral
FUs
X 3  36wks
PTX 80 mg/m2
UFT 267 mg/m2
X 3  36wks
S-1 80 mg/m2
DFS: Sequential, CD vs Monotherapy, AB
3yr DFS
AB, Mono: 54.0% (95%CI: 50.2-57.6)
CD, Seq. : 57.2% (95%CI: 53.4-60.8)
Superiority of Sequential
HR: 0.92 (95%CI: 0.80-1.07; p=0.273)
DFS: UFT base vs S-1 base
3yr DFS
AC, UFT base: 53.0% (95%CI: 49.2-56.6)
BD, S-1 base : 58.2% (95%CI: 54.4-61.8)
Non-inferiority of UFT
HR:1.23 (95%CI:1.07-1.43), p = 0.151
Superiority of S-1
HR: 0.81, p = 0.0057
DFS in Each Arms
Months
SAMIT Conclusions
• Sequential taxane -> fluoropyrimidine not superior
to fluoropyrimidine monotherapy
• 2 x 2 factorial design not optimal for assessing the
2nd component of a sequential regimen
– May alter PK, toxicity profile, select for resistance
pathways, early progressors are not evaluated
• Did not exclude HER2 amplified
• Biomarkers of taxane sensitivity should be
explored
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
Second Line Therapy of Advanced Gastric
Cancer
• N=40 compared IRI to BSC1
– PS 0-2
– OS 4 vs. 2.4 m [HR 0.48, p=.012]1
• Phase III of 2nd line chemo (N=133)vs. BSC
(N=69)2
– PS 0-1
– OS 5.3 vs. 3.8 m [HR 0.67, p=.007]
– No difference between IRI and docetaxel
• GRANITE: 439 randomized to everolimus, 217 to
placebo3
– Median OS everolimus 5.4 m vs 4.3 m [NS]
1. Thuss-Patience et al. Eu J Cancer 2011; 47:2306
2. Kang et al. J Clin Oncol 2012; 13:1513.
3. Van Cutsem et al. J Clin Oncol 30, 2012 (suppl 4; abstr LBA3)
Overall Survival: WJOG
n
Probability (%)
wPTX
Median HR (95% CI)
108
p
9.5M
CPT-11 111
8.4M 1.13 (0.86-1.49) 0.38
(Months)
Number at risk
wPTX 108
CPT-11 111
80
75
36
29
10
10
2
3
0
1
0
1
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
Stratified by:
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
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
Conclusions
• Second line therapy extends survival in advanced
gastric cancer and is an appropriate standard of
care
• Docetaxel is an appropriate choice, although toxic
in this population
• Patient selection based on performance status
and peritoneal carcinomatosis may be useful in
identifying group of patients in whom this strategy
will also be clinically meaningful
• Future studies may identify biomarkers to aid
selection between taxanes and irinotecan