esophagogastric cancer
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
Esophagogastric Cancer
Barbara Burtness, MDFox 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; 19:15832. 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 expressionMarker RECIST
ResponseOS medianmonths
p
EGFR > median
11% 3.3 0.24
EGFR <median
0% 5.7
HER2>median
13% 6.8 0.0031
HER2<median
0% 3.0
IL-8> median
0% 3.0 0.016
IL8< median
17% 5.6Iqbal S, et al. Ann Oncol. 2011;22:2610-5
TRIO-013/LOGiC Study Design
1. Confirmed histology
2. Local/central
HER-2+3. Confirmed
eligibility Stratification factors •Prior (neo)Adjuvant
therapy •Region (Asia, North America,
Rest of the World)
R
Day 1: Oxaliplatin 130 mg/m2
Day 1−14: Capecitabine 850 mg/m2, bidDay 1−21: Lapatinib 1250 mg, qd
(one cycle = 21 days)
Tumor tissue sent to central lab
Day 1: Oxaliplatin 130 mg/m2
Day 1−14: Capecitabine 850 mg/m2, bidDay 1−21: Placebo, qd
(one cycle = 21 days)
Primary Efficacy Population (PEP)(HER-2 status confirmed by FISH)
Primary Endpoint: Overall Survival (PEP)
CapeOx+L
CapeOx+P
1.0
0.8
0.6
0.4
0.2
0.0
Cum
ulat
ive
surv
ival
pr
obab
ility
0 5 10 15 20 25 30 35 40 45Time since randomization (months)
PEP CapeOx+LN=249
CapeOx+PN=238
Median (95% CI) (mo) 12.2 (10.6, 14.2) 10.5 (9.0, 11.3)
HR (95% CI) 0.91 (0.73, 1.12)
Subjects at risk CapeOx+L 249 199 133 83 47 24 9 3 3CapeOx+P 238 189 106 53 34 17 11 7 2 2
ITT analysis HR 0.91
Overall Survival: Subgroup Analysis Primary efficacy population (N=487)
Region Asia (n=193)North America (n=17)Rest of World (n=277)
Prior adjuvant use Yes (n=38)No (n=449)
Age (years) <60 (n=236)≥60 (n=251)
Baseline ECOG status 0−1 (n=444)2 (n=43)
Primary site Esophagus (n=20)GE Junction (n=43)
Gastric (n=424)
Histological type Diffuse (n=19)Intestinal (n=436)
Other (n=32)
Pylorus intact Yes (n=373)No (n=114)
HER2 status (all FISH+) IHC 0 (n=27)IHC 1+ (n=54)
IHC 2+ (n=108)IHC 3+ (n=297)
IHC 0−1+ (n=81)IHC 2−3+ (n=405)
1 2 3 4 5Hazard Ratio (CapeOx+L / CapeOx+P)
Favors CapeOx+PFavors CapeOx+L
0
Hazard ratio (95% CI)0.91 (0.73, 1.12)
0.68 (0.48, 0.96)1.61 (0.53, 4.83)1.04 (0.79, 1.37)
1.52 (0.68, 3.41)0.83 (0.67, 1.04)
0.69 (0.51, 0.94)1.08 (0.81, 1.45)
0.88 (0.70, 1.10)0.76 (0.41, 1.44)
0.87 (0.32, 2.35)0.90 (0.44, 1.85)0.89 (0.71, 1.11)
0.64 (0.25, 1.65)0.93 (0.75, 1.17)0.58 (0.26, 1.29)
0.80 (0.63, 1.01)1.06 (0.67, 1.68)
0.56 (0.24, 1.31)1.16 (0.61, 2.20)0.79 (0.50, 1.25)0.90 (0.69, 1.18)
0.91 (0.55, 1.51)0.86 (0.68, 1.09)
TRIO/LOGIC Vs. ToGATRIO/LOGIC ToGA
Chemo Duration Fluoropyrimidine not fixed
6 cycles
% from Asia 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
A phase III randomized clinical trial of adjuvant paclitaxel followed by oral
fluorinated pyrimidines for locally advanced gastric cancer –SAMIT Study-
K. 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,
Stomach Cancer Adjuvant Multi-institutional Trial, SAMIT, Group
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 [HR
0.56, P<.001] 1. Fuchs CS et al. Proc ASCO 20112. Bang et al. Proc ASCO 2011
Study schemeRandomized phase III, two-by-two factorial design
UFT S-1
Monotherapyoral FUs
Arm A Arm B: Control
SequentialPTXoral FUs
Arm C Arm D
S-1 80 mg/m2UFT 267 mg/m2
48wks 48wks
X 3 36wksPTX 80 mg/m2
X 3 36wks
DFS: Sequential, CD vs Monotherapy, AB
AB, Mono: 54.0% (95%CI: 50.2-57.6)CD, Seq. : 57.2% (95%CI: 53.4-60.8)
3yr DFS
Superiority of SequentialHR: 0.92 (95%CI: 0.80-1.07; p=0.273)
AC, UFT base: 53.0% (95%CI: 49.2-56.6)BD, S-1 base : 58.2% (95%CI: 54.4-61.8)
3yr DFS
Non-inferiority of UFTHR:1.23 (95%CI:1.07-1.43), p = 0.151Superiority of S-1HR: 0.81, p = 0.0057
DFS: UFT base vs S-1 base
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: 2006-005046-37ISRCTN 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; 47:23062. 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: WJOGPr
obab
ility
(%)
(Months)
108111
8075
3629
1010
23
01
wPTXCPT-11
Number at risk01
CPT-11wPTX
n
111108
Median
8.4M9.5M
p
0.38
HR (95% CI)
1.13 (0.86-1.49)
Trial Design
Adenocarcinoma of esophagus,
esophagus-gastric junction or
stomach refractory to platinum and fluoropyrimide
Arm A (n=84): Docetaxel 75mg/m2 IV every 3
weeks for up to 6 cycles+ ASC
Arm B (n=84): Active symptom control
May include: Radiotherapy, analgesia, anti-emetics,
steroids
Assess every 3 weeks for 18 weeks, then
every 6 weeks
RANDOMISE1:1
n=168
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)
0
25
50
75
100
0 2 4 6 8 10 12 14 16 18
Perc
enta
ge su
rviv
ing
Months from randomisation
DocetaxelASC
No. at Risk:Docetaxel 84 69 53 33 25 17 10 8 5 4 ASC 84 70 38 19 13 9 6 2 1 1
Overall survivalMedian 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
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